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Song YN, Xia S, Sun Z, Chen YC, Jiao L, Wan WH, Zhang HW, Guo X, Guo H, Jia SF, Li XX, Cao SX, Fu LB, Liu MM, Zhou T, Zhang LF, Jia QQ. Metabolic pathway modulation by olanzapine: Multitarget approach for treating violent aggression in patients with schizophrenia. World J Psychiatry 2025; 15:101186. [PMID: 39831024 PMCID: PMC11684224 DOI: 10.5498/wjp.v15.i1.101186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 11/05/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND The use of network pharmacology and blood metabolomics to study the pathogenesis of violent aggression in patients with schizophrenia and the related drug mechanisms of action provides new directions for reducing the risk of violent aggression and optimizing treatment plans. AIM To explore the metabolic regulatory mechanism of olanzapine in treating patients with schizophrenia with a moderate to high risk of violent aggression. METHODS Metabolomic technology was used to screen differentially abundant metabolites in patients with schizophrenia with a moderate to high risk of violent aggression before and after olanzapine treatment, and the related metabolic pathways were identified. Network pharmacology was used to establish protein-protein interaction networks of the core targets of olanzapine. Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were subsequently performed. RESULTS Compared with the healthy group, the patients with schizophrenia group presented significant changes in the levels of 24 metabolites related to the disruption of 9 metabolic pathways, among which the key pathways were the alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. After treatment with olanzapine, the levels of 10 differentially abundant metabolites were significantly reversed in patients with schizophrenia. Olanzapine effectively regulated six metabolic pathways, among which the key pathways were alanine, aspartate and glutamate metabolism and arginine biosynthesis pathways. Ten core targets of olanzapine were involved in several key pathways. CONCLUSION The metabolic pathways of alanine, aspartate, and glutamate metabolism and arginine biosynthesis are the key pathways involved in olanzapine treatment for aggressive schizophrenia.
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Affiliation(s)
- Yan-Ning Song
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shuang Xia
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Zhi Sun
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yong-Chao Chen
- Department of Pharmacy, Zhumadian First People's Hospital, Zhumadian 463000, Henan Province, China
| | - Lu Jiao
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Wen-Hua Wan
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Hong-Wei Zhang
- Scientific Education Section, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Xiao Guo
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Hua Guo
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shou-Feng Jia
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Xiao-Xin Li
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Shi-Xian Cao
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Li-Bin Fu
- Department of Pharmacy, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Meng-Meng Liu
- Clinical Laboratory, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Tian Zhou
- Publicity Division, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Lv-Feng Zhang
- Department of Psychiatry, The Affiliated Encephalopathy Hospital of Zhengzhou University (Zhumadian Second People's Hospital), Zhumadian 463000, Henan Province, China
| | - Qing-Quan Jia
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Diana MC, Peres FF, Justi V, Bressan RA, Lacerda ALT, Crippa JA, Hallak JEC, Abilio VC. Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia-related behaviors in an animal model: The SHR strain. CNS Neurosci Ther 2018; 24:624-632. [PMID: 29656549 DOI: 10.1111/cns.12852] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/20/2018] [Accepted: 03/10/2018] [Indexed: 12/16/2022] Open
Abstract
AIMS The treatment of schizophrenia with antipsychotics is still unsatisfactory. Therefore, the search for new treatments and prevention is crucial, and animal models are fundamental tools for this objective. Preclinical and clinical data evidence the antipsychotic profile of sodium nitroprusside (SNP), a nitric oxide (NO) donor. We aimed to investigate SNP in treating and/or preventing the schizophrenia-related behaviors presented by the spontaneously hypertensive rats (SHR) strain. METHODS Wistar rats (WR) and SHRs were submitted to two schemes of treatment: (i) a single injection of SNP or vehicle in adulthood; (ii) a long-term early treatment from 30 to 60 postnatal day with SNP or vehicle. The following behaviors were evaluated 24 hours after the acute treatment or 30 days after the long-term treatment: locomotion, social interaction, and contextual fear conditioning. RESULTS Spontaneously hypertensive rats presented hyperlocomotion, decreased social interaction, and impaired contextual fear conditioning. Single injection of SNP decreased social interaction in both strains and induced a deficit in contextual fear conditioning in WR. Oppositely, early treatment with SNP prevented the behavioral abnormalities in adult SHRs without promoting any effects in WR. CONCLUSION Our preclinical data point to SNP as a preventive and safe strategy with a broad range of effectiveness to the positive, negative, and cognitive symptoms of schizophrenia.
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Affiliation(s)
- Mariana C Diana
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil
| | - Fernanda F Peres
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil
| | - Veronica Justi
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil
| | - Rodrigo A Bressan
- LiNC-Laboratório Interdisciplinar de Neurociências Clínicas, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil
| | - Acioly L T Lacerda
- National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil.,LiNC-Laboratório Interdisciplinar de Neurociências Clínicas, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil
| | - José Alexandre Crippa
- National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil.,Department of Neurosciences and Behaviour, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Jaime E C Hallak
- National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil.,Department of Neurosciences and Behaviour, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Vanesssa Costhek Abilio
- Behavioral Neuroscience Laboratory, Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.,National Institute for Translational Medicine (INCT-TM, CNPq/FAPESP/CAPES), Ribeirão Preto, Brazil
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Chakroborty S, Geisbush TR, Dale E, Pehrson AL, Sánchez C, West AR. Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram. Front Pharmacol 2017; 8:764. [PMID: 29123483 PMCID: PMC5662919 DOI: 10.3389/fphar.2017.00764] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/11/2017] [Indexed: 11/28/2022] Open
Abstract
Prefrontal-subcortical circuits support executive functions which often become dysfunctional in psychiatric disorders. Vortioxetine is a multimodal antidepressant that is currently used in the clinic to treat major depressive disorder. Mechanisms of action of vortioxetine include serotonin (5-HT) transporter blockade, 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, and 5-HT1D, 5-HT3, and 5-HT7 receptor antagonism. Vortioxetine facilitates 5-HT transmission in the medial prefrontal cortex (mPFC), however, the impact of this compound on related prefrontal-subcortical circuits is less clear. Thus, the current study examined the impact of systemic vortioxetine administration (0.8 mg/kg, i.v.) on spontaneous spiking and spikes evoked by electrical stimulation of the mPFC in the anterior cingulate cortex (ACC), medial shell of the nucleus accumbens (msNAc), and lateral septal nucleus (LSN) in urethane-anesthetized rats. We also examined whether vortioxetine modulated afferent drive in the msNAc from hippocampal fimbria (HF) inputs. Similar studies were performed using the selective 5-HT reuptake inhibitor [selective serotonin reuptake inhibitors (SSRI)] escitalopram (1.6 mg/kg, i.v.) to enable comparisons between the multimodal actions of vortioxetine and SSRI-mediated effects. No significant differences in spontaneous activity were observed in the ACC, msNAc, and LSN across treatment groups. No significant impact of treatment on mPFC-evoked responses was observed in the ACC. In contrast, vortioxetine decreased mPFC-evoked activity recorded in the msNAc as compared to parallel studies in control and escitalopram treated groups. Thus, vortioxetine may reduce mPFC-msNAc afferent drive via a mechanism that, in addition to an SSRI-like effect, requires 5-HT receptor modulation. Recordings in the LSN revealed a significant increase in mPFC-evoked activity following escitalopram administration as compared to control and vortioxetine treated groups, indicating that complex modulation of 5-HT receptors by vortioxetine may offset SSRI-like effects in this region. Lastly, neurons in the msNAc were more responsive to stimulation of the HF following both vortioxetine and escitalopram administration, indicating that elevation of 5-HT tone and 5-HT receptor modulation may facilitate excitatory hippocampal synaptic drive in this region. The above findings point to complex 5-HT receptor-dependent effects of vortioxetine which may contribute to its unique impact on the function of prefrontal-subcortical circuits and the development of novel strategies for treating mood disorders.
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Affiliation(s)
- Shreaya Chakroborty
- Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Thomas R Geisbush
- Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Elena Dale
- Department of Neuroscience, Novartis Institutes for BioMedical Research, Cambridge, MA, United States
| | - Alan L Pehrson
- Department of Psychology, Montclair State University, Montclair, NJ, United States
| | - Connie Sánchez
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Anthony R West
- Department of Neuroscience, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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Schiavone S, Trabace L. Pharmacological targeting of redox regulation systems as new therapeutic approach for psychiatric disorders: A literature overview. Pharmacol Res 2016; 107:195-204. [PMID: 26995306 DOI: 10.1016/j.phrs.2016.03.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 03/14/2016] [Accepted: 03/14/2016] [Indexed: 12/20/2022]
Abstract
Redox dysregulation occurs following a disequilibrium between reactive oxygen species (ROS) producing and degrading systems, i.e. mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and nitric oxide synthase (NOS) on one hand and the principal antioxidant system, the glutathione, on the other hand. Increasing recent evidence points towards a pathogenetic role of an altered redox state in the development of several mental disorders, such as anxiety, bipolar disorders, depression, psychosis, autism and post-traumaticstress disorders (PTSD). In this regard, pharmacological targeting of the redox state regulating systems in the brain has been proposed as an innovative and promising therapeutic approach for the treatment of these mental diseases. This review will summarize current knowledge obtained from both pre-clinical and clinical studies in order to descant "lights and shadows" of targeting pharmacologically both the producing and degrading reactive oxygen species (ROS) systems in psychiatric disorders.
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Affiliation(s)
- Stefania Schiavone
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20 71122 Foggia, Italy.
| | - Luigia Trabace
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20 71122 Foggia, Italy.
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Nasyrova RF, Ivashchenko DV, Ivanov MV, Neznanov NG. Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects. Front Physiol 2015; 6:139. [PMID: 26029110 PMCID: PMC4426711 DOI: 10.3389/fphys.2015.00139] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 04/18/2015] [Indexed: 12/14/2022] Open
Abstract
Currently, schizophrenia is considered a multifactorial disease. Over the past 50 years, many investigators have considered the role of toxic free radicals in the etiology of schizophrenia. This is an area of active research which is still evolving. Here, we review the recent data and current concepts on the roles of nitric oxide (NO) and related molecules in the pathogenesis of schizophrenia. NO is involved in storage, uptake and release of mediators and neurotransmitters, including glutamate, acetylcholine, noradrenaline, GABA, taurine and glycine. In addition, NO diffuses across cell membranes and activates its own extrasynaptic receptors. Further, NO is involved in peroxidation and reactive oxidative stress. Investigations reveal significant disturbances in NO levels in the brain structures (cerebellum, hypothalamus, hippocampus, striatum) and fluids of subjects with schizophrenia. Given the roles of NO in central nervous system development, these changes may result in neurodevelopmental changes associated with schizophrenia. We describe here the recent literature on NOS gene polymorphisms on schizophrenia, which all point to consistent results. We also discuss how NO may be a new target for the therapy of mental disorders. Currently there have been 2 randomized double-blind placebo-controlled trials of L-lysine as an NOS inhibitor in the CNS.
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Affiliation(s)
- Regina F Nasyrova
- V.M. Bekhterev Saint Petersburg Psychoneurological Research Institute Saint Petersburg, Russia
| | - Dmitriy V Ivashchenko
- V.M. Bekhterev Saint Petersburg Psychoneurological Research Institute Saint Petersburg, Russia
| | - Mikhail V Ivanov
- V.M. Bekhterev Saint Petersburg Psychoneurological Research Institute Saint Petersburg, Russia
| | - Nikolay G Neznanov
- V.M. Bekhterev Saint Petersburg Psychoneurological Research Institute Saint Petersburg, Russia
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Fischer LK, McGaughy JA, Bradshaw SE, Weissner WJ, Amaral AC, Rosene DL, Mokler DJ, Fitzmaurice GM, Galler JR. Prenatal protein level impacts homing behavior in Long-Evans rat pups. Nutr Neurosci 2015; 19:187-95. [PMID: 25603489 DOI: 10.1179/1476830515y.0000000001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This study assessed the effect of varying prenatal protein levels on the development of homing behavior in rat pups. METHODS Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). RESULTS Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein diets. The 6 and 12% prenatal protein levels resulted in lower activity levels, with the greatest reduction on postnatal day 13. However, only the 6% pups had reduced success and higher latencies in reaching the nest quadrant when compared with pups from the three other nutrition groups. Latency in reaching the nest quadrant was significantly and negatively associated with adult brain weight. DISCUSSION Home orientation is a sensitive measure of developmental deficits associated with variations in prenatal protein levels, including levels of protein deficiency that do not lead to overt growth failure.
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Affiliation(s)
- L K Fischer
- a Judge Baker Children's Center and Department of Psychiatry , Harvard Medical School , Boston , MA , USA
| | - J A McGaughy
- b Department of Psychology , University of New Hampshire , Durham , NH , USA
| | - S E Bradshaw
- a Judge Baker Children's Center and Department of Psychiatry , Harvard Medical School , Boston , MA , USA
| | - W J Weissner
- c Department of Biological Sciences , University of New England , Biddeford , ME , USA
| | - A C Amaral
- d Department of Anatomy & Neurobiology , Boston University Medical Campus , Boston , MA , USA
| | - D L Rosene
- d Department of Anatomy & Neurobiology , Boston University Medical Campus , Boston , MA , USA
| | - D J Mokler
- c Department of Biological Sciences , University of New England , Biddeford , ME , USA
| | - G M Fitzmaurice
- e Department of Biostatistics , Harvard School of Public Health , Boston , MA , USA.,f Laboratory for Psychiatric Biostatistics , McLean Hospital , Belmont , MA , USA
| | - J R Galler
- a Judge Baker Children's Center and Department of Psychiatry , Harvard Medical School , Boston , MA , USA
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