精神分裂症中的神经胶质功能障碍：神经酸在临床前模型中具有潜在治疗效果的证据。
Glia dysfunction in schizophrenia: evidence of possible therapeutic effects of nervonic acid in a preclinical model.
机构信息
Research Institute for Marine Drugs and Nutrition, Guangdong Ocean University, Zhanjiang, 524088, Guangdong, China.
The Second Affiliated Hospital of Xinxiang Medical College, Xinxiang, 453002, Henan, China.
出版信息
Psychopharmacology (Berl). 2024 Nov;241(11):2271-2287. doi: 10.1007/s00213-024-06632-7. Epub 2024 Oct 21.
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.
背景
神经炎症可能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）可能改善脱髓鞘和神经退行性疾病。
目的
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和突触变性的关系，其次确定了神经酸在精神分裂症小鼠临床前模型中的治疗效果。
方法
收集了 18 名年龄在 18-55 岁的男性健康对照者和 18 名男性精神分裂症患者（DSM-V 诊断）的血浆样本。通过注射 5mg/kg 聚肌胞苷酸建立精神分裂症的母体免疫激活（MIA）模型，收集小鼠脑样本。雄性小鼠后代（2.5 月龄，n=12）用氯氮平（15mg/kg/天）或 0.5%NA 治疗 6 周。测量人血浆和小鼠脑样本中的细胞因子和多巴胺（DA）浓度以及神经胶质表型和髓鞘标志物。
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）上调有关，而抗炎细胞因子的减少与小胶质细胞（CD206）下调有关。星形胶质细胞标志物（p11）浓度降低，同时伴有少突胶质细胞和突触标志物浓度降低。然而，NA 和 DA 含量增加。与对照组小鼠相比，MIA 雄性小鼠出现类似精神分裂症的行为。额皮质中神经胶质细胞和星形胶质细胞标志物以及细胞因子浓度的变化与患者血浆中的观察结果一致。海马区少突胶质细胞和突触标志物的表达也减少。MIA 小鼠大脑中的 DA 含量和 DA/代谢物（DAPOC）增加。这些变化大部分通过氯氮平和 NA 得到了纠正。尽管一些 NA 的作用比氯氮平更明显，但只有氯氮平恢复了细胞因子功能。
结论
该数据为精神分裂症患者提供了一种可能的治疗途径。
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