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Luduvico KP, de Mello JE, Custódio SV, Besckow EM, Brüning CA, Bortolatto CF, de Souza LP, Domingues WB, Campos VF, Spanevello RM, Stefanello FM. Elucidating the Antidepressant-Like Effect of Tannic Acid in Mice: Modulation of Serotonergic System and Pro-Inflammatory Mediators. Mol Neurobiol 2025:10.1007/s12035-025-05065-3. [PMID: 40425908 DOI: 10.1007/s12035-025-05065-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 05/12/2025] [Indexed: 05/29/2025]
Abstract
This study aimed to evaluate the therapeutic action of tannic acid (TA) in male Swiss mice by investigating: i) the involvement of the serotonergic system in the acute TA antidepressant-like action per se using pharmacological tools, and ii) the neuroprotective activity of TA in a lipopolysaccharide (LPS)-induced depressive-like behavior. For mechanistic investigation of the acute TA antidepressant-like action, mice received i.p. the serotoninergic receptor antagonists: WAY-100135 (5-HT1 A antagonist), ketanserin (5-HT2 A/2 C antagonist), or ondansetron (5-HT3 antagonist); 15 min later, TA or water was given by gavage. After 1 h, mice were subjected to a tail suspension test (TST). TA in different doses was tested in acute open field test (OFT), TST, and forced swimming test (FST). In the LPS protocol, animals were pretreated once daily with TA (60 or 120 mg/kg), fluoxetine (20 mg/kg) or vehicle for 7 days. On the 7th day, mice received a single injection of LPS (830 μg/kg, i.p.). After 24 h, OFT and TST were assessed. Behavioral data concerning the acute antidepressant-like effects of TA demonstrated that this tannin acts via 5-HT1 A and 5-HT2 A/2 C receptors. Besides, monoamine oxidase A (MAO-A) in vitro activity was determined in total brain; the polyphenol action was able to decrease enzyme activity. In the LPS-induced depression model, TA prevented the increase in LPS-induced immobility time in the TST, downregulated the expression of NF-κB and IL-1β, and modulated MAO-A activity in the cerebral cortex. In conclusion, TA exhibited neuroprotective and antidepressant-like activities in mice, positioning it as a promising candidate for depression therapeutics.
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Affiliation(s)
- Karina Pereira Luduvico
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil.
| | - Julia Eisenhardt de Mello
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Neuroquímica, Inflamação E Câncer, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Solange Vega Custódio
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Neuroquímica, Inflamação E Câncer, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Evelyn Mianes Besckow
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Bioquímica E Neurofarmacologia Molecular, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - César Augusto Brüning
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Bioquímica E Neurofarmacologia Molecular, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Cristiani Folharini Bortolatto
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Bioquímica E Neurofarmacologia Molecular, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Lucas Petitemberte de Souza
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - William Borges Domingues
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Vinicius Farias Campos
- Laboratório de Genômica Estrutural, Programa de Pós-Graduação Em Biotecnologia, Centro de Desenvolvimento Tecnológico, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Roselia Maria Spanevello
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Neuroquímica, Inflamação E Câncer, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil
| | - Francieli Moro Stefanello
- Programa de Pós-Graduação Em Bioquímica E Bioprospecção - Laboratório de Biomarcadores, Centro de Ciências Químicas, Farmacêuticas E de Alimentos, Universidade Federal de Pelotas, Campus Universitário S/N, Pelotas, RS, Brazil.
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Schmidt J, Lückemann L, Schedlowski M, Hadamitzky M, Jakobs M. Increased tyrosine hydroxylase abundance in the ventral tegmental area after taste-immune associative learning with saccharin or sucrose in rats. Behav Brain Res 2025; 491:115646. [PMID: 40393580 DOI: 10.1016/j.bbr.2025.115646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/07/2025] [Accepted: 05/16/2025] [Indexed: 05/22/2025]
Abstract
Several animal studies have already demonstrated classical conditioning of immune responses, when a novel sweet solution was paired with the administration of an immunosuppressive drug. However, since sweet solutions are known to have an impact on central dopamine synthesis, their "neutrality" as conditioned stimuli has been questioned. In particular, it is not clear whether even re-exposure to water is sufficient to influence central dopamine synthesis when animals are on a specific fluid-restricted conditioning schedule and whether re-exposure to saccharin or sucrose has similar or different effects. To address this, we conducted a taste-immune associative learning study in rats, using saccharin or sucrose and the immunosuppressive drug fingolimod. Subsequently, we analyzed central tyrosine hydroxylase (TH) abundance and phosphorylation (pTH) to indirectly assess dopamine production. Moreover, we measured central monoamine oxidase A (MAO-A) abundance, thereby gaining information of possible immediate conversion of synthesized dopamine. Western blot analyses of the ventral tegmental area revealed no differences in pTH abundance among fluid-restricted rats that received either water, sucrose, saccharin or fingolimod. However, TH abundance was significantly increased in animals re-exposed to sucrose and saccharin compared to those given water. MAO-A abundance did not differ between groups. Analyses of the abundance and phosphorylation of dopamine-associated enzymes in the ventral and dorsal striatum, showed no differences between groups. These exploratory findings suggest that the consumption of sucrose and saccharin may be more rewarding than water consumption, when rats are maintained on a specific fluid-restricted conditioning schedule. However, further research is necessary to draw precise conclusions.
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Affiliation(s)
- Jasmin Schmidt
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro, & Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany
| | - Laura Lückemann
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro, & Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany
| | - Manfred Schedlowski
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro, & Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany; Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Martin Hadamitzky
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro, & Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany
| | - Marie Jakobs
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro, & Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany.
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Naoi M, Wu Y, Maruyama W, Shamoto-Nagai M. Phytochemicals Modulate Biosynthesis and Function of Serotonin, Dopamine, and Norepinephrine for Treatment of Monoamine Neurotransmission-Related Psychiatric Diseases. Int J Mol Sci 2025; 26:2916. [PMID: 40243512 PMCID: PMC11988947 DOI: 10.3390/ijms26072916] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/17/2025] [Accepted: 03/21/2025] [Indexed: 04/18/2025] Open
Abstract
Serotonin (5-HT), dopamine (DA), and norepinephrine (NE) are key monoamine neurotransmitters regulating behaviors, mood, and cognition. 5-HT affects early brain development, and its dysfunction induces brain vulnerability to stress, raising the risk of depression, anxiety, and autism in adulthood. These neurotransmitters are synthesized from tryptophan and tyrosine via hydroxylation and decarboxylation, and are metabolized by monoamine oxidase (MAO). This review aims to summarize the current findings on the role of dietary phytochemicals in modulating monoamine neurotransmitter biosynthesis, metabolism, and function, with an emphasis on their potential therapeutic applications in neuropsychiatric disorders. Phytochemicals exert antioxidant, neurotrophic, and neurohormonal activities, regulate gene expression, and induce epigenetic modifications. Phytoestrogens activate the estrogen receptors or estrogen-responsive elements of the promoter of target genes, enhance transcription of tryptophan hydroxylase and tyrosine hydroxylase, while inhibiting that of MAO. These compounds also influence the interaction between genetic and environmental factors, potentially reversing dysregulated neurotransmission and the brain architecture associated with neuropsychiatric conditions. Despite promising preclinical findings, clinical applications of phytochemicals remain challenging. Advances in nanotechnology and targeted delivery systems offer potential solutions to enhance clinical efficacy. This review discusses mechanisms, challenges, and strategies, underscoring the need for further research to advance phytochemical-based interventions for neuropsychiatric diseases.
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Affiliation(s)
- Makoto Naoi
- Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin 320-195, Aichi, Japan; (Y.W.); (W.M.); (M.S.-N.)
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Thorne BN, Ellenbroek BA, Day DJ. Reduced expression of the serotonin transporter impacts mitochondria in a sexually dimorphic manner. Biochem Biophys Rep 2025; 41:101895. [PMID: 39760099 PMCID: PMC11699461 DOI: 10.1016/j.bbrep.2024.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Neuropsychiatric and neurodevelopmental disorders are complex conditions that arise from a variety of interacting genetic and environmental factors. Among these factors, altered serotonergic signalling and mitochondrial dysfunction are strongly implicated, with a growing body of evidence to suggesting that serotonergic signalling is an important regulator of mitochondrial biogenesis. The serotonin transporter (SERT) functions to regulate synaptic 5-HT, and human allelic variants of the serotonin reuptake transporter-linked polymorphic region (5-HTTLPR) are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using the heterozygous (HET) variant of the SERT knockout rat to model reduced SERT expression, Western blotting was used to measure the abundance of TOMM20 and the complex I protein MT-CO1 as metrics for mitochondrial mass and abundance of respiratory complex IV. Mitochondrial activity was determined by dye reduction. We found sex-based and region-specific differences in mitochondrial mass and activity and that male and females show differing responses to reduced SERT expression. Our findings suggest that the sexually dimorphic differences in serotonergic signalling impact mitochondrial function and that these differences may be important for understanding sex differences in neuropsychiatric and neurodevelopmental disorders.
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Affiliation(s)
- Bryony N. Thorne
- School of Biological Sciences, Victoria University of Wellington Kelburn, Parade, 6012, Wellington, New Zealand
- Wicking Dementia Research and Education Centre, University of Tasmania, Hobart, TAS, Australia
| | - Bart A. Ellenbroek
- School of Psychology, Victoria University of Wellington Faculty of Science, 6012, Wellington, New Zealand
| | - Darren J. Day
- School of Biological Sciences, Victoria University of Wellington Kelburn, Parade, 6012, Wellington, New Zealand
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Naoi M, Maruyama W, Shamoto-Nagai M, Riederer P. Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration. J Neural Transm (Vienna) 2025; 132:387-406. [PMID: 39621110 DOI: 10.1007/s00702-024-02866-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 11/23/2024] [Indexed: 03/03/2025]
Abstract
Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene. The isoform-specific transcription organization regulates expression and function of MAO-A in response to cellular signaling pathways and environmental factors. MAO-A shows distinct properties and functions: isoform-specified polymorphisms, localization in catecholamine neurons, expression during early embryonic stage, regulation of brain architecture development and mediation of death and survival of neuronal cells. MAO-A is more flexible to genetic and environmental changes than MAO-B. Defective MAO-A expression impairs embryonic brain development and causes adult abnormal mood and behavior, as shown by human male cases with MAO-A deletion. This paper presents the regulation of brain MAO-A expression epigenetically by interaction between genetic and environmental factors. Association of aberrant MAO-A expression and activity with aggression, asocial behaviors, depressive disorders, and neurodegenerative diseases is discussed. Novel therapeutic strategy for psychiatric diseases by intervention to the regulation of MAO-A expression and activity is proposed.
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Affiliation(s)
- Makoto Naoi
- Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-Cho, Nissin, Aichi, 320-0195, Japan.
| | - Wakako Maruyama
- Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-Cho, Nissin, Aichi, 320-0195, Japan
| | - Masayo Shamoto-Nagai
- Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, 12 Araike, Iwasaki-Cho, Nissin, Aichi, 320-0195, Japan
| | - Peter Riederer
- Clinical Neurochemistry, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
- Department of Psychiatry, University of Southern Denmark, Odense, Denmark
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Oyovwi MO, Udi OA, Atere AD, Joseph GU, Ogbutor UG. Molecular pathways: the quest for effective MAO-B inhibitors in neurodegenerative therapy. Mol Biol Rep 2025; 52:240. [PMID: 39961877 DOI: 10.1007/s11033-025-10349-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 02/06/2025] [Indexed: 05/09/2025]
Abstract
Neurodegenerative diseases like Parkinson's and Alzheimer's are a global health challenge due to their progressive degeneration, leading to cognitive decline and motor dysfunction. Monoamine oxidase B (MAO-B) enzyme is implicated in neurodegeneration, and developing inhibitors could be a promising therapeutic strategy. This review explores MAO-B activity molecular pathways, evaluates MAO-B inhibitors in neurodegenerative therapy, identifies challenges, and suggests future research directions. This review synthesizes findings from a range of scientific literature, including experimental studies, clinical trials, and biochemical analyses that focus on the role of MAO-B in neurodegeneration. Information was gathered from databases such as PubMed, Scopus, and Web of Science, ensuring a comprehensive overview of recent advancements in MAO-B inhibition strategies. The review reveals several promising MAO-B inhibitors that have demonstrated efficacy in preclinical models, as well as some that have progressed to clinical trials. Compounds such as rasagiline and selegiline have shown neuroprotective effects and benefits in symptom management in patients with Parkinson's disease. Furthermore, the review discusses novel inhibitors that target specific molecular pathways, enhancing the potential for improved therapeutic outcomes. However, several inhibitors also present challenges regarding their selectivity, side effects, and long-term efficacy. Research on MAO-B inhibitors for neurodegenerative diseases is crucial, with ongoing studies aiming for selective, potent molecules with fewer side effects and multimodal therapies.
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Affiliation(s)
- Mega Obukohwo Oyovwi
- Department of Physiology, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria.
| | - Onoriode Andrew Udi
- Department of Human Anatomy, Federal University Otuoke, Yenagoa, Bayelsa State, Nigeria
| | - Adedeji David Atere
- Department of Medical Laboratory Science, College of Health Sciences, Osun State University, Osogbo, Nigeria
- Neurotoxicology Laboratory, Sefako Makgatho Health Sciences University, Molotlegi St, Ga-Rankuwa C Zone 1, Ga-Rankuwa City, 0208, South Africa
| | - Gregory Uchechukwu Joseph
- Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun State, Nigeria
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Martins CC, Nörnberg AB, Lima AS, Alves D, Luchese C, Fajardo AR, Wilhelm EA. Targeted delivery of a selenium-sulfa compound via cationic starch microparticles: Modulation of oxidative stress and pain pathways in fibromyalgia-like symptoms in mice. Int J Biol Macromol 2025; 286:138334. [PMID: 39638183 DOI: 10.1016/j.ijbiomac.2024.138334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 11/21/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Cationic starch microparticles (CStMPs) loaded with 4-amino-3 -(phenylselenyl)benzenesulfonamide (4-APSB) were prepared and investigated in a model of fibromyalgia (FM) induced by intermittent cold stress (ICS) in male and female Swiss mice. The CStMPs/4-APSB were characterized by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, zeta potential, and particle size measurements, providing information about their chemical composition, surface charge, morphology/microstructure, and size (1.50 ± 0.5 μm). Following ICS exposure, the animals were treated with free 4-APSB (1 mg/kg), CStMPs/4-APSB (containing 0.13 mg of 4-APSB per mg of microparticles), or CStMPs, from days 5 to 10. The results revealed the successful incorporation of 4-APBS in the CStMPs. Free 4-APSB and CStMPs/4-APSB reversed nociceptive- and depressive-related behaviors in male and female mice exposed to ICS, attenuating the hallmark symptoms of FM. Those treatments (free 4-APSB and CStMPs/4-APSB) normalized the monoamine oxidase (MAO)-A activity in the cerebral cortex and the oxidative damage, providing the correct functioning of the enzyme Ca2+ -ATPase in the cerebral cortex and hippocampus of mice exposed to ICS. The CStMPs/4-APSB modulated the oxidative stress markers, specifically in the spinal cord of mice - an anatomical region intricately linked to pain pathways.
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Affiliation(s)
- Carolina C Martins
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, 96010-900 Pelotas, RS, Brazil
| | - Andressa B Nörnberg
- Laboratório de Tecnologia e Desenvolvimento de Compósitos e Materiais Poliméricos (LaCoPol), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão s/n, 96010-900 Pelotas, RS, Brazil
| | - Ariana Silveira Lima
- Laboratório de Síntese Orgânica Limpa (LASOL), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, 96010-900 Pelotas, RS, Brazil
| | - Diego Alves
- Laboratório de Síntese Orgânica Limpa (LASOL), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, 96010-900 Pelotas, RS, Brazil
| | - Cristiane Luchese
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, 96010-900 Pelotas, RS, Brazil
| | - André R Fajardo
- Laboratório de Tecnologia e Desenvolvimento de Compósitos e Materiais Poliméricos (LaCoPol), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão s/n, 96010-900 Pelotas, RS, Brazil.
| | - Ethel A Wilhelm
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, 96010-900 Pelotas, RS, Brazil.
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Ongtanasup T, Tawanwongsri W, Manaspon C, Srisang S, Eawsakul K. Comprehensive investigation of niosomal red palm wax gel encapsulating ginger (Zingiber officinale Roscoe): Network pharmacology, molecular docking, In vitro studies and phase 1 clinical trials. Int J Biol Macromol 2024; 277:134334. [PMID: 39094890 DOI: 10.1016/j.ijbiomac.2024.134334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Ginger, a Zingeberaceae family member, is notable for its anti-inflammatory properties. This study explores the pharmaceutical mechanisms of ginger and red palm wax co-extract, developing novel niosomal formulations for enhanced transdermal delivery. Evaluations included physical characteristics, drug loading, in vitro release, network pharmacology, molecular docking, and biocompatibility. The niosomal ginger with red palm wax gel (NGPW) exhibited non-Newtonian fluid properties. The optimized niosome formulation (cholesterol: Tween80: Span60 = 12.5: 20: 5 w/w) showed a high yield (93.23 %), high encapsulation efficiency (54.71 %), and small size (264.33 ± 5.84 nm), prolonging in vitro anti-inflammatory activity. Human skin irritation and biocompatibility tests on 1 % NGPW showed favorable cytotoxicity and hemocompatibility results (ISO10993). Network pharmacology identified potential targets, while molecular docking highlighted high affinities between gingerol and red palm wax compounds with TRPM8 and TRPV1 proteins, suggesting pain inhibition via serotonergic synapse pathways. NGPW presents a promising transdermal pain inhibitory drug delivery strategy.
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Affiliation(s)
- Tassanee Ongtanasup
- School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | | | - Chawan Manaspon
- Biomedical Engineering Institute, Chiang Mai University, Chiang Mai 50200, Thailand; Biomedical Engineering and Innovation Research Center, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriwan Srisang
- Energy Engineering Division, Department of Engineering, King Mongkut's Institute of Technology Lad-krabang, Prince of Chumphon Campus, Chumphon 86160, Thailand
| | - Komgrit Eawsakul
- School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand; Research Excellence Center for Innovation and Health Products (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand.
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Colettis N, Higgs J, Wasowski C, Knez D, Gobec S, Pastore V, Marder M. 3,3-Dibromoflavanone, a synthetic flavonoid derivative for pain management with antidepressant-like effects and fewer side effects than those of morphine in mice. Chem Biol Interact 2024; 402:111189. [PMID: 39121896 DOI: 10.1016/j.cbi.2024.111189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/18/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
In the pursuit of new lead compounds with fewer side effects than opioids, the novel synthetic phytochemical core, 3,3-dibromoflavanone (3,3-DBF), has emerged as a promising candidate for pain management. Acute assays demonstrated dose-dependent central and peripheral antinociceptive activity of 3,3-DBF through the μ-opioid receptor. This study aimed to explore repeated administration effects of 3,3-DBF in mice and compare them with morphine. Mice were treated with 3,3-DBF (30 mg/kg), morphine (6 mg/kg), or vehicle for 10 days, alongside single-treatment groups. Unlike morphine, 3,3-DBF demonstrated antinociceptive effects in the hot plate test without inducing tolerance. Locomotor activity and motor coordination tests (evaluated through the inverted screen and rotarod tests) revealed no significant differences between the 3,3-DBF-treated and control groups. The gastrointestinal transit assay indicated that 3,3-DBF did not induce constipation, in contrast to morphine. Furthermore, withdrawal signs assessed with the Gellert-Holtzman scale were not comparable to morphine. Additionally, 3,3-DBF exhibited antidepressant-like activity, reducing immobility time in the forced swimming and tail suspension tests, akin to imipramine. In summary, 3,3-DBF demonstrated antinociceptive effects without inducing tolerance or dependence and exhibited antidepressant properties. These findings highlight the potential of 3,3-DBF as a promising therapeutic agent for pain management and its comorbidities, offering advantages over morphine by minimizing side effects.
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Affiliation(s)
- Natalia Colettis
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Neuro-Fito-Farmacología Medicinal, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
| | - Josefina Higgs
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Neuro-Fito-Farmacología Medicinal, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
| | - Cristina Wasowski
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Neuro-Fito-Farmacología Medicinal, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
| | - Damijan Knez
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.
| | - Stanislav Gobec
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000, Ljubljana, Slovenia.
| | - Valentina Pastore
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Neuro-Fito-Farmacología Medicinal, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
| | - Mariel Marder
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Neuro-Fito-Farmacología Medicinal, Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Junín 956 (C1113AAD), Buenos Aires, Argentina.
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Longoria KD, Nguyen TC, Franco-Rocha O, Garcia SR, Lewis KA, Gandra S, Cates F, Wright ML. A sum of its parts: A systematic review evaluating biopsychosocial and behavioral determinants of perinatal depression. PLoS One 2024; 19:e0290059. [PMID: 38995978 PMCID: PMC11244847 DOI: 10.1371/journal.pone.0290059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 06/28/2024] [Indexed: 07/14/2024] Open
Abstract
INTRODUCTION Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of its pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants (e.g., biological, behavioral, environmental, social) and interactions among determinants of perinatal depression and the quality of methods applied. METHODS Four databases (i.e., PubMed, CINAHL, APA PsycInfo, Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, depression was examined in a specific subpopulation evidenced to have psychological consequences due to situational stressors (e.g., fetal/infant loss, neonatal intensive care unit admission), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. RESULTS Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 32% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. CONCLUSIONS Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.
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Affiliation(s)
- Kayla D. Longoria
- School of Nursing, University of Texas at Austin, Austin, Texas, United States of America
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA, United States of America
| | - Tien C. Nguyen
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, United States of America
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Oscar Franco-Rocha
- School of Nursing, University of Texas at Austin, Austin, Texas, United States of America
| | - Sarina R. Garcia
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, United States of America
| | - Kimberly A. Lewis
- School of Nursing, University of Texas at Austin, Austin, Texas, United States of America
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA, United States of America
| | - Sreya Gandra
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, United States of America
- College of Liberal Arts, University of Texas at Austin, Austin, Texas, United States of America
| | - Frances Cates
- College of Liberal Arts, University of Texas at Austin, Austin, Texas, United States of America
| | - Michelle L. Wright
- School of Nursing, University of Texas at Austin, Austin, Texas, United States of America
- Department of Women’s Health, Dell Medical School at The University of Texas at Austin, Austin, Texas, United States of America
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Oyovwi MO, Ben-Azu B, Falajiki FY, Onome OB, Rotu RA, Rotu RA, Oyeleke AA, Okwute GP, Moke EG. D-ribose-L-cysteine exhibits restorative neurobehavioral functions through modulation of neurochemical activities and inhibition oxido-inflammatory perturbations in rats exposed to polychlorinated biphenyl. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:931-945. [PMID: 37542532 DOI: 10.1007/s00210-023-02637-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 07/18/2023] [Indexed: 08/07/2023]
Abstract
Polychlorinated biphenyl (PCB) is potentially harmful environmental toxicant causing cognitive decline with depressive features. PCB-induced behavioral deficits are associated with neurochemical dysfunctions, immune changes, and oxidative stress. This study investigated the neuroprotective effects of D-ribose-L-cysteine (DRLC), a neuroprotective precursor element of glutathione on PCB-induced neurobehavioral impairments. Following the initial 15 days of PCB (2 mg/kg) exposure to rats, DRLC (50 mg/kg) was given orally for an additional 15 days, from days 16 to 30. Animals were assessed for behavioral effect such as changes in locomotion, cognition, and depression. Oxidative/nitrergic stress markers; antioxidant regulatory proteins paraoxonase-1 (PON-1), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nfr2), NADPH oxidase-1 (NOX-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and neuroinflammation (NF-kβ, and TNF-α); and neurochemical metabolizing enzymes (acetylcholinesterase (AChE), monoamine oxidase-A and -B (MAO-A, MAO-B)) were carried out. The PCB-induced decline in locomotion, cognitive performance, and depressive-like features were reversed by DRLC. More specifically, PCB-induced oxidative and nitrergic stress, typified by reduced levels GSH, CAT, and SOD, accompanied by elevated MDA and nitrite were attenuated by DRLC. Additionally, DRLC restored the neuroinflammatory milieu indicated by decreased NF-kβ and TNF-α levels toward normal. Hyperactivities of AChE, MAO-A, MAO-B, PON-1, and NOX-1 levels as well as Nfr2, NQO1, and PON-1 due to PCB exposure were mitigated by DLRC. Our results suggest DRLC as a prospective neurotherapeutic agent against PCB-induced neurobehavioral impairments such as cognitive deficit and depressive-like feature through antioxidative and anti-nitrergic stress, anti-neuroinflammation, inhibition of brain metabolizing enzymes, and normalization of neurochemical homeostasis.
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Affiliation(s)
- Mega O Oyovwi
- Department of Human Physiology, Adeleke University, Ede, Osun State, Nigeria
| | - Benneth Ben-Azu
- Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria.
| | - Faith Y Falajiki
- Department of Human Physiology, Adeleke University, Ede, Osun State, Nigeria
| | - Oghenetega B Onome
- Department of Physiology, School of Basic Medical Science, Babcock University, Ilishan-Remo, Ogun State, Nigeria
| | - Rume A Rotu
- Department of Physiology, Faculty of Basic Medical Science, College of Health Sciences, University of Ibadan, Ibadan, Oyo State, Nigeria
| | - Rotu A Rotu
- Department of Industrial Safety and Environmental Management, School of Maritime Technology, Burutu, Delta State, Nigeria
| | - Abioye A Oyeleke
- Department of Physiology, Federal University Oye-Ekiti, Oye-Are Road, Oye-Ekiti, Ekiti State, Nigeria
| | - Godwin P Okwute
- Department of Physiology, School of Basic Medical Science, Babcock University, Ilishan-Remo, Ogun State, Nigeria
| | - Emuesiri G Moke
- Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria
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Choudhary D, Kaur R, Singh TG, Kumar B. Pyrazoline Derivatives as Promising MAO-A Targeting Antidepressants: An Update. Curr Top Med Chem 2024; 24:401-415. [PMID: 38318823 DOI: 10.2174/0115680266280249240126052505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 01/06/2024] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Depression is one of the key conditions addressed by the Mental Health Gap Action Programme (mhGAP) of WHO that can lead to self-harm and suicide. Depression is associated with low levels of neurotransmitters, which eventually play a key role in the progression and development of mental illness. The nitrogen-containing heterocyclic compounds exhibit the most prominent pharmacological profile as antidepressants. Pyrazoline, a dihydro derivative of pyrazole, is a well-known five-membered heterocyclic moiety that exhibits a broad spectrum of biological activities. Many researchers have reported pyrazoline scaffold-containing molecules as potential antidepressant agents with selectivity for monoamine oxidase enzyme (MAO) isoforms. Several studies indicated a better affinity of pyrazoline-based moiety as (monoamine oxidase inhibitors) MAOIs. In this review, we have focused on the recent advancements (2019-2023) in the development of pyrazoline-containing derivatives exhibiting promising inhibition of MAO-A enzyme to treat depression. This review provides structural insights on pyrazoline-based molecules along with their SAR analysis, in silico exploration of binding interactions between pyrazoline derivatives and MAO-A enzyme, and clinical trial status of various drug molecules against depression. The in-silico exploration of potent pyrazoline derivatives at the active site of the MAOA enzyme will provide further insights into the development of new potential MAO-A inhibitors for the treatment of depression.
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Affiliation(s)
- Diksha Choudhary
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Rajwinder Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | | | - Bhupinder Kumar
- Department of Pharmaceutical Sciences, HNB Garhwal University, Chauras Campus, Srinagar, Garhwal, Uttarakhand, 246174, India
- Department of Chemistry, Graphic Era (Deemed to be University), Dehradun, 248002, Uttrakhand, India
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Toledo-Lozano CG, López-Hernández LB, Suárez-Cuenca JA, Villalobos-Gallegos L, Jiménez-Hernández DA, Alcaraz-Estrada SL, Mondragón-Terán P, Joya-Laureano L, Coral-Vázquez RM, García S. Individual and Combined Effect of MAO-A/ MAO-B Gene Variants and Adverse Childhood Experiences on the Severity of Major Depressive Disorder. Behav Sci (Basel) 2023; 13:795. [PMID: 37887445 PMCID: PMC10603972 DOI: 10.3390/bs13100795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/07/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is a mood disorder with a high prevalence worldwide that causes disability and, in some cases, suicide. Although environmental factors play a crucial role in this disease, other biological factors may predispose individuals to MDD. Genetic and environmental factors influence mental disorders; therefore, a potential combined effect of MAO-A/MAO-B gene variants may be a target for the study of susceptibility to MDD. This study aimed to evaluate the effects of MAO-A and -B gene variants when combined with adverse childhood experiences (ACEs) on the susceptibility and severity of symptoms in MDD. METHODS A case-control study was performed, including 345 individuals, 175 MDD cases and 170 controls. Genotyping was performed using real-time PCR with hydrolysis probes. The analysis of the rs1465107 and rs1799836 gene variants of MAO-A and -B, respectively, was performed either alone or in combination with ACEs on the severity of depression, as determined through specific questionnaires, including DSM-IV diagnostic criteria for MDD. RESULTS According to individual effects, the presence of ACEs, as well as the allele G of the rs1465107 of MAO-A, is associated with a higher severity of depression, more significantly in females. Furthermore, the allele rs1799836 G of MAO-B was associated with the severity of depression, even after being adjusted by gene variants and ACEs (IRR = 1.67, p = 0.01). In males, the allele rs1799836 G of MAO-B was shown to interact with SNP with ACEs (IRR = 1.70, p < 0.001). According to combined effect analyses, the severity of depression was associated with ACEs when combined with either allele rs1465107 of MAO-A or allele rs17993836 of MAO-B, whereas SNP risk association was influenced by gender. CONCLUSIONS The severity of depression is related to either individual or combined effects of temperamental traits and genetic susceptibility of specific genes such as MAO-A and MAO-B.
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Affiliation(s)
- Christian Gabriel Toledo-Lozano
- Department of Clinical Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico; (C.G.T.-L.); (J.A.S.-C.); (D.A.J.-H.)
| | | | - Juan Antonio Suárez-Cuenca
- Department of Clinical Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico; (C.G.T.-L.); (J.A.S.-C.); (D.A.J.-H.)
| | - Luis Villalobos-Gallegos
- Facultad de Medicina y Psicología, Universidad Autónoma de Baja California, Tijuana 22390, Mexico;
| | - Dulce Adeí Jiménez-Hernández
- Department of Clinical Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico; (C.G.T.-L.); (J.A.S.-C.); (D.A.J.-H.)
| | | | - Paul Mondragón-Terán
- Coordination of Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico;
| | - Lilia Joya-Laureano
- Department of Psychiatry and Psychology, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico;
| | - Ramón Mauricio Coral-Vázquez
- Department of Teaching and Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico;
- Postgraduate Section, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Silvia García
- Department of Clinical Research, Centro Médico Nacional “20 de Noviembre”, ISSSTE, Mexico City 03229, Mexico; (C.G.T.-L.); (J.A.S.-C.); (D.A.J.-H.)
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Longoria KD, Nguyen TC, Franco-Rocha O, Garcia SR, Lewis KA, Gandra S, Cates F, Wright ML. A sum of its parts: A systematic review evaluating biopsychosocial and behavioral determinants of perinatal depression. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.08.02.23293552. [PMID: 37577597 PMCID: PMC10418297 DOI: 10.1101/2023.08.02.23293552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Introduction Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of the pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants and potential interactions among determinants of perinatal depression across four domains (i.e., biological, behavioral, environmental, social) and appraise the quality of methods applied. Methods Four databases (i.e., PubMed, CINAHL, APA PsycInfo, and Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, the evaluation of depression was specific to a discrete facet of the perinatal period with probable psychological consequences (e.g., abortion, fetal/infant loss, adoption), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. Results Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 28% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged when determinants across domains were aggregated. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. Conclusions Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.
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Affiliation(s)
- Kayla D. Longoria
- School of Nursing, University of Texas at Austin, Austin, Texas, USA
| | - Tien C. Nguyen
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, USA
- University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Sarina R. Garcia
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, USA
| | - Kimberly A. Lewis
- School of Nursing, University of Texas at Austin, Austin, Texas, USA
- Department of Physiological Nursing, School of Nursing, University of California, San Francisco
| | - Sreya Gandra
- College of Natural Sciences, University of Texas at Austin, Austin, Texas, USA
- College of Liberal Arts, University of Texas at Austin, Austin, Texas, USA
| | - Frances Cates
- College of Liberal Arts, University of Texas at Austin, Austin, Texas, USA
| | - Michelle L. Wright
- School of Nursing, University of Texas at Austin, Austin, Texas, USA
- Department of Women’s Health, Dell Medical School at The University of Texas at Austin, Austin, Texas, USA
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15
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Amerio A, Escelsior A, Martino E, Strangio A, Aguglia A, Marcatili M, Conio B, Sukkar SG, Saverino D. The Association between Blood SIRT1 and Ghrelin, Leptin, and Antibody Anti-Hypothalamus: A Comparison in Normal Weight and Anorexia Nervosa. J Pers Med 2023; 13:928. [PMID: 37373917 PMCID: PMC10303472 DOI: 10.3390/jpm13060928] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/12/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Sirtuin 1 (SIRT1) is a sensor of cell energy availability, regulating metabolic homeostasis as well as leptin and ghrelin, and it could be considered as a potential plasmatic marker. The aim of this study was to assess whether circulating SIRT1 varies consistently with leptin, ghrelin, body mass index (BMI), and IgG reactive to hypothalamic antigens in anorexia nervosa (AN). Fifty-four subjects were evaluated: 32 with AN and 22 normal-weight control subjects. Serum levels of SIRT1, leptin, ghrelin, and IgG reactive to hypothalamic antigens were evaluated by ELISA. Results showed that serum SIRT1 is increased in patients with AN, and the amount is decreased in relation to the duration of the illness. SIRT1 concentration approaches the values obtained for the control group, although the difference is still statistically significant. A negative correlation between serum SIRT1 values and leptin or BMI values has been found. On the contrary, a positive correlation between SIRT1 and ghrelin or IgG specific for hypothalamic antigens is reported. These findings suggest that a peripheral evaluation of SIRT1 could be a possible clinical/biochemical parameter related to AN. In addition, we can assume that SIRT1 is related to autoantibody production and may correlate with the intensity/severity of AN. Thus, reducing the production of autoantibodies specific for hypothalamic cells could be a sign of improvement of the clinical condition.
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Affiliation(s)
- Andrea Amerio
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Section of Psychiatry, University of Genoa, 16132 Genoa, Italy; (A.A.); (A.E.); (A.A.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
| | - Andrea Escelsior
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Section of Psychiatry, University of Genoa, 16132 Genoa, Italy; (A.A.); (A.E.); (A.A.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
| | - Eleonora Martino
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
- Dietetics and Clinical Nutrition Unit, University of Genoa, 16132 Genoa, Italy
| | - Antonella Strangio
- Department of Experimental Medicine (DiMeS), Section of Human Anatomy, University of Genoa, 16132 Genoa, Italy;
| | - Andrea Aguglia
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), Section of Psychiatry, University of Genoa, 16132 Genoa, Italy; (A.A.); (A.E.); (A.A.)
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
| | - Matteo Marcatili
- Department of Mental Health, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy;
| | - Benedetta Conio
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
| | - Samir Giuseppe Sukkar
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
- Dietetics and Clinical Nutrition Unit, University of Genoa, 16132 Genoa, Italy
| | - Daniele Saverino
- IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (E.M.); (B.C.); (S.G.S.)
- Department of Experimental Medicine (DiMeS), Section of Human Anatomy, University of Genoa, 16132 Genoa, Italy;
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Shahcheraghi SH, Ayatollahi J, Lotfi M, Aljabali AAA, Al-Zoubi MS, Panda PK, Mishra V, Satija S, Charbe NB, Serrano-Aroca Á, Bahar B, Takayama K, Goyal R, Bhatia A, Almutary AG, Alnuqaydan AM, Mishra Y, Negi P, Courtney A, McCarron PA, Bakshi HA, Tambuwala MM. Gene Therapy for Neuropsychiatric Disorders: Potential Targets and Tools. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:51-65. [PMID: 35249508 DOI: 10.2174/1871527321666220304153719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/16/2022] [Accepted: 01/16/2022] [Indexed: 01/01/2023]
Abstract
Neuropsychiatric disorders that affect the central nervous system cause considerable pressures on the health care system and have a substantial economic burden on modern societies. The present treatments based on available drugs are mostly ineffective and often costly. The molecular process of neuropsychiatric disorders is closely connected to modifying the genetic structures inherited or caused by damage, toxic chemicals, and some current diseases. Gene therapy is presently an experimental concept for neurological disorders. Clinical applications endeavor to alleviate the symptoms, reduce disease progression, and repair defective genes. Implementing gene therapy in inherited and acquired neurological illnesses entails the integration of several scientific disciplines, including virology, neurology, neurosurgery, molecular genetics, and immunology. Genetic manipulation has the power to minimize or cure illness by inducing genetic alterations at endogenous loci. Gene therapy that involves treating the disease by deleting, silencing, or editing defective genes and delivering genetic material to produce therapeutic molecules has excellent potential as a novel approach for treating neuropsychiatric disorders. With the recent advances in gene selection and vector design quality in targeted treatments, gene therapy could be an effective approach. This review article will investigate and report the newest and the most critical molecules and factors in neuropsychiatric disorder gene therapy. Different genome editing techniques available will be evaluated, and the review will highlight preclinical research of genome editing for neuropsychiatric disorders while also evaluating current limitations and potential strategies to overcome genome editing advancements.
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Affiliation(s)
- Seyed H Shahcheraghi
- Department of Medical Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Jamshid Ayatollahi
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Marzieh Lotfi
- Abortion Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Alaa A A Aljabali
- Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
| | - Mazhar S Al-Zoubi
- Yarmouk University, Faculty of Medicine, Department of Basic Medical Sciences, Irbid, Jordan
| | - Pritam K Panda
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, 75120 Uppsala, Sweden
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Saurabh Satija
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
| | - Nitin B Charbe
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX 78363, USA
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Lab, Translational Research Centre San Alberto Magno, Catholic University of Valencia San Vicente Mártir, C/Guillem de Castro 94, 46001 Valencia, Spain
| | - Bojlul Bahar
- Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, PR1 2HE, UK
| | - Kazuo Takayama
- Center for IPS Cell Research and Application, Kyoto University, Kyoto, 606-8397, Japan
| | - Rohit Goyal
- Neuropharmacology Laboratory, School of Pharmaceutical Sciences, Shoolini University, Post Box No. 9, Solan, Himachal Pradesh 173212, India
| | - Amit Bhatia
- Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Punjab 151001, India
| | - Abdulmajeed G Almutary
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Saudi Arabia
| | - Abdullah M Alnuqaydan
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Saudi Arabia
| | - Yachana Mishra
- Shri Shakti Degree College, Sankhahari, Ghatampur 209206, India
| | - Poonam Negi
- Shoolini University of Biotechnology and Management Sciences, Solan 173 212, India
| | - Aaron Courtney
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Paul A McCarron
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Hamid A Bakshi
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
| | - Murtaza M Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, BT52 1SA, Northern Ireland, United Kingdom
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17
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Provensi G, Costa A, Rani B, Becagli MV, Vaiano F, Passani MB, Tanini D, Capperucci A, Carradori S, Petzer JP, Petzer A, Vullo D, Costantino G, Blandina P, Angeli A, Supuran CT. New β-arylchalcogeno amines with procognitive properties targeting Carbonic Anhydrases and Monoamine Oxidases. Eur J Med Chem 2022; 244:114828. [DOI: 10.1016/j.ejmech.2022.114828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/22/2022] [Accepted: 10/01/2022] [Indexed: 11/16/2022]
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18
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Phạm TL, Noh C, Neupane C, Sharma R, Shin HJ, Park KD, Lee CJ, Kim HW, Lee SY, Park JB. MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling. THE JOURNAL OF PAIN 2022; 23:2092-2109. [PMID: 35940543 DOI: 10.1016/j.jpain.2022.07.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/05/2022] [Accepted: 07/20/2022] [Indexed: 01/04/2023]
Abstract
MAO-B inhibitors have been implicated to reverse neuropathic pain behaviors. Our previous study has demonstrated that KDS2010 (KDS), a newly developed reversible MAO-B inhibitor, could attenuate Paclitaxel (PTX)-induced tactile hypersensitivity in mice through suppressing reactive oxidant species (ROS)-decreased inhibitory GABA synaptic transmission in the spinal cord. In this study, we evaluated the analgesic effect of KDS under a new approach, in which KDS acts on dorsal horn sensory neurons to reduce excitatory transmission. Oral administration of KDS effectively enhanced mechanical thresholds in the spinal nerve ligation (SNL) induced neuropathic pain in rats. Moreover, we discovered that although treatment with KDS increased brain-derived neurotrophic factor (BDNF) levels, KDS inhibited Tropomyosin receptor kinase B (TrkB) receptor activation, suppressing increased p-NR2B-induced hyperexcitability in spinal dorsal horn sensory neurons after nerve injury. In addition, KDS showed its anti-inflammatory effects by reducing microgliosis and astrogliosis and the activation of MAPK and NF-ᴋB inflammatory pathways in these glial cells. The levels of ROS production in the spinal cords after the SNL procedure were also decreased with KDS treatment. Taken together, our results suggest that KDS may represent a promising therapeutic option for treating neuropathic pain. PERSPECTIVE: Our study provides evidence suggesting the mechanisms by which KDS, a novel MAO-B inhibitor, can be effective in pain relief. KDS, by targeting multiple mechanisms involved in BDNF/TrkB/NR2B-related excitatory transmission and neuroinflammation, may represent the next future of pain medicine.
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Affiliation(s)
- Thuỳ Linh Phạm
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Histo-Pathology, Hai Phong University of Medicine & Pharmacy, Hai Phong 042-12, Vietnam
| | - Chan Noh
- Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Chiranjivi Neupane
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea; Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Ramesh Sharma
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea; Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyun Jin Shin
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Ki Duk Park
- Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - C Justin Lee
- Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Republic of Korea
| | - Hyun-Woo Kim
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea
| | - So Yeong Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea
| | - Jin Bong Park
- Department of Medical Science, Graduate School, Chungnam National University, Daejeon 35015, Republic of Korea; Department of Physiology, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon 35015, Republic of Korea; Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of Korea.
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Castro Gonçalves AB, Ferreira Fratelli C, Saraiva Siqueira JW, Canongia de Abreu Cardoso Duarte L, Ribeiro Barros A, Possatti I, Lima dos Santos M, de Souza Silva CM, Rodrigues da Silva IC. MAOA uVNTR Genetic Variant and Major Depressive Disorder: A Systematic Review. Cells 2022; 11:cells11203267. [PMID: 36291132 PMCID: PMC9600429 DOI: 10.3390/cells11203267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 12/04/2022] Open
Abstract
Major Depressive Disorder (MDD) is a highly prevalent multifactorial psychopathology affected by neurotransmitter levels. Monoamine Oxidase A (MAOA) influences several neural pathways by modulating these levels. This systematic review (per PRISMA protocol and PECOS strategy) endeavors to understand the MAOA uVNTR polymorphism influence on MDD and evaluate its 3R/3R and 3R* genotypic frequencies fluctuation in MDD patients from different populations. We searched the Web of Science, PubMed, Virtual Health Library, and EMBASE databases for eligible original articles that brought data on genotypic frequencies related to the MAOA uVNTR variant in patients with MDD. We excluded studies with incomplete data (including statistical data), reviews, meta-analyses, and abstracts. Initially, we found 43 articles. After removing duplicates and applying the inclusion/exclusion criteria, seven articles remained. The population samples studied were predominantly Asians, with high 3R and 4R allele frequencies. Notably, we observed higher 3R/3R (female) and 3R* (male) genotype frequencies in the healthy control groups and higher 4R/4R (female) and 4R* (male) genotype frequencies in the MDD groups in the majority of different populations. Despite some similarities in the articles analyzed, there is still no consensus on the MAOA uVNTR variant’s role in MDD pathogenesis.
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Affiliation(s)
- Ana Beatriz Castro Gonçalves
- Pharmacy Course, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Caroline Ferreira Fratelli
- Postgraduate Program in Health Sciences and Technologies, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Jhon Willatan Saraiva Siqueira
- Pharmacy Course, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Ligia Canongia de Abreu Cardoso Duarte
- Postgraduate Program in Health Sciences and Technologies, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Aline Ribeiro Barros
- Postgraduate Program in Health Sciences and Technologies, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Isabella Possatti
- Postgraduate Program in Health Sciences and Technologies, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Maurício Lima dos Santos
- Clinical Analysis Laboratory, Molecular Pathology Sector, Pharmacy Department, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Calliandra Maria de Souza Silva
- Clinical Analysis Laboratory, Molecular Pathology Sector, Pharmacy Department, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
| | - Izabel Cristina Rodrigues da Silva
- Clinical Analysis Laboratory, Molecular Pathology Sector, Pharmacy Department, Faculty of Ceilândia, University of Brasília (UnB), Brasília—Federal District (DF), Brasília 72220-900, Brazil
- Correspondence: ; Tel.: +55-(61)-3107-8400
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Zou X, Gao S, Li J, Li C, Wu C, Cao X, Xia S, Shao P, Bao X, Yang H, Liu P, Xu Y. A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury. Front Pharmacol 2022; 13:1004215. [PMID: 36313349 PMCID: PMC9608666 DOI: 10.3389/fphar.2022.1004215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/03/2022] [Indexed: 11/13/2022] Open
Abstract
Microglia are the resident macrophages in the brain, which play a critical role in post-stroke neuroinflammation. Accordingly, targeting neuroinflammation could be a promising strategy to improve ischemic stroke outcomes. Ethyl ferulate (EF) has been confirmed to possess anti-inflammatory properties in several disease models, including acute lung injury, retinal damage and diabetes-associated renal injury. However, the effects of EF on microglial activation and the resolution of post-stroke neuroinflammation remains unknown. Here, we found that EF suppressed pro-inflammatory response triggered by lipopolysaccharide (LPS) stimulation in primary microglia and BV2 cell lines, as well as post-stroke neuroinflammation in an in vivo transient middle cerebral artery occlusion (tMCAO) stroke model in C57BL/6 mice, consequently ameliorating ischemic brain injury. Furthermore, EF could directly bind and inhibit the activity of monoamine oxidase B (MAO-B) to reduce pro-inflammatory response. Taken together, our study identified a MAO-B inhibitor, Ethyl ferulate, as an active compound with promising potentials for suppressing post-stroke neuroinflammation.
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Affiliation(s)
- Xinxin Zou
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, China
| | - Shenghan Gao
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Jiangnan Li
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Chenggang Li
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Chuyu Wu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Xiang Cao
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Shengnan Xia
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Pengfei Shao
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Xinyu Bao
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Haiyan Yang
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
| | - Pinyi Liu
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
- *Correspondence: Pinyi Liu, ; Yun Xu,
| | - Yun Xu
- Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, China
- Department of Neurology, Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Institute of Translational Medicine for Brain Critical Diseases, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Jiangsu Provincial Key Discipline of Neurology, Nanjing, China
- Nanjing Neurology Medical Center, Nanjing, China
- *Correspondence: Pinyi Liu, ; Yun Xu,
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Naoi M, Maruyama W, Shamoto-Nagai M. Neuroprotective Function of Rasagiline and Selegiline, Inhibitors of Type B Monoamine Oxidase, and Role of Monoamine Oxidases in Synucleinopathies. Int J Mol Sci 2022; 23:ijms231911059. [PMID: 36232361 PMCID: PMC9570229 DOI: 10.3390/ijms231911059] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 11/27/2022] Open
Abstract
Synucleinopathies are a group of neurodegenerative disorders caused by the accumulation of toxic species of α-synuclein. The common clinical features are chronic progressive decline of motor, cognitive, behavioral, and autonomic functions. They include Parkinson’s disease, dementia with Lewy body, and multiple system atrophy. Their etiology has not been clarified and multiple pathogenic factors include oxidative stress, mitochondrial dysfunction, impaired protein degradation systems, and neuroinflammation. Current available therapy cannot prevent progressive neurodegeneration and “disease-modifying or neuroprotective” therapy has been proposed. This paper presents the molecular mechanisms of neuroprotection by the inhibitors of type B monoamine oxidase, rasagiline and selegiline. They prevent mitochondrial apoptosis, induce anti-apoptotic Bcl-2 protein family, and pro-survival brain- and glial cell line-derived neurotrophic factors. They also prevent toxic oligomerization and aggregation of α-synuclein. Monoamine oxidase is involved in neurodegeneration and neuroprotection, independently of the catalytic activity. Type A monoamine oxidases mediates rasagiline-activated signaling pathways to induce neuroprotective genes in neuronal cells. Multi-targeting propargylamine derivatives have been developed for therapy in various neurodegenerative diseases. Preclinical studies have presented neuroprotection of rasagiline and selegiline, but beneficial effects have been scarcely presented. Strategy to improve clinical trials is discussed to achieve disease-modification in synucleinopathies.
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Affiliation(s)
- Makoto Naoi
- Correspondence: ; Tel.: +81-05-6173-1111 (ext. 3494); Fax: +81-561-731-142
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22
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Luo Y, Shan L, Xu L, Patnala S, Kanfer I, Li J, Yu P, Jun X. A network pharmacology-based approach to explore the therapeutic potential of Sceletium tortuosum in the treatment of neurodegenerative disorders. PLoS One 2022; 17:e0273583. [PMID: 36006974 PMCID: PMC9409587 DOI: 10.1371/journal.pone.0273583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Sceletium tortuosum (SCT) has been utilized medicinally by indigenous Koi-San people purportedly for mood elevation. SCT extracts are reported to be neuroprotective and have efficacy in improving cognition. However, it is still unclear which of the pharmacological mechanisms of SCT contribute to the therapeutic potential for neurodegenerative disorders. Hence, this study investigated two aspects–firstly, the abilities of neuroprotective sub-fractions from SCT on scavenging radicals, inhibiting some usual targets relevant to Alzheimer’s disease (AD) or Parkinson’s disease (PD), and secondly utilizing the network pharmacology related methods to search probable mechanisms using Surflex-Dock program to show the key targets and corresponding SCT constituents. The results indicated sub-fractions from SCT could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, inhibit acetylcholinesterase (AChE), monoamine oxidase type B (MAO-B) and N-methyl-D-aspartic acid receptor (NMDAR). Furthermore, the results of gene ontology and docking analyses indicated the key targets involved in the probable treatment of AD or PD might be AChE, MAO-B, NMDAR subunit2B (GluN2B-NMDAR), adenosine A2A receptor and cannabinoid receptor 2, and the corresponding constituents in Sceletium tortuosum might be N-trans-feruloyl-3-methyldopamine, dihydrojoubertiamine and other mesembrine type alkaloids. In summary, this study has provided new evidence for the therapeutic potential of SCT in the treatment of AD or PD, as well as the key targets and notable constituents in SCT. Therefore, we propose SCT could be a natural chemical resource for lead compounds in the treatment of neurodegenerative disorders.
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Affiliation(s)
- Yangwen Luo
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Luchen Shan
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Lipeng Xu
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Srinivas Patnala
- Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa
| | - Isadore Kanfer
- Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa
| | - Jiahao Li
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Pei Yu
- College of Pharmacy, Jinan University, Guangzhou, China
- * E-mail: (PY); (JX)
| | - Xu Jun
- College of Pharmacy, Jinan University, Guangzhou, China
- * E-mail: (PY); (JX)
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Fatoki T, Chukwuejim S, Ibraheem O, Oke C, Ejimadu B, Olaoye I, Oyegbenro O, Salami T, Basorun R, Oluwadare O, Salawudeen Y. Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.83332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches.
Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation.
Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS.
Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques.
Graphical abstract:
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Dai Y, Zhang C, Zhang L, Wen C, Zhu T. The modulation of mRNA levels of MAOA by electroacupuncture and psychotherapy in patients with pathological internet use. Front Psychiatry 2022; 13:918729. [PMID: 36032227 PMCID: PMC9403867 DOI: 10.3389/fpsyt.2022.918729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/27/2022] [Indexed: 01/09/2023] Open
Abstract
Objective The aim of this study was to observe the efficacy of electroacupuncture (EA) and psychotherapy (PT) effect on the mental status, sleep quality and impulsive trait in patients with pathological internet use, and to observe the changes of Monoamine oxidase type A (MAOA) messenger Ribonucleic acid (mRNA) levels in each group. Methods A total of 60 PIU patients were included for the present study. These patients were randomly divided into two groups: EA group and PT group. Baihui, Sishencong, Hegu, Neiguan, Shenmen, Taichong, Sanyinjiao and Xuanzhong were selected for acupuncture in the EA group, while group psychotherapy combined with individual psychotherapy was used for intervention in patients in the PT group. Young's Internet addiction Test (IAT), Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Barratt Impulse Scale (BIS-11) and Pittsburgh Sleep Quality Index (PSQI) were used to observe the severity of Internet addiction, mental status, sleep quality and impulsive trait of all patients at baseline and 40th days of treatment; and MAOA mRNA data were collected at baseline and 40th days of treatment. Results Electroacupuncture and psychological intervention effectively reduced IAT, SAS, SDS, Y-BOCS, BIS and PSQI scores of PIU patients. After 40 days treatment, the MAOA expression of the PT group was increased, and there was no significant change in EA group. The correlation analysis indicated that IAT scores were positively correlated with SAS, SDS, Y-BOCS, BIS and PSQI at baseline. In addition, after treatment the EA group showed that the change in IAT scores was positively correlated with the change in Y-BOCS and BIS scores, and the PT group showed that the change in IAT scores was positively correlated with the change in SDS, BIS and PSQI scores. Conclusion The present study showed that electroacupuncture and psychological intervention can improve severity of Internet addiction, mental status, sleep quality and impulsive trait of PIU patients. Simultaneously, neurobiological changes may be the underlying mechanisms of psychotherapy for internet additcion.
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Affiliation(s)
- Yu Dai
- Department of Traditional Chinese Medicine, Chengdu Eighth People’s Hospital (Geriatric Hospital of Chengdu Medical College), Chengdu, China
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chenchen Zhang
- Department of Rehabilitation, Traditional Chinese Medicine Hospital of Longquanyi District, Chengdu, China
| | - Lingrui Zhang
- Department of Medicine, Leshan Vocational and Technical College, Leshan, China
| | - Chao Wen
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tianmin Zhu
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Wang M, Peng C, Chang H, Yu M, Rong F, Yu Y. Interaction between Sirtuin 1 (SIRT1) polymorphisms and childhood maltreatment on aggression risk in Chinese male adolescents. J Affect Disord 2022; 309:37-44. [PMID: 35427711 DOI: 10.1016/j.jad.2022.04.063] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/22/2022] [Accepted: 04/10/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Aggressive behavior is a highly prevalent and serious public health problem among adolescents. However, the etiology and pathogenesis of aggressive behavior remain unclear. Childhood maltreatment is an acknowledged factor for aggressive behavior. SIRT1 is closely related to the occurrence and development of psychiatric disorders. We aimed to reveal the interactive effect between SIRT1 and childhood maltreatment on aggressive behavior among Chinese adolescents. METHODS Aggressive behavior and childhood maltreatment were evaluated by the Buss and Warren's Aggression Questionnaire (BWAQ) and short form Childhood Trauma Questionnaire (CTQ-SF), respectively. This study comprised 436 aggression cases and 435 controls. Four SIRT1 tagSNPs were selected for genotyping. Interaction between SIRT1 and childhood maltreatment was estimated by logistic regression models. RESULTS Individuals carrying SIRT1 rs4746720 minor allele and TAAC haplotype derived from SIRT1 variants was associated with reduced aggression risk when childhood maltreatment occurred (all P < 0.01). An antagonistic additive interaction between SIRT1 rs4746720 and childhood maltreatment on aggressive behavior (S = 0.421; 95%CI: 0.234 to 0.758) was further testified. No main effect of the SIRT1 SNPs or the haplotype block was observed (all P > 0.05). LIMITATIONS Since participants were only males, our findings were unable to be directly extended to females. Cross-sectional design, self-reported measurements and limited sample size were adopted. CONCLUSION This study provides the first evidence of SIRT1 × childhood maltreatment interaction on aggressive behavior in male adolescents. The minor allele of SIRT1 rs4746720 presents a protective effect on combination with childhood maltreatment on the risk of aggressive behavior.
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Affiliation(s)
- Mengni Wang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chang Peng
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongjuan Chang
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengying Yu
- Taizhou People's Hospital, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fajuan Rong
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yizhen Yu
- Department of Maternal, Child and Adolescent Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Blažević A, Iyer AM, van Velthuysen MLF, Hofland J, van Koestveld PM, Franssen GJH, Feelders RA, Zajec M, Luider TM, de Herder WW, Hofland LJ. Aberrant tryptophan metabolism in stromal cells is associated with mesenteric fibrosis in small intestinal neuroendocrine tumors. Endocr Connect 2022; 11:EC-22-0020. [PMID: 35275095 PMCID: PMC9066570 DOI: 10.1530/ec-22-0020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 03/10/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Increased levels of serotonin secretion are associated with mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs). However, the profibrotic potential of serotonin differs between patients, and in this study, we aimed to gain an understanding of the mechanisms underlying this variability. To this end, we analyzed the proteins involved in tryptophan metabolism in SI-NETs. METHODS Proteomes of tumor and stroma from primary SI-NETs and paired mesenteric metastases of patients with MF (n = 6) and without MF (n = 6) were identified by liquid chromatography-mass spectrometry (LC-MS). The differential expression of proteins involved in tryptophan metabolism between patients with and without MF was analyzed. Concurrently, monoamine oxidase A (MAO-A) expression was analyzed in the tumor and stromal compartment by immunohistochemistry (IHC) and reported as intensity over area (I/A). RESULTS Of the 42 proteins involved in tryptophan metabolism, 20 were detected by LC-MS. Lower abundance of ten proteins was found in mesenteric metastases stroma in patients with MF. No differential expression was found in primary SI-NETs. In patients with MF, IHC showed lower MAO-A expression in the stroma of the primary SI-NETs (median 4.2 I/A vs 6.5 I/A in patients without MF, P = 0.003) and mesenteric metastases (median 2.1 I/A vs 2.8 I/A in patients without MF, P= 0.019). CONCLUSION We found a decreased expression of tryptophan and serotonin-metabolizing enzymes in the stroma in patients with MF, most notably in the mesenteric stroma. This might account for the increased profibrotic potential of serotonin and explain the variability in the development of SI-NET-associated fibrotic complications.
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Affiliation(s)
- Anela Blažević
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Anand M Iyer
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | | | - Johannes Hofland
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Peter M van Koestveld
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Gaston J H Franssen
- Department of Surgery, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Richard A Feelders
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Marina Zajec
- Laboratory of Neuro-Oncology/Clinical & Cancer Proteomics, Department of Neurology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Theo M Luider
- Laboratory of Neuro-Oncology/Clinical & Cancer Proteomics, Department of Neurology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Wouter W de Herder
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Leo J Hofland
- Department of Internal Medicine, Section Endocrinology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, Netherlands
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Tagliarini C, Carbone MG, Pagni G, Marazziti D, Pomara N. Is there a relationship between morphological and functional platelet changes and depressive disorder? CNS Spectr 2022; 27:157-190. [PMID: 33092669 DOI: 10.1017/s1092852920001959] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Blood platelets, due to shared biochemical and functional properties with presynaptic serotonergic neurons, constituted, over the years, an attractive peripheral biomarker of neuronal activity. Therefore, the literature strongly focused on the investigation of eventual structural and functional platelet abnormalities in neuropsychiatric disorders, particularly in depressive disorder. Given their impact in biological psychiatry, the goal of the present paper was to review and critically analyze studies exploring platelet activity, functionality, and morpho-structure in subjects with depressive disorder. METHODS According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to March 2020 with the search terms: (1) platelets in depression [Title/Abstract]"; (2) "(platelets[Title]) AND depressive disorder[Title/Abstract]"; (3) "(Platelet[Title]) AND major depressive disorder[Title]"; (4) (platelets[Title]) AND depressed[Title]"; (5) (platelets[Title]) AND depressive episode[Title]"; (6) (platelets[Title]) AND major depression[Title]"; (7) platelet activation in depression[All fields]"; and (8) platelet reactivity in depression[All fields]." RESULTS After a detailed screening analysis and the application of specific selection criteria, we included in our review a total of 106 for qualitative synthesis. The studies were classified into various subparagraphs according to platelet characteristics analyzed: serotonergic system (5-HT2A receptors, SERT activity, and 5-HT content), adrenergic system, MAO activity, biomarkers of activation, responsivity, morphological changes, and other molecular pathways. CONCLUSIONS Despite the large amount of the literature examined, nonunivocal and, occasionally, conflicting results emerged. However, the findings on structural and metabolic alterations, modifications in the expression of specific proteins, changes in the aggregability, or in the responsivity to different pro-activating stimuli, may be suggestive of potential platelet dysfunctions in depressed subjects, which would result in a kind of hyperreactive state. This condition could potentially lead to an increased cardiovascular risk. In line with this hypothesis, we speculated that antidepressant treatments would seem to reduce this hyperreactivity while representing a potential tool for reducing cardiovascular risk in depressed patients and, maybe, in other neuropsychiatric conditions. However, the problem of the specificity of platelet biomarkers is still at issue and would deserve to be deepened in future studies.
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Affiliation(s)
- Claudia Tagliarini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Giovanni Pagni
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Donatella Marazziti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Saint Camillus International University of Health and Medical Sciences, UniCamillus, Roma, Italy
| | - Nunzio Pomara
- Geriatric Psychiatry Department, Nathan Kline Institute, Orangeburg, New York, USA
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Olasehinde TA, Olaniran AO. Neurotoxicity of anthracene and benz[a]anthracene involves oxidative stress-induced neuronal damage, cholinergic dysfunction and disruption of monoaminergic and purinergic enzymes. Toxicol Res 2022; 38:365-377. [DOI: 10.1007/s43188-021-00115-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 10/17/2021] [Accepted: 11/15/2021] [Indexed: 11/30/2022] Open
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Segura-Aguilar J, Paris I. Mechanisms of Dopamine Oxidation and Parkinson’s Disease. HANDBOOK OF NEUROTOXICITY 2022:1433-1468. [DOI: 10.1007/978-3-031-15080-7_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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30
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Tian J, Zhang C, Kang N, Wang J, Kong N, Zhou J, Wu M, Ding L, Sun H, Yan G, Sheng X. Attenuated monoamine oxidase a impairs endometrial receptivity in women with adenomyosis via downregulation of FOXO1†. Biol Reprod 2021; 105:1443-1457. [PMID: 34568943 DOI: 10.1093/biolre/ioab182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/13/2021] [Accepted: 09/21/2021] [Indexed: 11/12/2022] Open
Abstract
The establishment of endometrial receptivity is a prerequisite for successful pregnancy. Women with adenomyosis possess a lower chance of clinical pregnancy after assisted reproductive technology, which is partially due to impaired endometrial receptivity. The establishment of endometrial receptivity requires the participation of multiple processes, and proper endometrial epithelial cell (EEC) proliferation is indispensable. Monoamine oxidase A (MAOA) is a key molecule that regulates neurotransmitter metabolism in the nervous system. In the present study, we demonstrated a novel role for MAOA in the establishment of endometrial receptivity in women with adenomyosis and in an adenomyotic mouse model. Attenuated MAOA impairs endometrial receptivity by promoting inappropriate proliferation of EECs via the downregulation of FOXO1 during the window of implantation. These results revealed that MAOA plays a vital role in endometrial receptivity in female reproduction.
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Affiliation(s)
- Jiao Tian
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Chunxue Zhang
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Nannan Kang
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Junxia Wang
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Na Kong
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Jidong Zhou
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Min Wu
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Lijun Ding
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Haixiang Sun
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210032, China
| | - Guijun Yan
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
| | - Xiaoqiang Sheng
- Center for Reproductive Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
- Center for Molecular Reproductive Medicine, Nanjing University, Nanjing 210032, China
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Kamecki F, Knez D, Carvalho D, Marcucci C, Rademacher M, Higgs J, Žakelj S, Marcos A, de Tezanos Pinto F, Abin-Carriquiry JA, Gobec S, Colettis N, Marder M. Multitarget 2'-hydroxychalcones as potential drugs for the treatment of neurodegenerative disorders and their comorbidities. Neuropharmacology 2021; 201:108837. [PMID: 34653442 DOI: 10.1016/j.neuropharm.2021.108837] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/30/2021] [Accepted: 10/10/2021] [Indexed: 02/01/2023]
Abstract
The complex nature of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD) calls for multidirectional treatment. Restoring neurotransmitter levels by combined inhibition of cholinesterases (ChEs) and monoamine oxidases (MAOs, MAO-A and MAO-B), in conjunction with strategies to counteract amyloid β (Aβ) aggregation, may constitute a therapeutically strong multi-target approach for the treatment of NDDs. Chalcones are a subgroup of flavonoids with a broad spectrum of biological activity. We report here the synthesis of 2'-hydroxychalcones as MAO-A and MAO-B inhibitors. Compounds 5c (IC50 = 0.031 ± 0.001 μM), 5a (IC50 = 0.084 ± 0.003 μM), 2c (IC50 = 0.095 ± 0.019 μM) and 2a (IC50 = 0.111 ± 0.006 μM) were the most potent, selective and reversible inhibitors of human (h)MAO-B isoform. hMAO-B inhibitors 1a, 2a and 5a also inhibited murine MAO-B in vivo in mouse brain homogenates. Molecular modelling rationalised the binding mode of 2'-hydroxychalcones in the active site of hMAO-B. Additionally, several derivatives inhibited murine acetylcholinesterase (mAChE) (IC50 values from 4.37 ± 0.83 μM to 15.17 ± 6.03 μM) and reduced the aggregation propensity of Aβ. Moreover, some derivatives bound to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutyric acid A (GABAA) receptors (1a and 2a with Ki = 4.9 ± 1.1 μM and 5.0 ± 1.1 μM, respectively), and exerted sedative and/or anxiolytic like effects on mice. The biological results reported here on 2'-hydroxychalcones provide an extension to previous studies on chalcone scaffold and show them as a potential treatment strategy for NDDs and their associated comorbidities.
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Affiliation(s)
- Fabiola Kamecki
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Damijan Knez
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
| | - Diego Carvalho
- Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
| | - Carolina Marcucci
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Marina Rademacher
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Josefina Higgs
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Simon Žakelj
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
| | - Alejandra Marcos
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Felicitas de Tezanos Pinto
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Juan Andrés Abin-Carriquiry
- Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, 11600, Montevideo, Uruguay.
| | - Stanislav Gobec
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
| | - Natalia Colettis
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
| | - Mariel Marder
- Universidad de Buenos Aires. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química y Fisicoquímica Biológicas Prof. Dr. Alejandro C. Paladini, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.
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Goldstein DS, Castillo G, Sullivan P, Sharabi Y. Differential Susceptibilities of Catecholamines to Metabolism by Monoamine Oxidases. J Pharmacol Exp Ther 2021; 379:253-259. [PMID: 34503991 PMCID: PMC9164308 DOI: 10.1124/jpet.121.000826] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022] Open
Abstract
The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes; various clinical disorders; and effects of numerous drugs. Steps in intracellular catecholamine synthesis and metabolism were delineated long ago, but there remains a knowledge gap. Catecholamines are metabolized by two isoforms of monoamine oxidase (MAO), MAO-A and MAO-B, and although the anatomic localization of MAO-A and MAO-B and substrate specificities of enzyme inhibitors are well characterized, relative susceptibilities of the endogenous catecholamines to enzymatic oxidation by MAO-A and MAO-B have not been studied systematically. MAOs catalyze the conversion of catecholamines to catecholaldehydes-3,4-dihydroxyphenylacetaldehyde (DOPAL) from DA and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from NE and EPI. In this study we exploited the technical ability to assay DOPAL and DOPEGAL simultaneously with the substrate catecholamines to compare DA, NE, and EPI in their metabolism by MAO-A and MAO-B. For both MAO isoforms, DA was the better substrate compared to NE or EPI, which were metabolized equally. Since catecholaminergic neurons express mainly MAO-A, the finding that MAO-A is more efficient than MAO-B in metabolizing endogenous catecholamines reinforces the view that the predominant route of intraneuronal enzymatic oxidation of catecholamines is via MAO-A. The results have implications for clinical neurochemistry, experimental therapeutics, and computational models of catecholaminergic neurodegeneration. For instance, the greater susceptibility of DA than the other catecholamines to both MAO isoforms can help explain relatively high concentrations of the deaminated DA metabolite 3,4-dihydroxyphenylacetic acid than of the NE metabolite 3,4-dihydroxyphenylglycol in human plasma and urine. SIGNIFICANCE STATEMENT: Endogenous catecholamines are metabolized by monoamine oxidase (MAO)-A and -B, yielding the catecholaldehydes 3,4-dihydroxyphenylacetaldehyde (DOPAL) from dopamine (DA) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from norepinephrine (NE) and epinephrine (EPI). Based on measurements of DOPAL and DOPEGAL production, DA is a better substrate than NE or EPI for both MAO isoforms, and MAO-A is more efficient than MAO-B in metabolizing DA, NE, and EPI. MAO-A is the main route of intraneuronal metabolism of endogenous catecholamines.
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Affiliation(s)
- David S Goldstein
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland (D.G., G.C., P.S.); NIH Academy Enrichment Program, OD/NIH (G.C.); and Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.)
| | - Genessis Castillo
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland (D.G., G.C., P.S.); NIH Academy Enrichment Program, OD/NIH (G.C.); and Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.)
| | - Patti Sullivan
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland (D.G., G.C., P.S.); NIH Academy Enrichment Program, OD/NIH (G.C.); and Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.)
| | - Yehonatan Sharabi
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland (D.G., G.C., P.S.); NIH Academy Enrichment Program, OD/NIH (G.C.); and Sackler Faculty of Medicine, Tel Aviv University, Israel (Y.S.)
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Khadrawy YA, Hosny EN, Magdy M, Mohammed HS. Antidepressant effects of curcumin-coated iron oxide nanoparticles in a rat model of depression. Eur J Pharmacol 2021; 908:174384. [PMID: 34324858 DOI: 10.1016/j.ejphar.2021.174384] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/15/2021] [Accepted: 07/23/2021] [Indexed: 12/21/2022]
Abstract
The antidepressant effect of curcumin-coated iron oxide nanoparticles (Cur-IONPs) was investigated in the current study using depression rat model induced by reserpine. IONPs were synthesized by curcumin as a reducing agent producing Cur-IONPs. Rats were divided into control, depression rat model, and depressed rats treated with Cur-IONPs. After treatment rat behavior was evaluated using forced swimming test (FST). Serotonin (5-HT), norepinephrine (NE), dopamine (DA), monoamine oxidase (MAO), acetylcholinesterase (AchE), Na+, K+, ATPase, lipid peroxidation (MDA), reduced glutathione (GSH), glutathione-s-transferase (GST) and nitric oxide (NO) were measured in the cortex and hippocampus. In depressed rats, FST showed increased immobilization time and reduced swimming time. This was associated with a significant decrease in 5-HT, NE, DA and GSH and a significant increase in MDA and NO levels and GST, MAO, AchE and Na+, K+, ATPase activities in the cortex and hippocampus. Treatment with Cur-NONPs for two weeks increased the swimming time reduced the immobility time, and elevated 5-HT, NE and DA levels. Cur-IONPs attenuated the oxidative stress induced by reserpine and restored the MAO, AchE and Na+, K+, ATPase. The present green method used curcumin in the IONPs synthesis and has several merits; obtaining nanoform of iron oxide, increasing the bioavailability of curcumin and reducing the oxidative stress induced by iron. The present antidepressant effect of Cur-IONPs could be attributed to the ability of Cur-IONPs to restore monoamine neurotransmitter levels by increasing their synthesis and reducing their metabolism. In addition, the antioxidant activity of curcumin prevented oxidative stress in the depressed rats.
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Affiliation(s)
- Yasser A Khadrawy
- Medical Physiology Department, Medical Division, National Research Centre, Giza, Egypt.
| | - Eman N Hosny
- Medical Physiology Department, Medical Division, National Research Centre, Giza, Egypt
| | - Merna Magdy
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Haitham S Mohammed
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
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Roles of Hostility and Depression in the Association between the MAOA Gene Polymorphism and Internet Gaming Disorder. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18136910. [PMID: 34199135 PMCID: PMC8297287 DOI: 10.3390/ijerph18136910] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/23/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022]
Abstract
The metabolism of bioamine in the central nervous system contributes to the development of addiction. We examined the roles of hostility and depression in the association between internet gaming disorder (IGD) and monoamine oxidase-A (MAOA) EcoRV polymorphism (rs1137070). A total of 69 adults with IGD and 138 without IGD were recruited through diagnostic interviewing. We evaluated participants for rs1137070, depression, and hostility. The participants with the TT genotype of rs1137070 had a higher odds ratio of 2.52 (1.37–4.64) for IGD compared with the C carriers. Expressive hostility behavior and hostility cognition mediated the association between rs1137070 and IGD. Indicating lower MAOA activity, the TT genotype predicted IGD and higher expressive hostility behavior and hostility cognition. Expressive hostility behavior and hostility cognition may underline the association between rs1137070 and IGD. Assessment of and intervention for hostility behavior and cognition should be provided to attenuate the risk of IGD, particularly in those with the TT genotype. Further brain imaging or neurobiological studies are required to elucidate the possible mechanism underlying the association between MAOA activity and IGD.
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Goldstein DS. The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know. Int J Mol Sci 2021; 22:ijms22115999. [PMID: 34206133 PMCID: PMC8199574 DOI: 10.3390/ijms22115999] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 01/10/2023] Open
Abstract
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.
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Affiliation(s)
- David S Goldstein
- Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
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Cuperlovic-Culf M, Cunningham EL, Teimoorinia H, Surendra A, Pan X, Bennett SAL, Jung M, McGuiness B, Passmore AP, Beverland D, Green BD. Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS-COV-2 infection. Sci Rep 2021; 11:10629. [PMID: 34017039 PMCID: PMC8138024 DOI: 10.1038/s41598-021-90243-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/05/2021] [Indexed: 02/03/2023] Open
Abstract
Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer's disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein-protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.
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Affiliation(s)
- Miroslava Cuperlovic-Culf
- Digital Technologies Research Centre, National Research Council of Canada, Ottawa, Canada.
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
| | - Emma L Cunningham
- Centre for Public Health, Queen's University Belfast, Block B, Institute of Clinical Sciences, Royal Victoria Hospital Site, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland
| | - Hossen Teimoorinia
- NRC Herzberg Astronomy and Astrophysics, 5071 West Saanich Road, Victoria, BC, V9E 2E7, Canada
| | - Anuradha Surendra
- Digital Technologies Research Centre, National Research Council of Canada, Ottawa, Canada
| | - Xiaobei Pan
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, 8 Malone Road, Belfast, BT9 5BN, Northern Ireland
| | - Steffany A L Bennett
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
- Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Brain and Mind Research Institute, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Mijin Jung
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, 8 Malone Road, Belfast, BT9 5BN, Northern Ireland
| | - Bernadette McGuiness
- Centre for Public Health, Queen's University Belfast, Block B, Institute of Clinical Sciences, Royal Victoria Hospital Site, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland
| | - Anthony Peter Passmore
- Centre for Public Health, Queen's University Belfast, Block B, Institute of Clinical Sciences, Royal Victoria Hospital Site, Grosvenor Road, Belfast, BT12 6BA, Northern Ireland
| | - David Beverland
- Outcomes Assessment Unit, Musgrave Park Hospital, Stockman's Lane, Belfast, BT9 7JB, Northern Ireland
| | - Brian D Green
- Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, 8 Malone Road, Belfast, BT9 5BN, Northern Ireland.
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Gu S, Cui F, Yin J, Fang C, Liu L. Altered mRNA expression levels of autophagy- and apoptosis-related genes in the FOXO pathway in schizophrenia patients treated with olanzapine. Neurosci Lett 2021; 746:135669. [PMID: 33485989 DOI: 10.1016/j.neulet.2021.135669] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 12/31/2020] [Accepted: 01/14/2021] [Indexed: 12/17/2022]
Abstract
This study attempted to analyze the alterations in the mRNA expression levels of autophagy- and apoptosis-related genes in the forkhead box transcription factor O (FOXO) pathway in schizophrenia patients before and after olanzapine treatment. For a total of 32 acute schizophrenic inpatients, clinical data with PANSS were obtained before and after four weeks of olanzapine treatment (mean dose 14.24 ± 4.35 mg/d) along with data from 32 healthy volunteers. The mRNA expression levels of the FOXO pathway genes were measured by real-time qPCR after fasting venous blood was collected and analyzed. The mRNA expression levels of FOXO1, FOXO3A, FASLG, and BCL2L11 were observed to be significantly decreased in acute schizophrenia patients. After four weeks of olanzapine treatment, the expression levels of the first three genes were further reduced, but BCL2L11 expression levels were not significantly changed. The pairwise correlations between the mRNA expression level of FASLG and those of the other three genes were not observed in acute schizophrenia patients, while these relationships were observed in healthy controls. After olanzapine treatment, the FASLG mRNA expression level was restored and exhibited a pairwise correlation with the FOXO3A and BCL2L11 mRNA expression levels but not with the FOXO1 mRNA expression level, and FASLG mRNA expression was also correlated with the duration of the disease. The statuses and correlations of the mRNA expression levels of FOXO pathway-related genes were altered in schizophrenia patients and were affected by olanzapine treatment and the duration of the disease.
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Affiliation(s)
- Shuguang Gu
- Department of Geriatric Psychiatry, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, Jiangsu, 214151, China
| | - Fengwei Cui
- Department of Geriatric Psychiatry, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, Jiangsu, 214151, China
| | - Jiajun Yin
- Department of Geriatric Psychiatry, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, Jiangsu, 214151, China
| | - Chunxia Fang
- Combined TCM & Western Medicine Department, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, Jiangsu, 214151, China.
| | - Liang Liu
- Department of Geriatric Psychiatry, Wuxi Mental Health Center, Nanjing Medical University, Wuxi, Jiangsu, 214151, China.
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Qiu M, Zhang C, Dai Y, Zhang L, Wang Y, Peng W, Chen Y, Wen C, Li H, Zhu T. mRNA Levels of MAOA and 5-HT 2 A Receptor in Patients With Pathological Internet Use: Correlations With Comorbid Symptoms. Front Psychiatry 2021; 12:667699. [PMID: 34335325 PMCID: PMC8322446 DOI: 10.3389/fpsyt.2021.667699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 06/22/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: Uncontrolled internet use may lead to the emergence of pathological internet use (PIU). PIU has become a global public health concern that can cause a range of psychotic symptoms, including anxiety, depression, and impulse control disorder. To date, we know very little about the principal biological factors related to PIU. Monoamine oxidase type A (MAOA) and serotonin (5-HT) 5-HT2A receptor (5-HT2AR) play critical roles in the development of behavioural and drug addictions. Thus, the aim of this study was to measure the relative expression of mRNA of MAOA and 5-HT2AR in peripheral blood mononuclear cells (PBMCs) of patients with PIU and to determine the correlations between these biological indicators and the comorbid symptoms of patients with PIU. Methods: In this study, the mRNA of MAOA and 5-HT2AR was detected using real-time PCR in PBMCs of the patients with PIU (n = 24) and healthy controls (HCs, n = 25). The relationship between the mRNA levels of MAOA and 5-HT2AR and clinical symptoms in patients with PIU was further investigated. Results: MAOA mRNA in PBMCs was significantly upregulated in patients with PIU compared with that in HCs. mRNA levels of 5-HT2AR were not found to differ significantly between HCs and patients with PIU. Correlation analyses further revealed a significant positive correlation between the relative expression of MAOA mRNA in PBMCs of patients with PIU and the Young's Internet Addiction Test and Self-Rating Depression Scale scores. Conclusion: The present study revealed upregulated expression of MAOA mRNA in patients with PIU and an association between the expression of MAOA mRNA and clinical symptoms of PIU, suggesting that the neurobiological changes may be similar between PIU and substance addiction. Additionally, this study demonstrated a potential association between comorbid symptoms and mRNA levels of MAOA.
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Affiliation(s)
- Mimi Qiu
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chenchen Zhang
- Department of Rehabilitation, Traditional Chinese Medicine Hospital of Longquanyi District, Chengdu, China
| | - Yu Dai
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lingrui Zhang
- Department of Medicine, Leshan Vocational and Technical College, Leshan, China
| | - Yang Wang
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Peng
- College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yalin Chen
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chao Wen
- Department of Rehabilitation, Zigong Fifth People's Hospital, Zigong, China
| | - Hui Li
- College of Medicine, Chengdu University, Chengdu, China
| | - Tianmin Zhu
- College of Rehabilitation and Health Preservation, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Yi P, Zhang Z, Huang S, Huang J, Peng W, Yang J. Integrated meta-analysis, network pharmacology, and molecular docking to investigate the efficacy and potential pharmacological mechanism of Kai-Xin-San on Alzheimer's disease. PHARMACEUTICAL BIOLOGY 2020; 58:932-943. [PMID: 32956608 PMCID: PMC7534219 DOI: 10.1080/13880209.2020.1817103] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/09/2020] [Accepted: 08/15/2020] [Indexed: 05/02/2023]
Abstract
CONTEXT Kai-Xin-San (KXS) has been used to treat Alzheimer's disease (AD) for thousands of years. However, no quantitative data regarding AD treatment using KXS are available. Moreover, its active compounds and mechanism of action for the treatment of AD remain largely unclear. OBJECTIVES To evaluate the efficacy and the potential pharmacological mechanisms of KXS in AD treatment. MATERIALS AND METHODS A systematic collection of KXS experiments was conducted from PubMed, Web of Science, Embase, CNKI, VIP, and Wanfang Data up to February, 2020. Review Manager 5 software was used for meta-analysis. In network pharmacology, components of KXS were screened, AD-related genes were then identified and the 'component-target-pathway' network constructed. Molecular docking was finally employed for in silico simulation matching between representative KXS compounds and their target genes. RESULTS Meta-analysis revealed that KXS improves the cognitive benefits in AD models by reducing the time of escape latency (SMD = -16.84) as well as increasing the number of cross-platform (SMD = 2.56) and proportion of time in the target quadrant (SMD = 7.52). Network pharmacology identified 25 KXS active compounds and 44 genes targets. DRD2, MAOA, ACHE, ADRA2A and CHRM2 were core target proteins. Besides, 22 potential pathways of KXS were identified, like cholinergic synapses, the cGMP/PKG pathway and calcium signalling. Molecular docking showed that stigmasterol, aposcopolamine and inermin can closely bind three targets (ACHE, ADRA2A and CHRM2). DISCUSSION AND CONCLUSION These findings suggest that KXS exerts effect on AD through multi-target, multi-component and multi-pathway mechanism. Future studies may explore the active components of KXS.
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Affiliation(s)
- Pengji Yi
- Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Zheyu Zhang
- Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Siqi Huang
- Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiahua Huang
- Hunan Academy of Chinese Medicine, Changsha, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese and Western Medicine, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Jingjing Yang
- Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, China
- Xiangya Nursing School, Central South University, Changsha, China
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40
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Detention in Juvenile Correctional Facilities Is Associated with Higher Platelet Monoamine Oxidase B Activity in Males. Biomolecules 2020; 10:biom10111555. [PMID: 33203099 PMCID: PMC7697475 DOI: 10.3390/biom10111555] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/06/2020] [Accepted: 11/13/2020] [Indexed: 01/16/2023] Open
Abstract
Juvenile delinquency is related to several biological factors, yet very few vulnerability biomarkers have been identified. Previous data suggest that the enzyme monoamine oxidase B (MAO-B) influences several personality traits linked to the propensity to engage in delinquent behavior. Building on this evidence, we assessed whether conduct disorder (CD), juvenile delinquency adjudications, or detention in a correctional facility were associated with either platelet MAO-B activity or the MAOB rs1799836 polymorphism. The study enrolled 289 medication-free male youths, including 182 individuals detained in a correctional facility (with or without a diagnosis of CD). Of the remaining 107 participants, 26 subjects had a diagnosis of CD, and 81 were mentally healthy controls. Platelet MAO-B activity was determined by spectrophotofluorometry, while MAOB rs1799836 was genotyped using qPCR. Platelet MAO-B activity, corrected for age and smoking, was significantly higher in juvenile detainees (p < 0.001), irrespective of CD diagnosis. MAOB rs1799836 was not associated with platelet MAO-B activity or with detention in a correctional facility, CD diagnosis, or delinquent behavior. These data suggest that detention in a juvenile correctional facility increases platelet MAO-B activity in male adolescents. Future studies are needed to determine the mechanisms and functional significance of MAO-B peripheral elevation in juvenile male detainees.
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41
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Luan D, Zhao MG, Shi YC, Li L, Cao YJ, Feng HX, Zhang ZJ. Mechanisms of repetitive transcranial magnetic stimulation for anti-depression: Evidence from preclinical studies. World J Psychiatry 2020; 10:223-233. [PMID: 33134113 PMCID: PMC7582130 DOI: 10.5498/wjp.v10.i10.223] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/11/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023] Open
Abstract
This review summarizes the anti-depressant mechanisms of repetitive transcranial magnetic stimulation in preclinical studies, including anti-inflammatory effects mediated by activation of nuclear factor-E2-related factor 2 signaling pathway, anti-oxidative stress effects, enhancement of synaptic plasticity and neurogenesis via activation of the endocannabinoid system and brain derived neurotrophic factor signaling pathway, increasing the content of monoamine neurotransmitters via inhibition of Sirtuin 1/monoamine oxidase A signaling pathway, and reducing the activity of the hypothalamic-pituitary-adrenocortical axis. We also discuss the shortcomings of transcranial magnetic stimulation in preclinical studies such as inaccurate positioning, shallow depth of stimulation, and difficulty in elucidating the neural circuit mechanism up- and down-stream of the stimulation target brain region.
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Affiliation(s)
- Di Luan
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ming-Ge Zhao
- Department of Nursing, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ya-Chen Shi
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ling Li
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Jia Cao
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Hai-Xia Feng
- Department of Nursing, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Zhi-Jun Zhang
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Department of Psychology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
- Mental Health Center, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang province, China
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Neshan M, Campbell A, Malakouti SK, Zareii M, Ahangari G. Gene expression of serotonergic markers in peripheral blood mononuclear cells of patients with late-onset Alzheimer's disease. Heliyon 2020; 6:e04716. [PMID: 32904297 PMCID: PMC7452509 DOI: 10.1016/j.heliyon.2020.e04716] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 06/06/2020] [Accepted: 08/11/2020] [Indexed: 01/14/2023] Open
Abstract
Serotonin or 5-hydroxytryptamine (5-HT) is primarily involved in the regulation of learning and memory. Pathological changes in metabolism or functional imbalance of 5-HT has been associated with Alzheimer's disease (AD). The hypothesis tested is that in peripheral blood, markers of the serotonergic pathway can be used as a diagnostic tool for AD. The current study measured the relative expression of 5-HT receptors (5-HTR2A and 5-HTR3A) as well as the 5-HT catalytic enzyme, Monoamine oxidase A (MAO-A) mRNA in Peripheral Blood Mononuclear Cells (PBMCs) of patients with late-onset Alzheimer's disease (LOAD) and age-matched controls. 5-HTR2A, 5-HTR3A, and MAO-A mRNA expressions were examined in PBMCs of 30 patients with LOAD and 30 control individuals. Real-time quantitative PCR was used to measure mRNA expression. The dementia status of patients in this study was assessed using a Mini-Mental State Examination (MMSE). Mean data of relative mRNA expression of 5-HTR2A, 5-HTR3A and MAO-A were significantly lower in PBMCs of patients with LOAD compared with controls. Based on the down-regulation of serotonergic markers in PBMCs, our findings may be another claim to the systemic nature of LOAD. The role of peripheral serotonergic downregulation, in the pathogenesis of AD, needs to be further studied. Given the extremely convenient access to PBMCs, these molecular events may represent more complete dimensions of AD neuropathophysiology or possibly lead to a new direction in studies focused on blood-based markers.
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Affiliation(s)
- Masoud Neshan
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Arezoo Campbell
- Department of Pharmaceutical Sciences, Western University of Health Sciences, California, USA
| | - Seyed Kazem Malakouti
- Mental Health Research Center, Tehran Institute of Psychiatry–School of Behavioral Sciences and Mental Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Zareii
- Mental Health Research Center, Tehran Institute of Psychiatry–School of Behavioral Sciences and Mental Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ghasem Ahangari
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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Zagórska A, Jaromin A. Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer's Disease Therapy. Molecules 2020; 25:E3337. [PMID: 32717806 PMCID: PMC7435667 DOI: 10.3390/molecules25153337] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 12/23/2022] Open
Abstract
Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer's disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H3 receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.
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Affiliation(s)
- Agnieszka Zagórska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland
| | - Anna Jaromin
- Department of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, Wroclaw, 50-383 Wrocław, Poland;
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Müller T. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease. Expert Opin Drug Metab Toxicol 2020; 16:403-414. [DOI: 10.1080/17425255.2020.1750596] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany
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45
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Cheng Y, Buchan M, Vitanova K, Aitken L, Gunn-Moore FJ, Ramsay RR, Doherty G. Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function. J Neurochem 2020; 155:191-206. [PMID: 32157699 DOI: 10.1111/jnc.15003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/12/2022]
Abstract
Mitochondrial dysfunction has a recognised role in the progression of Alzheimer's disease (AD) pathophysiology. Cerebral perfusion becomes increasingly inefficient throughout ageing, leading to unbalanced mitochondrial dynamics. This effect is exaggerated by amyloid β (Aβ) and phosphorylated tau, two hallmark proteins of AD pathology. A neuroprotective role for the adipose-derived hormone, leptin, has been demonstrated in neuronal cells. However, its effects with relation to mitochondrial function in AD remain largely unknown. To address this question, we have used both a glucose-serum-deprived (CGSD) model of ischaemic stroke in SH-SY5Y cells and a Aβ1-42 -treatment model of AD in differentiated hippocampal cells. Using a combination of 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and MitoRed staining techniques, we show that leptin prevents depolarisation of the mitochondrial membrane and excessive mitochondrial fragmentation induced by both CGSD and Aβ1-42 . Thereafter, we used ELISAs and a number of activity assays to reveal the biochemical underpinnings of these processes. Specifically, leptin was seen to inhibit up-regulation of the mitochondrial fission protein Fis1 and down-regulation of the mitochondrial fusion protein, Mfn2. Furthermore, leptin was seen to up-regulate the expression and activity of the antioxidant enzyme, monoamine oxidase B. Herein we provide the first demonstration that leptin is sufficient to protect against aberrant mitochondrial dynamics and resulting loss of function induced by both CGSD and Aβ1-42 . We conclude that the established neuroprotective actions of leptin may be facilitated through regulation of mitochondrial dynamics.
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Affiliation(s)
- Ying Cheng
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
| | - Matthew Buchan
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
| | - Karina Vitanova
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
| | - Laura Aitken
- School of Biology, University of St Andrews, St Andrews, UK
| | | | - Rona R Ramsay
- School of Biology, University of St Andrews, St Andrews, UK
| | - Gayle Doherty
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
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Rafehi M, Faltraco F, Matthaei J, Prukop T, Jensen O, Grytzmann A, Blome FG, Berger RG, Krings U, Vormfelde SV, Tzvetkov MV, Brockmöller J. Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A. Front Pharmacol 2019; 10:1297. [PMID: 31736764 PMCID: PMC6831736 DOI: 10.3389/fphar.2019.01297] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/10/2019] [Indexed: 11/17/2022] Open
Abstract
Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity.
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Affiliation(s)
- Muhammad Rafehi
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Frank Faltraco
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Johannes Matthaei
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Thomas Prukop
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Ole Jensen
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Aileen Grytzmann
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Felix G Blome
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | | | - Ulrich Krings
- Institute of Food Chemistry, Leibniz University, Hannover, Germany
| | - Stefan V Vormfelde
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Mladen V Tzvetkov
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
| | - Jürgen Brockmöller
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany
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Moreno-Fernández J, López-Aliaga I, García-Burgos M, J.M. Alférez M, Díaz-Castro J. Fermented Goat Milk Consumption Enhances Brain Molecular Functions during Iron Deficiency Anemia Recovery. Nutrients 2019; 11:nu11102394. [PMID: 31591353 PMCID: PMC6835798 DOI: 10.3390/nu11102394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 12/13/2022] Open
Abstract
Iron deficiency anemia (IDA) is one of the most prevalent nutritional deficiencies worldwide. Iron plays critical roles in nervous system development and cognition. Despite the known detrimental consequences of IDA on cognition, available studies do not provide molecular mechanisms elucidating the role of iron in brain functions during iron deficiency and recovery with dairy components. In this study, 100 male Wistar rats were placed on a pre-experimental period of 40 days and randomly divided in two groups: a control group receiving a normal-Fe diet, (45 mg/kg), and an Fe-deficient group receiving a low-Fe diet (5 mg/kg). At day 40, 10 rats per group were sacrificed to anemia control, and 80 rats were divided into eight experimental groups fed with fermented goat or cow milk-based diets, with normal Fe content or Fe overload (450 mg/kg) for 30 days. IDA decreased most of the parameters related to brain molecular functions, namely dopamine, irisin, MAO-A, oxytocin, β-endorphin, and α-MSH, while it increased synaptophysin. These alterations result in an impairment of brain molecular functions. In general, during anemia recovery, fermented goat milk diet consumption increased dopamine, oxytocin, serotonin, synaptophysin, and α-MSH, and decreased MAO-A and MAO-B, suggesting a potential neuroprotective effect in brain functions, which could enhance brain molecular functions.
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Affiliation(s)
- Jorge Moreno-Fernández
- Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, E-18071 Granada, Spain; (J.M.-F.); (I.L.-A.); (M.G.-B.); (J.D.-C.)
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, E-18071 Granada, Spain
| | - Inmaculada López-Aliaga
- Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, E-18071 Granada, Spain; (J.M.-F.); (I.L.-A.); (M.G.-B.); (J.D.-C.)
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, E-18071 Granada, Spain
| | - María García-Burgos
- Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, E-18071 Granada, Spain; (J.M.-F.); (I.L.-A.); (M.G.-B.); (J.D.-C.)
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, E-18071 Granada, Spain
| | - María J.M. Alférez
- Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, E-18071 Granada, Spain; (J.M.-F.); (I.L.-A.); (M.G.-B.); (J.D.-C.)
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, E-18071 Granada, Spain
- Correspondence: ; Tel.: +34-958-243883
| | - Javier Díaz-Castro
- Department of Physiology, Faculty of Pharmacy, Campus Universitario de Cartuja, E-18071 Granada, Spain; (J.M.-F.); (I.L.-A.); (M.G.-B.); (J.D.-C.)
- Institute of Nutrition and Food Technology “José Mataix Verdú”, University of Granada, E-18071 Granada, Spain
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Chen D, Qin W, Fang H, Wang L, Peng B, Li L, Huang W. Recent progress in two-photon small molecule fluorescent probes for enzymes. CHINESE CHEM LETT 2019. [DOI: 10.1016/j.cclet.2019.08.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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49
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Multi-target design strategies for the improved treatment of Alzheimer's disease. Eur J Med Chem 2019; 176:228-247. [DOI: 10.1016/j.ejmech.2019.05.020] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/06/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022]
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50
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Müller T, Möhr JD. Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson’s disease: current status. Expert Opin Drug Metab Toxicol 2019; 15:429-435. [DOI: 10.1080/17425255.2019.1607292] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany
| | - Jan-Dominique Möhr
- Department of Neurology, St. Joseph Hospital Berlin-Weißensee, Berlin, Germany
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