INTRODUCTION Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. METHODS In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. RESULTS Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its downstream signaling pathways. CONCLUSION PGRMC1-overexpression could protect hippocampus-dependent cognitive impairment induced by clozapine. This effect appears to arise, in part, from the upregulated expression of PGRMC1/EGFR/GLP1R and the activation of downstream PI3K-Akt-BDNF and caspase-3 signaling pathways.

中文翻译：

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PGRMC1 信号传导参与长期氯氮平治疗引起的大鼠认知障碍。

简介 黄体酮受体成分 1 (PGRMC1) 已被确定为非典型抗精神病药物引起的代谢紊乱以及中枢神经系统神经保护的潜在靶点。在我们的研究中，我们旨在弄清楚 PGRMC1 信号通路在氯氮平诱导的认知障碍中的重要作用。方法在雄性SD大鼠中，我们利用重组腺相关病毒（BBB 2.0）和PGRMC1特异性抑制剂（AG205）来调节PGRMC1在大脑中的表达，特别是海马体。氯氮平和AG205治疗进行28天，随后进行包括改良高架十字迷宫和莫里斯水迷宫在内的行为测试来评估认知表现。通过蛋白质印迹法测量海马蛋白表达。结果我们的研究表明，长期服用氯氮平会导致认知障碍，这一点经行为测试和海马组织病理学检查证实。氯氮平通过PGRMC1/EGFR/GLP1R-PI3K-Akt信号通路抑制神经存活，导致下游存活因子脑源性神经营养因子（BDNF）减少，同时促进大鼠海马神经细胞凋亡。有趣的是，通过针对海马 PGRMC1，我们发现抑制 PGRMC1 模拟物，而其上调可通过 PGRMC1 及其下游信号通路显着减轻氯氮平诱导的认知障碍。结论 PGRMC1过表达可以保护氯氮平引起的海马依赖性认知障碍。这种效应的部分原因似乎是 PGRMC1/EGFR/GLP1R 表达上调以及下游 PI3K-Akt-BDNF 和 caspase-3 信号通路的激活。