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Qiu Y, Zhu L, Cai W, Zhu L. Research Progress on BDNF and Depression. ACS Chem Neurosci 2025. [PMID: 40359301 DOI: 10.1021/acschemneuro.5c00193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025] Open
Abstract
Depression is a potentially life-threatening psychiatric disorder that affects the physical and mental health of millions of individuals worldwide. It can manifest at any stage of life, inducing profound emotional despondency, negative cognitions, and, in severe cases, suicidal ideation, often accompanied by physical symptoms, bringing a significant burden on both families and society. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is widely expressed in the central nervous system (CNS), particularly in regions, such as the hippocampus and cortex. Numerous studies have shown that an imbalance or inadequate conversion of pro-brain-derived neurotrophic factor (proBDNF) into its mature form, mature BDNF (mBDNF), may impair neuronal plasticity, which is crucial to the pathogenesis of depression. This paper provides a comprehensive review of the neurotrophic mechanisms implicated in depression, covering the location, expression, and release of BDNF; the relationship between proBDNF, mBDNF, and depression; and the downstream signaling pathways triggered by BNDF binding to its receptors. This review aims to provide a theoretical foundation for understanding the pathogenesis and clinical treatment of depression.
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Affiliation(s)
- Yahong Qiu
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lixia Zhu
- Patent Examination Cooperation (JIANGSU) Center of the Patent Office, China National Intellectual Property Administration (CNIPA), Suzhou, Jiangsu 215163, China
| | - Wenyan Cai
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lijuan Zhu
- The Key Laboratory of Developmental Genes and Human Disease, Department of Histology and Embryology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
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Zhao X, Yao M, Wang Y, Feng C, Yang Y, Tian L, Bao C, Li X, Zhu X, Zhang X. Neuroregulation during Bone Formation and Regeneration: Mechanisms and Strategies. ACS APPLIED MATERIALS & INTERFACES 2025; 17:7223-7250. [PMID: 39869030 DOI: 10.1021/acsami.4c16786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
The skeleton is highly innervated by numerous nerve fibers. These nerve fibers, in addition to transmitting information within the bone and mediating bone sensations, play a crucial role in regulating bone tissue formation and regeneration. Traditional bone tissue engineering (BTE) often fails to achieve satisfactory outcomes when dealing with large-scale bone defects, which is frequently related to the lack of effective reconstruction of the neurovascular network. In recent years, increasing research has revealed the critical role of nerves in bone metabolism. Nerve fibers regulate bone cells through neurotransmitters, neuropeptides, and peripheral glial cells. Furthermore, nerves also coordinate with the vascular and immune systems to jointly construct a microenvironment favorable for bone regeneration. As a signaling driver of bone formation, neuroregulation spans the entire process of bone physiological activities from the embryonic formation to postmaturity remodeling and repair. However, there is currently a lack of comprehensive summaries of these regulatory mechanisms. Therefore, this review sketches out the function of nerves during bone formation and regeneration. Then, we elaborate on the mechanisms of neurovascular coupling and neuromodulation of bone immunity. Finally, we discuss several novel strategies for neuro-bone tissue engineering (NBTE) based on neuroregulation of bone, focusing on the coordinated regeneration of nerve and bone tissue.
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Affiliation(s)
- Xiangrong Zhao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu 610041, Sichuan, China
| | - Meilin Yao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu 610041, Sichuan, China
| | - Yuyi Wang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
| | - Cong Feng
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
| | - Yuhan Yang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu 610041, Sichuan, China
| | - Luoqiang Tian
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
| | - Chongyun Bao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Med-X Center for Materials, Sichuan University, Chengdu 610041, Sichuan, China
| | - Xiangfeng Li
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China
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Romero Garavito A, Díaz Martínez V, Juárez Cortés E, Negrete Díaz JV, Montilla Rodríguez LM. Impact of physical exercise on the regulation of brain-derived neurotrophic factor in people with neurodegenerative diseases. Front Neurol 2025; 15:1505879. [PMID: 39935805 PMCID: PMC11810746 DOI: 10.3389/fneur.2024.1505879] [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: 10/03/2024] [Accepted: 12/13/2024] [Indexed: 02/13/2025] Open
Abstract
This review explores the impact of physical exercise on brain-derived neurotrophic factor (BDNF) and its relationship with neurodegenerative diseases. The key role of BDNF in maintaining brain health is highlighted, and recent studies are analyzed that indicate an increase in BDNF levels following physical activity, particularly in young adults. Additionally, the interaction between the BDNF Val66Met genetic polymorphism and exercise on cognitive function is examined. The review emphasizes the possibility of exercise as a complementary therapy for neurodegenerative diseases, although further research is required to fully understand its effects.
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Affiliation(s)
- Ana Romero Garavito
- Facultad de medicina, Universidad Cooperativa de Colombia, Villavicencio, Colombia
| | - Valery Díaz Martínez
- Facultad de medicina, Universidad Cooperativa de Colombia, Villavicencio, Colombia
| | | | - José Vicente Negrete Díaz
- Programa de Fisioterapia, Universidad de Guanajuato, Guanajuato, Mexico
- Programa de Psicologia Clinica, Universidad de Guanajuato, Guanajuato, Mexico
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Sharma S, Chawla S, Kumar P, Ahmad R, Kumar Verma P. The chronic unpredictable mild stress (CUMS) Paradigm: Bridging the gap in depression research from bench to bedside. Brain Res 2024; 1843:149123. [PMID: 39025397 DOI: 10.1016/j.brainres.2024.149123] [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: 05/21/2024] [Revised: 07/04/2024] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Depression is a complicated neuropsychiatric condition with an incompletely understoodetiology, making the discovery of effective therapies challenging. Animal models have been crucial in improving our understanding of depression and enabling antidepressant medication development. The CUMS model has significant face validity since it induces fundamental depression symptoms in humans, such as anhedonia, behavioral despair, anxiety, cognitive impairments, and changes in sleep, food, and social behavior. Its construct validity is demonstrated by the dysregulation of neurobiological systems involved in depression, including monoaminergic neurotransmission, the hypothalamic-pituitary-adrenal axis, neuroinflammatory processes, and structural brain alterations. Critically, the model's predictive validity is demonstrated by the reversal of CUMS-induced deficits following treatment with clinically effective antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors. This review comprehensivelyassesses the multifarious depressive-like phenotypes in the CUMS model using behavioral paradigms like sucrose preference, forced swim, tail suspension, elevated plus maze, and novel object recognition tests. It investigates the neurobiological mechanisms that underlie CUMS-induced behaviors, including signaling pathways involving tumor necrosis factor-alpha, brain-derived neurotrophic factor and its receptor TrkB, cyclooxygenase-2, glycogen synthase kinase-3 beta, and the kynurenine pathway. This review emphasizes the CUMS model's importance as a translationally relevant tool for unraveling the complex mechanisms underlying depression and facilitating the development of improved and targeted interventions for this debilitating neuropsychiatric disorder by providing a comprehensive overview of its validity, behavioral assessments, and neurobiological underpinnings.
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Affiliation(s)
- Shweta Sharma
- Department of Pharmacology, School of PharmaceuticalEducation & Research, Jamia Hamdard, New Delhi 110062, India
| | - Shivani Chawla
- Shri Baba Mastnath Institute of Pharmaceutical Sciences and Research, Baba Mastnath University, Rohtak, Haryana 124001, India
| | - Praveen Kumar
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Rizwan Ahmad
- Department of Pharmacology, School of PharmaceuticalEducation & Research, Jamia Hamdard, New Delhi 110062, India
| | - Prabhakar Kumar Verma
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana 124001, India.
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Aharoni R, Milo R, Arnon R. Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair. Pharmacol Rev 2024; 76:1133-1158. [PMID: 39406508 DOI: 10.1124/pharmrev.124.000927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 10/18/2024] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.
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Affiliation(s)
- Rina Aharoni
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel (Ri.A., Ru.A.); and Department of Neurology, Barzilai Medical Center, Ashkelon, Israel, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (R.M.)
| | - Ron Milo
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel (Ri.A., Ru.A.); and Department of Neurology, Barzilai Medical Center, Ashkelon, Israel, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (R.M.)
| | - Ruth Arnon
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel (Ri.A., Ru.A.); and Department of Neurology, Barzilai Medical Center, Ashkelon, Israel, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel (R.M.)
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Giesler LP, Mychasiuk R, Shultz SR, McDonald SJ. BDNF: New Views of an Old Player in Traumatic Brain Injury. Neuroscientist 2024; 30:560-573. [PMID: 37067029 PMCID: PMC11423547 DOI: 10.1177/10738584231164918] [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] [Indexed: 04/18/2023]
Abstract
Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.
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Affiliation(s)
| | - Richelle Mychasiuk
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
| | - Sandy R. Shultz
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
| | - Stuart J. McDonald
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Neurology, The Alfred Hospital, Melbourne, Australia
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Pramanik S, Devi M H, Chakrabarty S, Paylar B, Pradhan A, Thaker M, Ayyadhury S, Manavalan A, Olsson PE, Pramanik G, Heese K. Microglia signaling in health and disease - Implications in sex-specific brain development and plasticity. Neurosci Biobehav Rev 2024; 165:105834. [PMID: 39084583 DOI: 10.1016/j.neubiorev.2024.105834] [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: 05/05/2024] [Revised: 07/21/2024] [Accepted: 07/27/2024] [Indexed: 08/02/2024]
Abstract
Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.
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Affiliation(s)
- Subrata Pramanik
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
| | - Harini Devi M
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Saswata Chakrabarty
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Berkay Paylar
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Ajay Pradhan
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Manisha Thaker
- Eurofins Lancaster Laboratories, Inc., 2425 New Holland Pike, Lancaster, PA 17601, USA
| | - Shamini Ayyadhury
- The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Arulmani Manavalan
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India
| | - Per-Erik Olsson
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Gopal Pramanik
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133791, the Republic of Korea.
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Hino M, Nakanishi M, Nomoto H. The expression system affects the binding affinity between p75NTR and proNGF. Biochem Biophys Rep 2024; 38:101702. [PMID: 38596407 PMCID: PMC11001769 DOI: 10.1016/j.bbrep.2024.101702] [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: 01/25/2024] [Revised: 03/13/2024] [Accepted: 03/28/2024] [Indexed: 04/11/2024] Open
Abstract
ProNGF (nerve growth factor) is a precursor of NGF and a signaling peptide exerting opposite effects on neuronal cells, i.e., apoptotic or neuritogenic. The conflicting biological activity of proNGF depends on the relative levels of two membrane receptors, TrkA and p75NTR. The effect of proNGF depends on the expression levels of these receptor proteins and their affinity to proNGF. Since the affinity of proteins has been studied with various recombinant proteins, it is worth comparing the affinity of these proteins within one experiment with the same method. This study examined the affinity between a recombinant proNGF and p75NTR expressed in common systems: bacterial, insect, and mammalian cells. The extracellular domain of p75NTR expressed in the insect or mammalian systems bound to native mature NGF, with a higher affinity for the insect receptor. The uncleavable proNGF was expressed in the three systems and they showed neuritogenic activity in PC12 cells. These recombinant proteins were used to compare their binding affinity to p75NTR. The insect p75NTR showed a higher binding affinity to proNGF than the mammalian p75NTR. The insect p75NTR bound proNGF from the insect system with the highest affinity, then from the mammalian system, and the lowest from the bacterial system. Conversely, the mammalian p75NTR showed no such preference for proNGF. Because the recombinant proNGF and p75NTR from different expression systems are supposed to have the same amino acid sequences, these differences in the affinity depend likely on their post-translational modifications, most probably on their glycans. Each recombinant proNGF and p75NTR in various expression systems exhibited different mobilities on SDS-PAGE and reactivities with glycosidases and lectins.
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Affiliation(s)
- Mami Hino
- Laboratory of Biochemistry, School of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime, 790-8578, Japan
| | - Masayuki Nakanishi
- Laboratory of Biochemistry, School of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime, 790-8578, Japan
| | - Hiroshi Nomoto
- Laboratory of Biochemistry, School of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime, 790-8578, Japan
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Pravikova PD, Arssan MA, Zalivina EA, Kondaurova EM, Kulikova EA, Belokopytova II, Naumenko VS. Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6 J). Vavilovskii Zhurnal Genet Selektsii 2024; 28:407-415. [PMID: 39027124 PMCID: PMC11253014 DOI: 10.18699/vjgb-24-46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 07/20/2024] Open
Abstract
Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.
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Affiliation(s)
- P D Pravikova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - M A Arssan
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E A Zalivina
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E M Kondaurova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E A Kulikova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - I I Belokopytova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - V S Naumenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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Nicola L, Loo SJQ, Lyon G, Turknett J, Wood TR. Does resistance training in older adults lead to structural brain changes associated with a lower risk of Alzheimer's dementia? A narrative review. Ageing Res Rev 2024; 98:102356. [PMID: 38823487 DOI: 10.1016/j.arr.2024.102356] [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: 03/10/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
Dementia, particularly Alzheimer's Disease (AD), has links to several modifiable risk factors, especially physical inactivity. When considering the relationship between physcial activity and dementia risk, cognitive benefits are generally attributed to aerobic exercise, with resistance exercise (RE) receiving less attention. This review aims to address this gap by evaluating the impact of RE on brain structures and cognitive deficits associated with AD. Drawing insights from randomized controlled trials (RCTs) utilizing structural neuroimaging, the specific influence of RE on AD-affected brain structures and their correlation with cognitive function are discussed. Preliminary findings suggest that RE induces structural brain changes in older adults that could reduce the risk of AD or mitigate AD progression. Importantly, the impacts of RE appear to follow a dose-response effect, reversing pathological structural changes and improving associated cognitive functions if performed at least twice per week for at least six months, with greatest effects in those already experiencing some element of cognitive decline. While more research is eagerly awaited, this review contributes insights into the potential benefits of RE for cognitive health in the context of AD-related changes in brain structure and function.
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Affiliation(s)
| | | | | | | | - Thomas R Wood
- Department of Pediatrics, University of Washington, Seattle, WA, USA; Institute for Human and Machine Cognition, Pensacola, FL, USA.
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Kang Y, Toyoda H, Saito M. Search for unknown neural link between the masticatory and cognitive brain systems to clarify the involvement of its impairment in the pathogenesis of Alzheimer's disease. Front Cell Neurosci 2024; 18:1425645. [PMID: 38994328 PMCID: PMC11236757 DOI: 10.3389/fncel.2024.1425645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 06/12/2024] [Indexed: 07/13/2024] Open
Abstract
Brain degenerations in sporadic Alzheimer's disease (AD) are observed earliest in the locus coeruleus (LC), a population of noradrenergic neurons, in which hyperphosphorylated tau protein expression and β-amyloid (Aβ) accumulation begin. Along with this, similar changes occur in the basal forebrain cholinergic neurons, such as the nucleus basalis of Meynert. Neuronal degeneration of the two neuronal nuclei leads to a decrease in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex, which results in the accumulation of Aβ and hyperphosphorylated tau protein and ultimately causes neuronal cell death in those cortices. On the other hand, a large number of epidemiological studies have shown that tooth loss or masticatory dysfunction is a risk factor for dementia including AD, and numerous studies using experimental animals have also shown that masticatory dysfunction causes brain degeneration in the basal forebrain, hippocampus, and cerebral cortex similar to those observed in human AD, and that learning and memory functions are impaired accordingly. However, it remains unclear how masticatory dysfunction can induce such brain degeneration similar to AD, and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, we provide clues to the search for such "missing link" by discussing the embryological, anatomical, and physiological relationship between LC and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.
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Affiliation(s)
- Youngnam Kang
- Department of Behavioral Physiology, Osaka University Graduate School of Human Sciences, Osaka, Japan
| | - Hiroki Toyoda
- Department of Oral Physiology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Mitsuru Saito
- Department of Oral Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
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Vints WAJ, Levin O, van Griensven M, Vlaeyen JWS, Masiulis N, Verbunt J, van Laake-Geelen CCM. Neuromuscular electrical stimulation to combat cognitive aging in people with spinal cord injury: protocol for a single case experimental design study. BMC Neurol 2024; 24:197. [PMID: 38862912 PMCID: PMC11165793 DOI: 10.1186/s12883-024-03699-9] [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: 02/21/2024] [Accepted: 05/31/2024] [Indexed: 06/13/2024] Open
Abstract
INTRODUCTION Individuals with spinal cord injury (SCI) can experience accelerated cognitive aging. Myokines (factors released from muscle cells during contractions), such as brain-derived neurotrophic factor (BDNF), are thought to have beneficial effects on cognition. Neuromuscular electrical stimulation (NMES) was shown to elicit a large release of myokines. However, the effects of NMES on cognitive function have not been studied. OBJECTIVE To present the study protocol for a clinical trial evaluating the effects of NMES aimed at improving cognition and BDNF. METHODS A replicated randomized three-phases single-case experimental design (SCED) with sequential multiple baseline time series and a single-armed prospective trial will be conducted with 15 adults with chronic SCI (> 12 months after injury) above L1 neurological level undergoing 30-min quadriceps NMES, 3 days per week for 12 weeks. MAIN STUDY ENDPOINTS Primary endpoint is cognitive performance (assessed by a smartphone test) conducted three times per week during the baseline phase with random duration of 3 to 8 weeks, the intervention phase of 12 weeks, and the follow-up phase of 3 weeks after a no measurement rest period of 12 weeks. Secondary endpoints are changes in BDNF levels and cognitive performance measured before the baseline period, before and after intervention and after a 12 weeks follow-up. CONCLUSION This will be the first study investigating the effects of 12 weeks NMES on both cognition and BDNF levels in individuals with SCI. The SCED results provide information on individual treatment effect courses which may direct future research. TRIAL REGISTRATION ClinicalTrials.gov (NCT05822297, 12/01/2023).
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Affiliation(s)
- Wouter A J Vints
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto Str. 6, Kaunas, LT-44221, Lithuania.
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, Maastricht, 6200 MD, The Netherlands.
- Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, Hoensbroek, 6430 AB, The Netherlands.
| | - Oron Levin
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto Str. 6, Kaunas, LT-44221, Lithuania
- Movement Control & Neuroplasticity Research Group, Group Biomedical Sciences, KU Leuven, Tervuursevest 101, Heverlee, 3001, Belgium
| | - Martijn van Griensven
- Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, Maastricht, 6200 MD, The Netherlands
| | - Johan W S Vlaeyen
- Experimental Health Psychology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands
- Health Psychology Research Group, Faculty of Psychology and Educational Sciences, KU Leuven, Tiensestraat 102, Louvain, 3000, Belgium
| | - Nerijus Masiulis
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto Str. 6, Kaunas, LT-44221, Lithuania
- Department of Rehabilitation, Physical and Sports Medicine, Faculty of Medicine, Institute of Health Science, Vilnius University, M. K. Čiurlionio Str. 21, Vilnius, 03101, Lithuania
| | - Jeanine Verbunt
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, Maastricht, 6200 MD, The Netherlands
- Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, Hoensbroek, 6430 AB, The Netherlands
| | - Charlotte C M van Laake-Geelen
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, Maastricht, 6200 MD, The Netherlands
- Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, Hoensbroek, 6430 AB, The Netherlands
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13
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Zou J, Hao S. A potential research target for cardiac rehabilitation: brain-derived neurotrophic factor. Front Cardiovasc Med 2024; 11:1348645. [PMID: 38707889 PMCID: PMC11069312 DOI: 10.3389/fcvm.2024.1348645] [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: 12/03/2023] [Accepted: 03/19/2024] [Indexed: 05/07/2024] Open
Abstract
Cardiovascular diseases pose a major threat to human life, functional activity, and quality of life. Once the disease is present, patients can experience varying degrees of problems or limitations on three levels: physical, psychological, and social. Patients with cardiovascular disease are always at risk for adverse cardiac events, decreased physical activity, psychoemotional disturbances, and limited social participation due to their varying pathologies. Therefore, personalized cardiac rehabilitation is of great significance in improving patients' physical and mental functions, controlling disease progression, and preventing deterioration. There is a consensus on the benefits of cardiac rehabilitation in improving patients' quality of life, enhancing functional activity, and reducing mortality. As an important part of cardiac rehabilitation, Exercise plays an irreplaceable role. Aerobic exercise, resistance training, flexibility training, and other forms of exercise are recommended by many experts. Improvements in exercise tolerance, lipid metabolism, cardiac function, and psychological aspects of the patients were evident with appropriate exercise interventions based on a comprehensive assessment. Further studies have found that brain-derived neurotrophic factor may be an important mediator of exercise's ability to improve cardiovascular health. Brain-derived neurotrophic factor exerts multiple biological effects on the cardiovascular system. This article provides another perspective on the cardiac effects of exercise and further looks at the prospects for the use of brain-derived neurotrophic factor in cardiac rehabilitation. Meanwhile, the new idea that brain-derived neurotrophic factor is a key mediator connecting the brain-cardiac axis is proposed in light of the current research progress, to provide new ideas for clinical rehabilitation and scientific research.
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Affiliation(s)
- Jianpeng Zou
- Department of Rehabilitation and Physiotherapy, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shijie Hao
- College of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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14
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Dell'Osso L, Nardi B, Massoni L, Gravina D, Benedetti F, Cremone IM, Carpita B. Neuroprotective Properties of Antiepileptics: What are the Implications for Psychiatric Disorders? Curr Med Chem 2024; 31:3447-3472. [PMID: 37226791 DOI: 10.2174/0929867330666230523155728] [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: 12/31/2022] [Revised: 03/29/2023] [Accepted: 04/14/2023] [Indexed: 05/26/2023]
Abstract
Since the discovery of the first antiepileptic compound, increasing attention has been paid to antiepileptic drugs (AEDs), and recently, with the understanding of the molecular mechanism underlying cells death, a new interest has revolved around a potential neuroprotective effect of AEDs. While many neurobiological studies in this field have focused on the protection of neurons, growing data are reporting how exposure to AEDs can also affect glial cells and the plastic response underlying recovery; however, demonstrating the neuroprotective abilities of AEDs remains a changeling task. The present work aims to summarize and review the literature available on the neuroprotective properties of the most commonly used AEDs. Results highlighted how further studies should investigate the link between AEDs and neuroprotective properties; while many studies are available on valproate, results for other AEDs are very limited and the majority of the research has been carried out on animal models. Moreover, a better understanding of the biological basis underlying neuro-regenerative defects may pave the way for the investigation of further therapeutic targets and eventually lead to an improvement in the actual treatment strategies.
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Affiliation(s)
- Liliana Dell'Osso
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Benedetta Nardi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Leonardo Massoni
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Davide Gravina
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Francesca Benedetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Ivan Mirko Cremone
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
| | - Barbara Carpita
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56127, Italy
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15
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Shaikh A, Li YQ, Lu J. Perspectives on pain in Down syndrome. Med Res Rev 2023; 43:1411-1437. [PMID: 36924439 DOI: 10.1002/med.21954] [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: 05/07/2021] [Revised: 01/08/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023]
Abstract
Down syndrome (DS) or trisomy 21 is a genetic condition often accompanied by chronic pain caused by congenital abnormalities and/or conditions, such as osteoarthritis, recurrent infections, and leukemia. Although DS patients are more susceptible to chronic pain as compared to the general population, the pain experience in these individuals may vary, attributed to the heterogenous structural and functional differences in the central nervous system, which might result in abnormal pain sensory information transduction, transmission, modulation, and perception. We tried to elaborate on some key questions and possible explanations in this review. Further clarification of the mechanisms underlying such abnormal conditions induced by the structural and functional differences is needed to help pain management in DS patients.
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Affiliation(s)
- Ammara Shaikh
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China
| | - Yun-Qing Li
- Department of Anatomy, Histology, and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, Shaanxi Province, China
- Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, China
| | - Jie Lu
- Department of Human Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning Province, China
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16
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Tripathi A, Nasrallah HA, Pillai A. Pimavanserin treatment increases plasma brain-derived neurotrophic factor levels in rats. Front Neurosci 2023; 17:1237726. [PMID: 37712092 PMCID: PMC10499044 DOI: 10.3389/fnins.2023.1237726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023] Open
Abstract
Background Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play a key role in neuroplasticity and neurogenesis. The present study tested the hypothesis that treatment with Pimavanserin is associated with higher and sustained elevations of mBDNF. Methods Adult Sprague-Dawley male rats were treated with Pimavanserin, Fluoxetine or vehicle for 4 weeks (chronic) or 2 h (acute). BDNF levels were determined by enzyme-linked Immunosorbent assay (ELISA). Results We found significant increases in plasma mBDNF levels in rats following chronic Pimavanserin treatment, but not in Fluoxetine-treated rats. No significant changes in mBDNF levels were found in the prefrontal cortex or hippocampus following Pimavanserin or Fluoxetine treatment. Conclusion These findings suggest that increase in mBDNF levels could be a contributing mechanism for the neuroprotective potential of Pimavanserin.
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Affiliation(s)
- Ashutosh Tripathi
- Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - Henry A. Nasrallah
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States
| | - Anilkumar Pillai
- Faillace Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
- Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States
- Charlie Norwood VA Medical Center, Augusta, GA, United States
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17
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Malliou F, Andriopoulou CE, Kofinas A, Katsogridaki A, Leondaritis G, Gonzalez FJ, Michaelidis TM, Darsinou M, Skaltsounis LA, Konstandi M. Oleuropein Promotes Neural Plasticity and Neuroprotection via PPARα-Dependent and Independent Pathways. Biomedicines 2023; 11:2250. [PMID: 37626746 PMCID: PMC10452728 DOI: 10.3390/biomedicines11082250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. The current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of the ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. However, fenofibrate, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against β-amyloid and H2O2 toxicity independently from PPARα activation. In conclusion, OLE and similar drugs, acting either as PPARα agonists or via PPARα independent mechanisms, could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions.
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Affiliation(s)
- Foteini Malliou
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
| | - Christina E. Andriopoulou
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
| | - Aristeidis Kofinas
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
| | - Allena Katsogridaki
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
| | - George Leondaritis
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
- Institute of Biosciences (I.BS.), University Research Center of Ioannina (U.R.C.I.), 45110 Ioannina, Greece
| | - Frank J. Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA;
| | - Theologos M. Michaelidis
- Department of Biological Applications & Technology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (T.M.M.); (M.D.)
- Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110 Ioannina, Greece
| | - Marousa Darsinou
- Department of Biological Applications & Technology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (T.M.M.); (M.D.)
| | - Leandros A. Skaltsounis
- Department of Pharmacognosy, Faculty of Pharmacy, National and Kapodestrian University of Athens, 11527 Athens, Greece;
| | - Maria Konstandi
- Department of Pharmacology, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (F.M.); (C.E.A.); (A.K.); (A.K.); (G.L.)
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18
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Shimizu N, Saito T, Wada N, Hashimoto M, Shimizu T, Kwon J, Cho KJ, Saito M, Karnup S, de Groat WC, Yoshimura N. Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury. Int J Mol Sci 2023; 24:7885. [PMID: 37175592 PMCID: PMC10177842 DOI: 10.3390/ijms24097885] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/21/2023] [Accepted: 04/22/2023] [Indexed: 05/15/2023] Open
Abstract
This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder-urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.
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Affiliation(s)
- Nobutaka Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Pelvic Floor Center, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Tetsuichi Saito
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Naoki Wada
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Mamoru Hashimoto
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Takahiro Shimizu
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Joonbeom Kwon
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Kang Jun Cho
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Sergei Karnup
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - William C. de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (N.S.)
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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19
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Jiang F, Bello ST, Gao Q, Lai Y, Li X, He L. Advances in the Electrophysiological Recordings of Long-Term Potentiation. Int J Mol Sci 2023; 24:ijms24087134. [PMID: 37108295 PMCID: PMC10138642 DOI: 10.3390/ijms24087134] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/01/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Understanding neuronal firing patterns and long-term potentiation (LTP) induction in studying learning, memory, and neurological diseases is critical. However, recently, despite the rapid advancement in neuroscience, we are still constrained by the experimental design, detection tools for exploring the mechanisms and pathways involved in LTP induction, and detection ability of neuronal action potentiation signals. This review will reiterate LTP-related electrophysiological recordings in the mammalian brain for nearly 50 years and explain how excitatory and inhibitory neural LTP results have been detected and described by field- and single-cell potentials, respectively. Furthermore, we focus on describing the classic model of LTP of inhibition and discuss the inhibitory neuron activity when excitatory neurons are activated to induce LTP. Finally, we propose recording excitatory and inhibitory neurons under the same experimental conditions by combining various electrophysiological technologies and novel design suggestions for future research. We discussed different types of synaptic plasticity, and the potential of astrocytes to induce LTP also deserves to be explored in the future.
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Affiliation(s)
- Feixu Jiang
- Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong
| | | | - Qianqian Gao
- Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong
| | - Yuanying Lai
- Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong
| | - Xiao Li
- Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong
- Research Institute of City University of Hong Kong, Shenzhen 518057, China
| | - Ling He
- Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong
- Research Institute of City University of Hong Kong, Shenzhen 518057, China
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20
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Pisani A, Paciello F, Del Vecchio V, Malesci R, De Corso E, Cantone E, Fetoni AR. The Role of BDNF as a Biomarker in Cognitive and Sensory Neurodegeneration. J Pers Med 2023; 13:jpm13040652. [PMID: 37109038 PMCID: PMC10140880 DOI: 10.3390/jpm13040652] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) has a crucial function in the central nervous system and in sensory structures including olfactory and auditory systems. Many studies have highlighted the protective effects of BDNF in the brain, showing how it can promote neuronal growth and survival and modulate synaptic plasticity. On the other hand, conflicting data about BDNF expression and functions in the cochlear and in olfactory structures have been reported. Several clinical and experimental research studies showed alterations in BDNF levels in neurodegenerative diseases affecting the central and peripheral nervous system, suggesting that BDNF can be a promising biomarker in most neurodegenerative conditions, including Alzheimer's disease, shearing loss, or olfactory impairment. Here, we summarize current research concerning BDNF functions in brain and in sensory domains (olfaction and hearing), focusing on the effects of the BDNF/TrkB signalling pathway activation in both physiological and pathological conditions. Finally, we review significant studies highlighting the possibility to target BDNF as a biomarker in early diagnosis of sensory and cognitive neurodegeneration, opening new opportunities to develop effective therapeutic strategies aimed to counteract neurodegeneration.
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Affiliation(s)
- Anna Pisani
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Fabiola Paciello
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Valeria Del Vecchio
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Rita Malesci
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
| | - Eugenio De Corso
- Department of Otolaryngology Head and Neck Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Elena Cantone
- Department of Neuroscience, Reproductive Sciences and Dentistry-ENT Section, University of Naples Federico II, 80131 Naples, Italy
| | - Anna Rita Fetoni
- Department of Neuroscience, Reproductive Sciences and Dentistry-Audiology Section, University of Naples Federico II, 80131 Naples, Italy
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21
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Gilbreath D, Hagood D, Alatorre-Cruz GC, Andres A, Downs H, Larson-Prior LJ. Effects of Early Nutrition Factors on Baseline Neurodevelopment during the First 6 Months of Life: An EEG Study. Nutrients 2023; 15:1535. [PMID: 36986265 PMCID: PMC10055905 DOI: 10.3390/nu15061535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/18/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Throughout infancy, the brain undergoes rapid changes in structure and function that are sensitive to environmental influences, such as diet. Breastfed (BF) infants score higher on cognitive tests throughout infancy and into adolescence than formula fed (FF) infants, and these differences in neurocognitive development are reflected in higher concentrations of white and grey matter as measured by MRI. To further explore the effect diet has on cognitive development, electroencephalography (EEG) is used as a direct measure of neuronal activity and to assess specific frequency bands associated with cognitive processes. Task-free baseline EEGs were collected from infants fed with human milk (BF), dairy-based formula (MF), or soy-based formula (SF) at 2, 3, 4, 5, and 6 months of age to explore differences in frequency bands in both sensor and source space. Significant global differences in sensor space were seen in beta and gamma bands between BF and SF groups at ages 2 and 6 months, and these differences were further observed through volumetric modeling in source space. We conclude that BF infants exhibit earlier brain maturation reflected in greater power spectral density in these frequency bands.
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Affiliation(s)
- Dylan Gilbreath
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72207, USA
| | - Darcy Hagood
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
| | - Graciela Catalina Alatorre-Cruz
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72207, USA
| | - Aline Andres
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72207, USA
| | - Heather Downs
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
| | - Linda J. Larson-Prior
- Arkansas Children’s Nutrition Center (ACNC), Little Rock, AR 72202, USA
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72207, USA
- Department of Pediatrics, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72207, USA
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22
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Forte A, Lessa P, Chaves A, de Aquino P, Brito L, Pinheiro L, Juruena M, de Lucena D, de Rezende P, de Vasconcelos S. Oxidative stress and inflammatory process in borderline personality disorder (BPD): a narrative review. Braz J Med Biol Res 2023; 56:e12484. [PMID: 36946840 PMCID: PMC10021502 DOI: 10.1590/1414-431x2023e12484] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/13/2023] [Indexed: 03/23/2023] Open
Abstract
Borderline personality disorder (BPD) is a severe psychiatric condition that affects up to 2.7% of the population and is highly linked to functional impairment and suicide. Despite its severity, there is a lack of knowledge about its pathophysiology. Studies show genetic influence and childhood violence as factors that may contribute to the development of BPD; however, the involvement of neuroinflammation in BPD remains poorly investigated. This article aimed to explore the pathophysiology of BPD according to the levels of brain-derived neurotrophic factor (BDNF), inflammatory cytokines, and oxidative stress substances that exacerbate neuronal damage. Few articles have been published on this theme. They show that patients with BPD have a lower level of BDNF and a higher level of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in peripheral blood, associated with increased plasma levels of oxidative stress markers, such as malondialdehyde and 8-hydroxy-2-deoxyguanosine. Therefore, more research on the topic is needed, mainly with a pre-clinical and clinical focus.
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Affiliation(s)
- A.R.C.C. Forte
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.H.C. Lessa
- Curso de Medicina, Departamento de Ciências Biológicas e da Saúde (DCBS), Universidade Federal do Amapá, Macapá, AP, Brasil
| | - A.J.M. Chaves
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.E.A. de Aquino
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - L.M. Brito
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - L.C. Pinheiro
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - M.F. Juruena
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - D.F. de Lucena
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - P.H.F. de Rezende
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
| | - S.M.M. de Vasconcelos
- Laboratório de Neuropsicofarmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil
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23
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Silva F, Masella G, Madeira MF, Duarte CB, Santos M. TrkC Intracellular Signalling in the Brain Fear Network During the Formation of a Contextual Fear Memory. Mol Neurobiol 2023; 60:3507-3521. [PMID: 36882590 PMCID: PMC10122637 DOI: 10.1007/s12035-023-03292-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/21/2023] [Indexed: 03/09/2023]
Abstract
Learned fear is orchestrated by a brain fear network that comprises the amygdala, hippocampus and the medial prefrontal cortex. Synaptic plasticity within this network is critical for the formation of proper fear memories. Known for their role in the promotion of synaptic plasticity, neurotrophins position as obvious candidates in the regulation of fear processes. Indeed, recent evidence from our laboratory and others associates dysregulated signalling through neurotrophin-3 and its receptor TrkC with the pathophysiology of anxiety and fear-related disorders. Here, we put wild-type C57Bl/6J mice through a contextual fear conditioning paradigm in order to characterize TrkC activation and expression in the main brain regions involved in (learned) fear - amygdala, hippocampus, and prefrontal cortex - during the formation of a fear memory. We report an overall decreased activation of TrkC in the fear network during fear consolidation and reconsolidation. During reconsolidation, hippocampal TrkC downregulation was accompanied by a decrease in the expression and activation of Erk, a critical signalling pathway in fear conditioning. Moreover, we did not find evidence that the observed decrease of TrkC activation was caused by altered expression of dominant negative form of TrkC, neurotrophin-3, or the PTP1B phosphatase. Our results indicate hippocampal TrkC inactivation through Erk signalling as a potential mechanism in the regulation of contextual fear memory formation.
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Affiliation(s)
- Francisca Silva
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal
| | - Gianluca Masella
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal
| | | | - Carlos B Duarte
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Mónica Santos
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
- Institute of Interdisciplinary Research, University of Coimbra (iiiUC), Coimbra, Portugal.
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24
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Pourkhodadad S, Hosseinkazemi H, Bonakdar S, Nekounam H. Biomimetic engineered approaches for neural tissue engineering: Spinal cord injury. J Biomed Mater Res B Appl Biomater 2023; 111:701-716. [PMID: 36214332 DOI: 10.1002/jbm.b.35171] [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: 12/13/2021] [Revised: 07/16/2022] [Accepted: 09/03/2022] [Indexed: 01/21/2023]
Abstract
The healing process for spinal cord injuries is complex and presents many challenges. Current advances in nerve regeneration are based on promising tissue engineering techniques, However, the chances of success depend on better mimicking the extracellular matrix (ECM) of neural tissue and better supporting neurons in a three-dimensional environment. The ECM provides excellent biological conditions, including desirable morphological features, electrical conductivity, and chemical compositions for neuron attachment, proliferation and function. This review outlines the rationale for developing a construct for neuron regrowth in spinal cord injury using appropriate biomaterials and scaffolding techniques.
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Affiliation(s)
| | - Hessam Hosseinkazemi
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Shahin Bonakdar
- National Cell Bank Department, Pasteur Institute of Iran, Tehran, Iran
| | - Houra Nekounam
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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25
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Oral Administration of TrkB Agonist, 7, 8-Dihydroxyflavone Regenerates Hair Cells and Restores Function after Gentamicin-Induced Vestibular Injury in Guinea Pig. Pharmaceutics 2023; 15:pharmaceutics15020493. [PMID: 36839815 PMCID: PMC9966733 DOI: 10.3390/pharmaceutics15020493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8-dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista ampullaris after gentamicin (GM)-induced injury. Twenty animals treated with GM received daily administration of DHF or saline for 14 or 28 days (DHF (+) or DHF (-) group; N = 5, each). At 14 days after GM treatment, almost all of the HCs had disappeared in both groups. At 28 days, the HCs number in DHF (+) and DHF (-) groups was 74% and 49%, respectively, compared to GM-untreated control. In the ampullary nerves, neurofilament 200 positive rate in the DHF (+) group was 91% at 28 days, which was significantly higher than 42% in DHF (-). On day 28, the synaptic connections observed between C-terminal-binding protein 2-positive and postsynaptic density protein-95-positive puncta were restored, and caloric response was significantly improved in DHF (+) group (canal paresis: 57.4% in DHF (+) and 100% in DHF (-)). Taken together, the oral administration of DHF may be a novel therapeutic approach for treating vestibular dysfunction in humans.
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26
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Lekk I, Cabrera-Cabrera F, Turconi G, Tuvikene J, Esvald EE, Rähni A, Casserly L, Garton DR, Andressoo JO, Timmusk T, Koppel I. Untranslated regions of brain-derived neurotrophic factor mRNA control its translatability and subcellular localization. J Biol Chem 2023; 299:102897. [PMID: 36639028 PMCID: PMC9943900 DOI: 10.1016/j.jbc.2023.102897] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 01/04/2023] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and growth during development. In the adult nervous system, BDNF is important for synaptic function in several biological processes such as memory formation and food intake. In addition, BDNF has been implicated in development and maintenance of the cardiovascular system. The Bdnf gene comprises several alternative untranslated 5' exons and two variants of 3' UTRs. The effects of these entire alternative UTRs on translatability have not been established. Using reporter and translating ribosome affinity purification analyses, we show that prevalent Bdnf 5' UTRs, but not 3' UTRs, exert a repressive effect on translation. However, contrary to previous reports, we do not detect a significant effect of neuronal activity on BDNF translation. In vivo analysis via knock-in conditional replacement of Bdnf 3' UTR by bovine growth hormone 3' UTR reveals that Bdnf 3' UTR is required for efficient Bdnf mRNA and BDNF protein production in the brain, but acts in an inhibitory manner in lung and heart. Finally, we show that Bdnf mRNA is enriched in rat brain synaptoneurosomes, with higher enrichment detected for exon I-containing transcripts. In conclusion, these results uncover two novel aspects in understanding the function of Bdnf UTRs. First, the long Bdnf 3' UTR does not repress BDNF expression in the brain. Second, exon I-derived 5' UTR has a distinct role in subcellular targeting of Bdnf mRNA.
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Affiliation(s)
- Ingrid Lekk
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | | | - Giorgio Turconi
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jürgen Tuvikene
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Eli-Eelika Esvald
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Annika Rähni
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia,Protobios Llc, Tallinn, Estonia
| | - Laoise Casserly
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Daniel R. Garton
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland,Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jaan-Olle Andressoo
- Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.
| | - Tõnis Timmusk
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia; Protobios Llc, Tallinn, Estonia.
| | - Indrek Koppel
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
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27
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Mukherjee D, Kanold PO. Changing subplate circuits: Early activity dependent circuit plasticity. Front Cell Neurosci 2023; 16:1067365. [PMID: 36713777 PMCID: PMC9874351 DOI: 10.3389/fncel.2022.1067365] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/16/2022] [Indexed: 01/12/2023] Open
Abstract
Early neural activity in the developing sensory system comprises spontaneous bursts of patterned activity, which is fundamental for sculpting and refinement of immature cortical connections. The crude early connections that are initially refined by spontaneous activity, are further elaborated by sensory-driven activity from the periphery such that orderly and mature connections are established for the proper functioning of the cortices. Subplate neurons (SPNs) are one of the first-born mature neurons that are transiently present during early development, the period of heightened activity-dependent plasticity. SPNs are well integrated within the developing sensory cortices. Their structural and functional properties such as relative mature intrinsic membrane properties, heightened connectivity via chemical and electrical synapses, robust activation by neuromodulatory inputs-place them in an ideal position to serve as crucial elements in monitoring and regulating spontaneous endogenous network activity. Moreover, SPNs are the earliest substrates to receive early sensory-driven activity from the periphery and are involved in its modulation, amplification, and transmission before the maturation of the direct adult-like thalamocortical connectivity. Consequently, SPNs are vulnerable to sensory manipulations in the periphery. A broad range of early sensory deprivations alters SPN circuit organization and functions that might be associated with long term neurodevelopmental and psychiatric disorders. Here we provide a comprehensive overview of SPN function in activity-dependent development during early life and integrate recent findings on the impact of early sensory deprivation on SPNs that could eventually lead to neurodevelopmental disorders.
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Affiliation(s)
- Didhiti Mukherjee
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States
| | - Patrick O. Kanold
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States,Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, United States,*Correspondence: Patrick O. Kanold ✉
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28
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Chavushyan VA, Simonyan KV, Danielyan MH, Avetisyan LG, Darbinyan LV, Isoyan AS, Lorikyan AG, Hovhannisyan LE, Babakhanyan MA, Sukiasyan LM. Pathology and prevention of brain microvascular and neuronal dysfunction induced by a high-fructose diet in rats. Metab Brain Dis 2023; 38:269-286. [PMID: 36271967 DOI: 10.1007/s11011-022-01098-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 10/08/2022] [Indexed: 02/03/2023]
Abstract
A high-fructose diet causes metabolic abnormalities in rats, and the cluster of complications points to microvascular and neuronal disorders of the brain. The aim of this study was to evaluate i) the involvement of microvascular disorders and neuronal plasticity in the deleterious effects of a high-fructose diet on the rat brain and ii) a comparative assessment of the effectiveness of Phytocollection therapy (with antidiabetic, antioxidant, and acetylcholinesterase inhibitory activities) compared to Galantamine as first-line therapy for dementia and Diabeton as first-line therapy for hyperglycemia. The calcium adenosine triphosphate non-injection histoangiological method was used to assess capillary network diameter and density. A high-fructose diet resulted in a significant decrease in the diameter and density of the capillary bed, and pharmacological manipulations had a modulatory effect on microcirculatory adaptive mechanisms. In vivo single-unit extracellular recording was used to investigate short-term plasticity in the medial prefrontal cortex. Differences in the parameters of spike background activity and expression of excitatory and inhibitory responses of cortical neurons have been discovered, allowing for flexibility and neuronal function stabilization in pathology and pharmacological prevention. Integration of the coupling mechanism between microvascular function and neuronal spike activity could delay the progressive decline in cognitive function in rats fed a high fructose diet.
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Affiliation(s)
- V A Chavushyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - K V Simonyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia.
| | - M H Danielyan
- Histochemistry and Electron Microscopy Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - L G Avetisyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - L V Darbinyan
- Sensorimotor Integration Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - A S Isoyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - A G Lorikyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
| | - L E Hovhannisyan
- G.S. Davtyan Institute of Hydroponics Problems NAS RA, 0082, Yerevan, Armenia
| | - M A Babakhanyan
- G.S. Davtyan Institute of Hydroponics Problems NAS RA, 0082, Yerevan, Armenia
| | - L M Sukiasyan
- Neuroendocrine Relationships Lab, Orbeli Institute of Physiology NAS RA, 0028, Yerevan, Armenia
- Yerevan State Medical University After M. Heratsi, 0025, Yerevan, Armenia
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29
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Su X, Liu H, Wang X, Pan X, Zhang X, Lu X, Zhao L, Chen Y, Shang Y, Wu F, Xiu M. Neuronavigated Repetitive Transcranial Stimulation Improves Neurocognitive Functioning in Veterans with Schizophrenia: A Possible Role of BDNF Polymorphism. Curr Neuropharmacol 2023; 21:142-150. [PMID: 35927806 PMCID: PMC10193754 DOI: 10.2174/1570159x20666220803154820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/24/2022] [Accepted: 06/02/2022] [Indexed: 02/04/2023] Open
Abstract
It has been reported in the previous literatures that high-frequency (HF) neuronavigated repetitive transcranial magnetic stimulation (rTMS) may improve neurocognitive functioning in patients with schizophrenia. Nonetheless, the heterogeneity of the research findings with regards to the effectiveness of HF-rTMS on the neurocognitive functioning in patients with schizophrenia greatly hinders its clinical application. The current study was designed to determine the predictive role of BDNF variants for neurocognitive improvements after rTMS administration in veterans with schizophrenia. 109 hospitalized veterans with schizophrenia were randomly allocated to active HF-rTMS (n=63) or sham stimulation (n=46) over left DLPFC for 4 consecutive weeks. Neurocognitive functions were assessed by using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at baseline and at the end of week 4. BDNF polymorphism was genotyped by the technicians. Compared with sham stimulation sessions, the immediate memory performance was significantly increased in active sessions after neuronavigated HF-rTMS administration. In addition, patients with the CC homozygotes demonstrated greater improvement of immediate memory after rTMS treatment, while T allele carriers showed no significant improvement in immediate memory domain relative to baseline performance of immediate memory. Our findings suggest that add-on neuronavigated HF-rTMS is beneficial on immediate memory only in patients with CC homozygotes, but not in T allele carriers. This pilot study provides further evidence for BDNF as a promise biomarker in predicting the clinical response to rTMS stimulation.
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Affiliation(s)
- Xiuru Su
- Hebei Province Veterians hospital, Baoding, China
| | - Haixia Liu
- Department of Psychiatry, Shandong Mental Health Center, Shandong University, Jinan, China
| | - Xuan Wang
- Hebei Province Veterians hospital, Baoding, China
| | - Xiuling Pan
- Hebei Province Veterians hospital, Baoding, China
| | - Xuan Zhang
- Hebei Province Veterians hospital, Baoding, China
| | - Xinyan Lu
- Hebei Province Veterians hospital, Baoding, China
| | - Long Zhao
- Hebei Province Veterians hospital, Baoding, China
| | - Yingnan Chen
- Hebei Province Veterians hospital, Baoding, China
| | - Yujie Shang
- Hebei Province Veterians hospital, Baoding, China
| | - Fengchun Wu
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China; Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, China
| | - Meihong Xiu
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
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30
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Nayak M, Das D, Pradhan J, Ahmed R, Laureano-Melo R, Dandapat J. Epigenetic signature in neural plasticity: the journey so far and journey ahead. Heliyon 2022; 8:e12292. [PMID: 36590572 PMCID: PMC9798197 DOI: 10.1016/j.heliyon.2022.e12292] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Neural plasticity is a remarkable characteristic of the brain which allows neurons to rewire their structure in response to internal and external stimuli. Many external stimuli collectively referred to as 'epigenetic factors' strongly influence structural and functional reorganization of the brain, thereby acting as a potential driver of neural plasticity. DNA methylation and demethylation, histone acetylation, and deacetylation are some of the frontline epigenetic mechanisms behind neural plasticity. Epigenetic signature molecules (mostly proteins) play a pivotal role in epigenetic reprogramming. Though neuro-epigenetics is an incredibly important field of emerging research, the critical role of signature proteins associated with epigenetic alteration and their involvement in neural plasticity needs further attention. This study gives an integrated and systematic overview of the current state of knowledge with a clear idea of types of neural plasticity and the context-dependent role of epigenetic signature molecules and their modulation by some natural bioactive compounds.
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Affiliation(s)
- Madhusmita Nayak
- Post-Graduate Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India,Centre of Excellence in Integrated Omics and Computational Biology, Utkal University, Bhubaneswar 751004, Odisha, India
| | - Diptimayee Das
- Post-Graduate Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India,Faculty of Allied Health Science, Chettinad Academy of Research and Education, Chettinad Hospital and Research Institute, Chennai India
| | - Jyotsnarani Pradhan
- Post-Graduate Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India,Corresponding author.
| | - R.G. Ahmed
- Division of Anatomy and Embryology, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Roberto Laureano-Melo
- Barra Mansa University Center, R. Ver. Pinho de Carvalho, 267, 27330-550, Barra Mansa, Rio de Janeiro, Brazil
| | - Jagneshwar Dandapat
- Post-Graduate Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India,Centre of Excellence in Integrated Omics and Computational Biology, Utkal University, Bhubaneswar 751004, Odisha, India,Corresponding author.
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31
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Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations. iScience 2022; 26:105728. [PMID: 36582822 PMCID: PMC9793278 DOI: 10.1016/j.isci.2022.105728] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/25/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
In Neurodevelopmental Disorders, alterations of synaptic plasticity may trigger structural changes in neuronal circuits involved in cognitive functions. This hypothesis was tested in mice carrying the human R451C mutation of Nlgn3 gene (NLG3R451C KI), found in some families with autistic children. To this aim, the spike time dependent plasticity (STDP) protocol was applied to immature GABAergic Mossy Fibers (MF)-CA3 connections in hippocampal slices from NLG3R451C KI mice. These animals failed to exhibit STD-LTP, an effect that persisted in adulthood when these synapses became glutamatergic. Similar results were obtained in mice lacking the Nlgn3 gene (NLG3 KO mice), suggesting a loss of function. The loss of STD-LTP was associated with a premature shift of GABA from the depolarizing to the hyperpolarizing direction, a reduced BDNF availability and TrkB phosphorylation at potentiated synapses. These effects may constitute a general mechanism underlying cognitive deficits in those forms of Autism caused by synaptic dysfunctions.
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32
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Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders. Brain Sci 2022; 12:brainsci12121666. [PMID: 36552127 PMCID: PMC9775399 DOI: 10.3390/brainsci12121666] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/22/2022] [Accepted: 11/29/2022] [Indexed: 12/09/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses.
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33
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Effects of Subchronic Aluminum Exposure on Learning, Memory, and Neurotrophic Factors in Rats. Neurotox Res 2022; 40:2046-2060. [PMID: 36342585 DOI: 10.1007/s12640-022-00599-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022]
Abstract
Aluminum (Al) is a neurotoxin that gradually accumulates in the brain in human life, resulting in oxidative brain injury related to Alzheimer's disease (AD) and other diseases. In this study, the learning and memory of rats exposed to different aluminum concentrations (0.0 g/L, 2.0 g/L, 4.0 g/L, and 8.0 g/L) were studied, and the learning and memory of rats were observed by shuttle box experiment. With hematoxylin and eosin staining, Western blot, immunofluorescence, and RT-PCR, the morphology of nerve cells in the hippocampus of rat brain were observed, and the levels of activator protein-1 (AP-1) gene and protein, nerve growth factor (NGF), neurotrophin-3 (NT3), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) gene and protein level, etc. The experimental results showed that subchronic aluminum exposure damaged learning and memory in rats. The cognitive function damage in rats was more evident after increasing the aluminum intake dose. The more aluminum intake, the more pronounced the histological changes in the hippocampus will be. The expression level and protein content of neurotrophic factors in the hippocampus of rats showed a negative correlation with aluminum intake. In this experiment, we explored the mechanism of aluminum exposure in learning and memory disorders, and provided some data reference for further elucidation of the damage mechanism of aluminum on the nervous system and subsequent preventive measures.
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Cutuli D, Sampedro-Piquero P. BDNF and its Role in the Alcohol Abuse Initiated During Early Adolescence: Evidence from Preclinical and Clinical Studies. Curr Neuropharmacol 2022; 20:2202-2220. [PMID: 35748555 PMCID: PMC9886842 DOI: 10.2174/1570159x20666220624111855] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 02/23/2022] [Accepted: 04/19/2022] [Indexed: 11/22/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a crucial brain signaling protein that is integral to many signaling pathways. This neurotrophin has shown to be highly involved in brain plastic processes such as neurogenesis, synaptic plasticity, axonal growth, and neurotransmission, among others. In the first part of this review, we revise the role of BDNF in different neuroplastic processes within the central nervous system. On the other hand, its deficiency in key neural circuits is associated with the development of psychiatric disorders, including alcohol abuse disorder. Many people begin to drink alcohol during adolescence, and it seems that changes in BDNF are evident after the adolescent regularly consumes alcohol. Therefore, the second part of this manuscript addresses the involvement of BDNF during adolescent brain maturation and how this process can be negatively affected by alcohol abuse. Finally, we propose different BNDF enhancers, both behavioral and pharmacological, which should be considered in the treatment of problematic alcohol consumption initiated during the adolescence.
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Affiliation(s)
- Debora Cutuli
- Department of Psychology, Medicine and Psychology Faculty, University Sapienza of Rome, Rome, Italy; ,I.R.C.C.S. Fondazione Santa Lucia, Laboratorio di Neurofisiologia Sperimentale e del Comportamento, Via del Fosso di Fiorano 64, 00143 Roma, Italy; ,Address correspondence to these authors at the Department of Biological and Health Psychology, Psychology Faculty, Autonomous University of Madrid, Madrid, Spain, Spain and Cutuli, D. at Fondazione Santa Lucia. Laboratorio di Neurofisiologia Sperimentale e del Comportamento. Via del Fosso di Fiorano 64, 00143 Roma, Italy; E-mails: ;
| | - Piquero Sampedro-Piquero
- Department of Biological and Health Psychology, Psychology Faculty, Autonomous University of Madrid, Madrid, Spain,Address correspondence to these authors at the Department of Biological and Health Psychology, Psychology Faculty, Autonomous University of Madrid, Madrid, Spain, Spain and Cutuli, D. at Fondazione Santa Lucia. Laboratorio di Neurofisiologia Sperimentale e del Comportamento. Via del Fosso di Fiorano 64, 00143 Roma, Italy; E-mails: ;
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Li Y, Li F, Qin D, Chen H, Wang J, Wang J, Song S, Wang C, Wang Y, Liu S, Gao D, Wang ZH. The role of brain derived neurotrophic factor in central nervous system. Front Aging Neurosci 2022; 14:986443. [PMID: 36158555 PMCID: PMC9493475 DOI: 10.3389/fnagi.2022.986443] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/23/2022] [Indexed: 11/15/2022] Open
Abstract
Brain derived neurotrophic factor (BDNF) has multiple biological functions which are mediated by the activation of two receptors, tropomyosin receptor kinase B (TrkB) receptor and the p75 neurotrophin receptor, involving in physiological and pathological processes throughout life. The diverse presence and activity of BDNF indicate its potential role in the pathogenesis, progression and treatment of both neurological and psychiatric disorders. This review is to provide a comprehensive assessment of the current knowledge and future directions in BDNF-associated research in the central nervous system (CNS), with an emphasis on the physiological and pathological functions of BDNF as well as its potential treatment effects in CNS diseases, including depression, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and cerebral ischemic stroke.
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Affiliation(s)
- Yiyi Li
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang Li
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dongdong Qin
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongyu Chen
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jianhao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiabei Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shafei Song
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yamei Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Songyan Liu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dandan Gao
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhi-Hao Wang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
- Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China
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Rentería I, García-Suárez PC, Fry AC, Moncada-Jiménez J, Machado-Parra JP, Antunes BM, Jiménez-Maldonado A. The Molecular Effects of BDNF Synthesis on Skeletal Muscle: A Mini-Review. Front Physiol 2022; 13:934714. [PMID: 35874524 PMCID: PMC9306488 DOI: 10.3389/fphys.2022.934714] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
The brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which is generated mainly by the brain. Its main role involve synaptic modulation, neurogenesis, neuron survival, immune regulation, myocardial contraction, and angiogenesis in the brain. Together with the encephalon, some peripheral tissues synthesize BDNF like skeletal muscle. On this tissue, this neurotrophin participates on cellular mechanisms related to muscle function maintenance and plasticity as reported on recent scientific works. Moreover, during exercise stimuli the BDNF contributes directly to strengthening neuromuscular junctions, muscle regeneration, insulin-regulated glucose uptake and β-oxidation processes in muscle tissue. Given its vital relevance on many physiological mechanisms, the current mini-review focuses on discussing up-to-date knowledge about BDNF production in skeletal muscle and how this neurotrophin impacts skeletal muscle biology.
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Affiliation(s)
- I Rentería
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - P C García-Suárez
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico.,Department of Health, Sports and Exercise Sciences, University of Kansas, Lawrence, KS, United States
| | - A C Fry
- Department of Health, Sports and Exercise Sciences, University of Kansas, Lawrence, KS, United States
| | - J Moncada-Jiménez
- Human Movement Sciences Research Center (CIMOHU), University of Costa Rica, San José, Costa Rica
| | - J P Machado-Parra
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - B M Antunes
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
| | - A Jiménez-Maldonado
- Facultad de Deportes, Universidad Autónoma de Baja California, Ensenada, Mexico
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Vints WAJ, Levin O, Fujiyama H, Verbunt J, Masiulis N. Exerkines and long-term synaptic potentiation: Mechanisms of exercise-induced neuroplasticity. Front Neuroendocrinol 2022; 66:100993. [PMID: 35283168 DOI: 10.1016/j.yfrne.2022.100993] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 03/03/2022] [Accepted: 03/06/2022] [Indexed: 01/30/2023]
Abstract
Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.
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Affiliation(s)
- Wouter A J Vints
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands; Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, 6430 AB Hoensbroek, the Netherlands.
| | - Oron Levin
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Movement Control & Neuroplasticity Research Group, Group Biomedical Sciences, Catholic University Leuven, Tervuursevest 101, 3001 Heverlee, Belgium.
| | - Hakuei Fujiyama
- Department of Psychology, Murdoch University, 90 South St., WA 6150 Perth, Australia; Centre for Healthy Ageing, Health Futures Institute, Murdoch University, 90 South St., WA 6150 Perth, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, 90 South St., WA 6150 Perth, Australia.
| | - Jeanine Verbunt
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands; Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, 6430 AB Hoensbroek, the Netherlands.
| | - Nerijus Masiulis
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Department of Rehabilitation, Physical and Sports Medicine, Institute of Health Science, Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, LT-03101 Vilnius, Lithuania.
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Covaceuszach S, Peche LY, Konarev PV, Grdadolnik J, Cattaneo A, Lamba D. Untangling the Conformational Plasticity of V66M Human proBDNF Polymorphism as a Modifier of Psychiatric Disorder Susceptibility. Int J Mol Sci 2022; 23:ijms23126596. [PMID: 35743044 PMCID: PMC9224406 DOI: 10.3390/ijms23126596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/10/2022] [Accepted: 06/11/2022] [Indexed: 01/27/2023] Open
Abstract
The human genetic variant BDNF (V66M) represents the first example of neurotrophin family member that has been linked to psychiatric disorders. In order to elucidate structural differences that account for the effects in cognitive function, this hproBDNF polymorph was expressed, refolded, purified, and compared directly to the WT variant for the first time for differences in their 3D structures by DSF, limited proteolysis, FT-IR, and SAXS measurements in solution. Our complementary studies revealed a deep impact of V66M polymorphism on hproBDNF conformations in solution. Although the mean conformation in solution appears to be more compact in the V66M variant, overall, we demonstrated a large increase in flexibility in solution upon V66M mutation. Thus, considering that plasticity in IDR is crucial for protein function, the observed alterations may be related to the functional alterations in hproBDNF binding to its receptors p75NTR, sortilin, HAP1, and SorCS2. These effects can provoke altered intracellular neuronal trafficking and/or affect proBDNF physiological functions, leading to many brain-associated diseases and conditions such as cognitive impairment and anxiety. The structural alterations highlighted in the present study may pave the way to the development of drug discovery strategies to provide greater therapeutic responses and of novel pharmacologic strategy in human populations with this common polymorphism, ultimately guiding personalized medicine for neuropsychiatric disorders.
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Affiliation(s)
- Sonia Covaceuszach
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, Italy;
- Correspondence: (S.C.); (D.L.)
| | - Leticia Yamila Peche
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, Italy;
| | - Petr Valeryevich Konarev
- A.V. Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics” of Russian Academy of Sciences, 119333 Moscow, Russia;
| | - Joze Grdadolnik
- Laboratory for Molecular Structural Dynamics, Theory Department, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia;
| | - Antonino Cattaneo
- European Brain Research Institute, 00161 Roma, Italy;
- Scuola Normale Superiore, 56126 Pisa, Italy
| | - Doriano Lamba
- Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, 34149 Trieste, Italy;
- Consorzio Interuniversitario “Istituto Nazionale Biostrutture e Biosistemi”, 00136 Roma, Italy
- Correspondence: (S.C.); (D.L.)
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Morais FA, Lemos IS, Matiola RT, Freitas MLS, Alano CG, Cabral J, Wessler LB, Generoso JS, Scaini G, Réus GZ, Streck EL. Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease. Metab Brain Dis 2022; 37:1585-1596. [PMID: 35394251 DOI: 10.1007/s11011-022-00969-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/21/2022] [Indexed: 10/18/2022]
Abstract
Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.
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Affiliation(s)
- Fábio A Morais
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Isabela S Lemos
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Rafaela T Matiola
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Maria Luísa S Freitas
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Carolina G Alano
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Julia Cabral
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Leticia B Wessler
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Jaqueline S Generoso
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Giselli Scaini
- Laboratório de Fisiopatologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Gislaine Z Réus
- Laboratório de Psiquiatria Translacional, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil
| | - Emilio L Streck
- Laboratório de Doenças Neurometabólicas, Laboratório de Neurologia Experimental, Programa de Pós-Graduação Em Ciências da Saúde, Universidade Do Extremo Sul Catarinense, Criciúma, SC, Brasil.
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BDNF and Pro-BDNF in Amyotrophic Lateral Sclerosis: A New Perspective for Biomarkers of Neurodegeneration. Brain Sci 2022; 12:brainsci12050617. [PMID: 35625004 PMCID: PMC9139087 DOI: 10.3390/brainsci12050617] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/28/2022] [Accepted: 05/06/2022] [Indexed: 02/01/2023] Open
Abstract
Amyotrophic Lateral Sclerosis (ALS) is characterized by the progressive degeneration of upper or lower motor neurons, leading to muscle wasting and paralysis, resulting in respiratory failure and death. The precise ALS aetiology is poorly understood, mainly due to clinical and genetic heterogeneity. Thus, the identification of reliable biomarkers of disease could be helpful in clinical practice. In this study, we investigated whether the levels of brain-derived neurotrophic factor (BDNF) and its precursor Pro-BDNF in serum and cerebrospinal fluid (CSF) may reflect the pathological changes related to ALS. We found higher BDNF and lower Pro-BDNF levels in ALS sera compared to healthy controls. BDNF/Pro-BDNF ratio turned out to be accurate in distinguishing ALS patients from controls. Then, the correlations of these markers with several ALS clinical variables were evaluated. This analysis revealed three statistically significant associations: (1) Patients carrying the C9orf72 expansion significantly differed from non-carrier patients and showed serum BDNF levels comparable to control subjects; (2) BDNF levels in CSF were significantly higher in ALS patients with faster disease progression; (3) lower serum levels of Pro-BDNF were associated with a shorter survival. Therefore, we suggest that BDNF and Pro-BDNF, alone or in combination, might be used as ALS prognostic biomarkers.
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Omar NA, Kumar J, Teoh SL. Neurotrophin-3 and neurotrophin-4: The unsung heroes that lies behind the meninges. Neuropeptides 2022; 92:102226. [PMID: 35030377 DOI: 10.1016/j.npep.2022.102226] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 12/06/2021] [Accepted: 01/04/2022] [Indexed: 11/17/2022]
Abstract
Neurotrophin is a growth factor that regulates the development and repair of the nervous system. From all factors, two pioneer groups, the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), have been widely explored for their role in disease pathogenesis and potential use as therapeutic agents. Nonetheless, neurotrophin-3 (NT3) and neurotrophin-4 (NT4) also have promising potential, albeit less popular than their counterparts. This review focuses on the latter two factors and their roles in the pathogenesis of brain disorders and potential therapies. An extensive literature search of NT3 and NT4 with their receptors, the TrkB and TrkC on the nervous system were extracted and analyzed. We found that NT3 and NT4 are not only involved in the pathogenesis of some neurodegenerative diseases, but also have promising therapeutic potential on injury- and vascular-related nervous system disease, neuropsychiatry, neurodegeneration and peripheral nerve diseases. In conclusion, the role of NT3 and NT4 should be further emphasized, and more studies could be explored on the potential use of these neurotrophins in the human study.
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Affiliation(s)
- Noor Azzizah Omar
- Department of Anatomy, Universiti Kebangsaan Malaysia Medical Centre, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; Department of Medical Sciences, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, 71800 Nilai, Negeri Sembilan, Malaysia.
| | - Jaya Kumar
- Department of Physiology, Universiti Kebangsaan Malaysia Medical Centre, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia.
| | - Seong Lin Teoh
- Department of Anatomy, Universiti Kebangsaan Malaysia Medical Centre, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia.
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Madhusudhan U, M K, Singaravelu V, Ganji V, John N, Gaur A. Brain-Derived Neurotrophic Factor-Mediated Cognitive Impairment in Hypothyroidism. Cureus 2022; 14:e23722. [PMID: 35506116 PMCID: PMC9056880 DOI: 10.7759/cureus.23722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2022] [Indexed: 11/16/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF), which is expressed at high levels in the limbic system, has been shown to regulate learning, memory and cognition. Thyroid hormone is crucial for brain development. Hypothyroidism is a clinical condition in which thyroid hormones are reduced and it affects the growth and development of the brain in neonates and progresses to cognitive impairment in adults. The exact mechanism of how reduced thyroid hormones impairs cognition and memory is not well understood. This review explores the possible role of BDNF-mediated cognitive impairment in hypothyroid patients.
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Reis PA, Castro-Faria-Neto HC. Systemic Response to Infection Induces Long-Term Cognitive Decline: Neuroinflammation and Oxidative Stress as Therapeutical Targets. Front Neurosci 2022; 15:742158. [PMID: 35250433 PMCID: PMC8895724 DOI: 10.3389/fnins.2021.742158] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/31/2021] [Indexed: 12/29/2022] Open
Abstract
In response to pathogens or damage signs, the immune system is activated in order to eliminate the noxious stimuli. The inflammatory response to infectious diseases induces systemic events, including cytokine storm phenomenon, vascular dysfunction, and coagulopathy, that can lead to multiple-organ dysfunction. The central nervous system (CNS) is one of the major organs affected, and symptoms such as sickness behavior (depression and fever, among others), or even delirium, can be observed due to activation of endothelial and glial cells, leading to neuroinflammation. Several reports have been shown that, due to CNS alterations caused by neuroinflammation, some sequels can be developed in special cognitive decline. There is still no any treatment to avoid cognitive impairment, especially those developed due to systemic infectious diseases, but preclinical and clinical trials have pointed out controlling neuroinflammatory events to avoid the development of this sequel. In this minireview, we point to the possible mechanisms that triggers long-term cognitive decline, proposing the acute neuroinflammatory events as a potential therapeutical target to treat this sequel that has been associated to several infectious diseases, such as malaria, sepsis, and, more recently, the new SARS-Cov2 infection.
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Affiliation(s)
- Patricia Alves Reis
- Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
- Biochemistry Department, Roberto Alcântara Gomes Biology Institute, Rio de Janeiro State University, Rio de Janeiro, Brazil
- *Correspondence: Patricia Alves Reis,
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Muthu SJ, Lakshmanan G, Seppan P. Influence of Testosterone depletion on Neurotrophin-4 in Hippocampal synaptic plasticity and its effects on learning and memory. Dev Neurosci 2022; 44:102-112. [PMID: 35086088 DOI: 10.1159/000522201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/22/2022] [Indexed: 11/19/2022] Open
Abstract
Sex steroids are neuromodulators that play a crucial role in learning, memory, and synaptic plasticity, providing circuit flexibility and dynamic functional connectivity in mammals. Previous studies indicate that testosterone is crucial for neuronal functions and required further investigation on various frontiers. However, it is surprising to note that studies on testosterone-induced NT-4 expression and its influence on synaptic plasticity and learning and memory moderation are scanty. The present study is focused on analyzing the localized influence of neurotrophin-4 (NT4) on hippocampal synaptic plasticity and associated moderation in learning and memory under testosterone deprivation. Adult Wistar albino rats were randomly divided into various groups, control (Cont), orchidectomy (ORX), orchidectomy + testosterone supplementation (ORX+T) and control + testosterone (Cont+T). After two weeks, the serum testosterone level was undetectable in ORX rats. The behavioural assessment showed a decline in the learning ability of ORX rats with increased working and reference memory errors in the behavioural assessment in the 8-arm radial maze. The mRNA and protein expressions of NT-4 and androgen receptors were significantly reduced in the ORX group. In addition, there was a decrease in the number of neuronal dendrites in Golgi-Cox staining. These changes were not seen in ORX+T rats with improved learning behaviour. Indicating that testosterone exerts its protective effect on hippocampal synaptic plasticity through androgen receptor-dependent neurotrophin-4 regulation in learning and memory upgrade.
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Affiliation(s)
- Sakthi Jothi Muthu
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
| | - Ganesh Lakshmanan
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
| | - Prakash Seppan
- Department of Anatomy, Dr. Arcot Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
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45
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Kikuta S, Kuboki A, Yamasoba T. Protective Effect of Insulin in Mouse Nasal Mucus Against Olfactory Epithelium Injury. Front Neural Circuits 2022; 15:803769. [PMID: 35002636 PMCID: PMC8733614 DOI: 10.3389/fncir.2021.803769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/26/2021] [Indexed: 11/15/2022] Open
Abstract
Insulin is present in nasal mucus and plays an important role in the survival and activity of individual olfactory sensory neurons (OSNs) via insulin receptor-mediated signaling. However, it is unclear whether insulin acts prophylactically against olfactotoxic drug-induced olfactory epithelium (OE) injury, and whether the degree of damage is affected by the concentration of insulin in the nasal mucus. The apoptosis-inducing drug methimazole was administered to the nasal mucus of diabetic and normal mice along with different concentrations of insulin. Immunohistochemical analysis was used to assess the relationship between damage to the OE and the mucus insulin concentration and the protective effect of insulin administration against eosinophilic cationic protein (ECP)-induced OE injury. Diabetic mice had lower concentrations of insulin in their nasal mucus than normal mice (diabetic vs. normal mice, p < 0.001). Methimazole administration reduced the number of OSNs in normal mice and had a more marked effect in diabetic mice. However, unilateral insulin administration prevented the methimazole-induced reduction in the number of OSNs on the ipsilateral side but not on the contralateral side (OSNs; Insulin vs. contralateral side, p < 0.001). Furthermore, intranasal ECP administration damaged the OE by inducing apoptosis (OSNs; ECP vs. contralateral side, p < 0.001), but this damage was largely prevented by insulin administration (OSNs; Insulin + ECP vs. contralateral side, p = 0.36), which maintained the number of mature OSNs. The severity of methimazole-induced damage to the OE is related to the insulin concentration in the nasal mucus (Correlation between the insulin concentration in nasal mucus and the numbers of OSNs, R2 = 0.91, p < 0.001), which may imply that nasal insulin protects OSNs and that insulin administration might lead to the development of new therapeutic agents for ECP-induced OE injury.
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Affiliation(s)
- Shu Kikuta
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo, Japan
| | - Akihito Kuboki
- Department of Otorhinolaryngology, The Jikei University School of Medicine, Minato, Japan
| | - Tatsuya Yamasoba
- Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo, Japan
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Pandey S, Mudgal J. A Review on the Role of Endogenous Neurotrophins and Schwann Cells in Axonal Regeneration. J Neuroimmune Pharmacol 2022; 17:398-408. [PMID: 34843075 PMCID: PMC9810669 DOI: 10.1007/s11481-021-10034-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 11/13/2021] [Indexed: 01/13/2023]
Abstract
Injury to the peripheral nerve is traditionally referred to acquired nerve injury as they are the result of physical trauma due to laceration, stretch, crush and compression of nerves. However, peripheral nerve injury may not be completely limited to acquired physical trauma. Peripheral nerve injury equally implies clinical conditions like Guillain-Barré syndrome (GBS), Carpal tunnel syndrome, rheumatoid arthritis and diabetes. Physical trauma is commonly mono-neuropathic as it engages a single nerve and produces focal damage, while in the context of pathological conditions the damage is divergent involving a group of the nerve causing polyneuropathy. Damage to the peripheral nerve can cause a diverse range of manifestations from sensory impairment to loss of function with unpredictable recovery patterns. Presently no treatment option provides complete or functional recovery in nerve injury, as nerve cells are highly differentiated and inert to regeneration. However, the regenerative phenotypes in Schwann cells get expressed when a signalling cascade is triggered by neurotrophins. Neurotrophins are one of the promising biomolecules that are released naturally post-injury with the potential to exhibit better functional recovery. Pharmacological intervention modulating the expression of these neurotrophins such as brain-derived neurotrophic factor (BDNF) and pituitary adenylyl cyclase-activating peptide (PACAP) can prove to be a significant treatment option as endogenous compounds which may have remarkable innate advantage showing maximum 'biological relevance'.
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Affiliation(s)
- Samyak Pandey
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104.
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Wada N, Karnup S, Kadekawa K, Shimizu N, Kwon J, Shimizu T, Gotoh D, Kakizaki H, de Groat W, Yoshimura N. Current knowledge and novel frontiers in lower urinary tract dysfunction after spinal cord injury: Basic research perspectives. UROLOGICAL SCIENCE 2022; 33:101-113. [PMID: 36177249 PMCID: PMC9518811 DOI: 10.4103/uros.uros_31_22] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
This review article aims to summarize the recent advancement in basic research on lower urinary tract dysfunction (LUTD) following spinal cord injury (SCI) above the sacral level. We particularly focused on the neurophysiologic mechanisms controlling the lower urinary tract (LUT) function and the SCI-induced changes in micturition control in animal models of SCI. The LUT has two main functions, the storage and voiding of urine, that are regulated by a complex neural control system. This neural system coordinates the activity of two functional units in the LUT: the urinary bladder and an outlet including bladder neck, urethra, and striated muscles of the pelvic floor. During the storage phase, the outlet is closed and the bladder is quiescent to maintain a low intravesical pressure and continence, and during the voiding phase, the outlet relaxes and the bladder contracts to promote efficient release of urine. SCI impairs voluntary control of voiding as well as the normal reflex pathways that coordinate bladder and sphincter function. Following SCI, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. However, the bladder does not empty efficiently because coordination between the bladder and urethral sphincter is lost. In animal models of SCI, hyperexcitability of silent C-fiber bladder afferents is a major pathophysiological basis of neurogenic LUTD, especially detrusor overactivity. Reflex plasticity is associated with changes in the properties of neuropeptides, neurotrophic factors, or chemical receptors of afferent neurons. Not only C-fiber but also Aδ-fiber could be involved in the emergence of neurogenic LUTD such as detrusor sphincter dyssynergia following SCI. Animal research using disease models helps us to detect the different contributing factors for LUTD due to SCI and to find potential targets for new treatments.
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Klaus B, Müller P, van Wickeren N, Dordevic M, Schmicker M, Zdunczyk Y, Brigadski T, Leßmann V, Vielhaber S, Schreiber S, Müller NG. OUP accepted manuscript. Brain Commun 2022; 4:fcac018. [PMID: 35198977 PMCID: PMC8856136 DOI: 10.1093/braincomms/fcac018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/05/2021] [Accepted: 01/31/2022] [Indexed: 11/14/2022] Open
Abstract
Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described. However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients. Eleven myasthenia gravis patients (age: 70.64 ± 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 ± 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors. Structural brain changes were determined by applying voxel-based morphometry using high-resolution T1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels. Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200). Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions. Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.
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Affiliation(s)
- Benita Klaus
- Correspondence to: Benita Klaus German Center for Neurodegenerative Diseases (DZNE) Leipziger Str 44 Haus 64, D-39120 Magdeburg, Germany E-mail:
| | - Patrick Müller
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Nora van Wickeren
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Milos Dordevic
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Marlen Schmicker
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
| | - Yael Zdunczyk
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
| | - Tanja Brigadski
- Institute of Physiology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Department of Informatics and Microsystems Technology, University of Kaiserslautern, 67659 Zweibrücken, Germany
| | - Volkmar Leßmann
- Institute of Physiology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), 39120 Magdeburg, Germany
| | - Stefan Vielhaber
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), 39120 Magdeburg, Germany
| | - Stefanie Schreiber
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Center for Behavioral Brain Sciences (CBBS), 39120 Magdeburg, Germany
| | - Notger G. Müller
- German Centre for Neurodegenerative Diseases, 39120 Magdeburg, Germany
- Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany
- Faculty of Health Sciences, University of Potsdam, 14476 Potsdam, Germany
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Naletova I, Greco V, Sciuto S, Attanasio F, Rizzarelli E. Ionophore Ability of Carnosine and Its Trehalose Conjugate Assists Copper Signal in Triggering Brain-Derived Neurotrophic Factor and Vascular Endothelial Growth Factor Activation In Vitro. Int J Mol Sci 2021; 22:13504. [PMID: 34948299 PMCID: PMC8706131 DOI: 10.3390/ijms222413504] [Citation(s) in RCA: 1] [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: 10/25/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 12/11/2022] Open
Abstract
l-carnosine (β-alanyl-l-histidine) (Car hereafter) is a natural dipeptide widely distributed in mammalian tissues and reaching high concentrations (0.7-2.0 mM) in the brain. The molecular features of the dipeptide underlie the antioxidant, anti-aggregating and metal chelating ability showed in a large number of physiological effects, while the biological mechanisms involved in the protective role found against several diseases cannot be explained on the basis of the above-mentioned properties alone, requiring further research efforts. It has been reported that l-carnosine increases the secretion and expression of various neurotrophic factors and affects copper homeostasis in nervous cells inducing Cu cellular uptake in keeping with the key metal-sensing system. Having in mind this l-carnosine ability, here we report the copper-binding and ionophore ability of l-carnosine to activate tyrosine kinase cascade pathways in PC12 cells and stimulate the expression of BDNF. Furthermore, the study was extended to verify the ability of the dipeptide to favor copper signaling inducing the expression of VEGF. Being aware that the potential protective action of l-carnosine is drastically hampered by its hydrolysis, we also report on the behavior of a conjugate of l-carnosine with trehalose that blocks the carnosinase degradative activity. Overall, our findings describe a copper tuning effect on the ability of l-carnosine and, particularly its conjugate, to activate tyrosine kinase cascade pathways.
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Affiliation(s)
- Irina Naletova
- Institute of Crystallography, National Council of Research—CNR, Via Paolo Gaifami 18, 95126 Catania, Italy;
- National Inter-University Consortium Metals Chemistry in Biological Systems (CIRCMSB), Via Celso Ulpiani 27, 70126 Bari, Italy
| | - Valentina Greco
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; (V.G.); (S.S.)
| | - Sebastiano Sciuto
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; (V.G.); (S.S.)
| | - Francesco Attanasio
- Institute of Crystallography, National Council of Research—CNR, Via Paolo Gaifami 18, 95126 Catania, Italy;
| | - Enrico Rizzarelli
- Institute of Crystallography, National Council of Research—CNR, Via Paolo Gaifami 18, 95126 Catania, Italy;
- National Inter-University Consortium Metals Chemistry in Biological Systems (CIRCMSB), Via Celso Ulpiani 27, 70126 Bari, Italy
- Department of Chemical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; (V.G.); (S.S.)
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Neurotrophic factors combined with stem cells in the treatment of sciatic nerve injury in rats:a meta-analysis. Biosci Rep 2021; 42:230438. [PMID: 34897384 PMCID: PMC8762346 DOI: 10.1042/bsr20211399] [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] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 11/02/2021] [Accepted: 12/09/2021] [Indexed: 12/02/2022] Open
Abstract
Treatment of peripheral nerve regeneration with stem cells (SCs) alone has some limitations. For this reason, we evaluate the efficacy of neurotrophic factors combined with stem cell transplantation in the treatment of sciatic nerve injury (SNI) in rats. PubMed, Cochrane Library, Embase, WanFang, VIP and China National Knowledge Infrastructure databases were retrieved from inception to October 2021, and control experiments on neurotrophic factors combined with stem cells in the treatment of SNI in rats were searched. Nine articles and 551 rats were included in the meta-analysis. The results of meta-analysis confirmed that neurotrophic factor combined with stem cells for the treatment of SNI yielded more effective repair than normal rats with regard to sciatic nerve index, electrophysiological detection index, electron microscope observation index, and recovery rate of muscle wet weight. The conclusion is that neurotrophic factor combined with stem cells is more conducive to peripheral nerve regeneration and functional recovery than stem cells alone. However, due to the limitation of the quality of the included literature, the above conclusions need to be verified by randomized controlled experiments with higher quality and larger samples.
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