Glia dysfunction in schizophrenia: evidence of possible therapeutic effects of nervonic acid in a preclinical model.

IF 3.5 3区医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-11-01 Epub Date: 2024-10-21 DOI:10.1007/s00213-024-06632-7

Xiaona Wang, Jiacheng Fu, Huiying Wang, Cong Liu, Yongping Zhang, Cai Song, Changhong Wang

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Abstract

Rationale: Neuroinflammation may inhibit oligodendrocyte and astrocyte differentiation, which causes demyelination and synaptic degeneration. The myelin component nervonic acid (NA) may improve demyelinating and neurodegenerative diseases.

Objectives: This study firstly explored relationships between glial cell dysfunction and demyelination or synaptic degeneration in schizophrenia patients, and secondly determined nervonic acid therapeutic effects in a preclinical schizophrenia model of mice.

Methods: Plasma samples were collected from 18 male healthy controls and 18 male schizophrenic patients (diagnosed by DSM-V) at aged 18-55. Mouse brain samples were collected from a maternal immune activation (MIA) model of schizophrenia via injecting 5 mg/kg polyinosinic-polycytidylic acid. Male mouse offspring (age 2.5 months, n = 12) were treated by clozapine (15 mg/kg/day) or fed 0.5% NA for 6 weeks. Cytokine and dopamine (DA) concentrations, and glial phenotypes and myelin markers were measured in both human plasma and mouse brain samples.

Results: In patient plasma, increased proinflammatory cytokines were associated with reactive microglia (Iba-1) up-regulation, while decreased anti-inflammatory cytokines were related to microglia (CD206) downregulation. Decreased astrocyte marker (p11) concentrations were accompanied by reduced concentrations of oligodendrocyte and synaptic markers. However, NA and DA contents were increased. Compared with control mice, SZ-like behaviors appeared in MIA male mice. Changes in microglia and astrocytes markers, and cytokine concentrations in the frontal cortex were consistent with those observed in patients' plasma. Hippocampal oligodendrocyte and synaptic marker expression were also decreased. DA content and DA/metabolite (DAPOC) were increased in MIA mouse brains. Most of these changes were normalized by both clozapine and NA. Even though some NA effects were more pronounced than clozapine, only clozapine restored cytokine function.

Conclusion: The data suggest a possible therapeutic route for schizophrenia patients.

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精神分裂症中的胶质细胞功能障碍：神经酸在临床前模型中的可能治疗效果证据。

理由：神经炎症可能会抑制少突胶质细胞和星形胶质细胞的分化，从而导致脱髓鞘和突触变性。髓鞘成分神经酸（NA）可改善脱髓鞘和神经退行性疾病：本研究首先探讨了精神分裂症患者神经胶质细胞功能障碍与脱髓鞘或突触变性之间的关系，其次确定了神经酸在临床前精神分裂症小鼠模型中的治疗效果：方法：收集 18 名男性健康对照组和 18 名男性精神分裂症患者（根据 DSM-V 诊断）的血浆样本，患者年龄在 18-55 岁之间。从母体免疫激活（MIA）精神分裂症模型中采集小鼠脑部样本，方法是注射 5 毫克/千克聚肌苷酸。雄性小鼠后代（2.5 个月大，n = 12）接受氯氮平（15 毫克/千克/天）治疗或喂食 0.5% NA 6 周。在人体血浆和小鼠大脑样本中测量了细胞因子和多巴胺（DA）浓度、神经胶质表型和髓鞘标记物：结果：在患者血浆中，促炎细胞因子的增加与反应性小胶质细胞（Iba-1）的上调有关，而抗炎细胞因子的减少与小胶质细胞（CD206）的下调有关。在星形胶质细胞标记物（p11）浓度降低的同时，少突胶质细胞和突触标记物的浓度也有所降低。然而，NA 和 DA 的含量却增加了。与对照组小鼠相比，MIA 雄性小鼠出现了类似 SZ 的行为。小胶质细胞和星形胶质细胞标记物的变化以及额叶皮质中细胞因子浓度的变化与在患者血浆中观察到的一致。海马少突胶质细胞和突触标记表达也有所下降。MIA小鼠大脑中的DA含量和DA/代谢物（DAPOC）均有所增加。氯氮平和 NA 可使这些变化中的大部分恢复正常。尽管 NA 的某些作用比氯氮平更明显，但只有氯氮平可恢复细胞因子的功能：结论：这些数据为精神分裂症患者提供了一种可能的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.