He Yifang, Wang Liwei, Cao Ting, Jiao Shimeng, Chen Hui, Lin Chenquan, Guo Qiujin, He Feng, Cai Hualin
Department of Pharmacy and Institute of Clinical Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, China; Department of Psychiatry, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
Department of Nuclear Medicine, The Second Xiangya Hospital of Central South University, Changsha, China.
Biochem Pharmacol. 2025 Oct;240:117091. doi: 10.1016/j.bcp.2025.117091. Epub 2025 Jun 28.
Chronic use of antipsychotics for schizophrenia (SCZ) often causes metabolic disturbances that exacerbate cognitive impairment, and the underlying mechanisms remain unclear. As a classic antipsychotic, the metabolic toxicity of clozapine (CLZ) has been associated with the novel target progesterone receptor membrane component 1 (PGRMC1), which interacts with the glucagon-like peptide-1 receptor (GLP-1R). This study aimed to investigate the role of the GLP-1R signaling pathway in CLZ-induced metabolic toxicity and explore its potential therapeutic implications. Rats (n = 7/group) were treated with CLZ (20 mg/kg, i.p.), the GLP-1R agonist LIRA (LIRA, 0.4 mg/kg, i.p.), the GLP-1R antagonist Exendin9-39 (Ex9, 50 μg/kg, i.p.) or their combinations for three weeks, and then subjected to assess the cognitive function, neuronal activity, mitochondrial integrity and signaling pathways. The results demonstrated that CLZ impaired cognitive function and induced neuronal apoptosis, as shown by the behavioral performance and morphology staining. Electron microscopy imaging and related detections also revealed that CLZ damaged mitochondrial structure and function by decreasing TCA cycle intermediates, which resulted in reduced adenosine triphosphate (ATP) production and increased oxidative stress in both the hippocampus and prefrontal cortex. Western blotting results showed that CLZ inhibited the PGRMC1/GLP-1R/Mfn2 signaling pathway, whereas combination of LIRA treatment reversed the inhibitory changes, presenting restorative effects on CLZ-induced mitochondrial dysfunction and disturbed energy metabolism. Adversely, further addition toEx9 could abolish the protective effects of LIRA. This study highlights the importance of PGRMC1/GLP-1R/Mfn2 signaling in antipsychotic-induced neurotoxicity in mitochondria, suggesting that upregulating this pathway by GLP-1R agonist may provide a novel adjunctive therapeutic approach for SCZ.
长期使用抗精神病药物治疗精神分裂症（SCZ）常导致代谢紊乱，进而加重认知障碍，其潜在机制尚不清楚。作为一种经典的抗精神病药物，氯氮平（CLZ）的代谢毒性与新靶点孕酮受体膜成分1（PGRMC1）有关，该成分与胰高血糖素样肽-1受体（GLP-1R）相互作用。本研究旨在探讨GLP-1R信号通路在CLZ诱导的代谢毒性中的作用，并探索其潜在的治疗意义。将大鼠（每组n = 7）用CLZ（20 mg/kg，腹腔注射）、GLP-1R激动剂利拉鲁肽（LIRA，0.4 mg/kg，腹腔注射）、GLP-1R拮抗剂艾塞那肽9-39（Ex9，50 μg/kg，腹腔注射）或它们的组合进行处理，持续三周，然后评估认知功能、神经元活性、线粒体完整性和信号通路。结果表明，CLZ损害了认知功能并诱导了神经元凋亡，行为表现和形态学染色显示了这一点。电子显微镜成像和相关检测还显示，CLZ通过减少三羧酸循环中间体来破坏线粒体结构和功能，这导致海马体和前额叶皮质中三磷酸腺苷（ATP）生成减少以及氧化应激增加。蛋白质免疫印迹结果表明，CLZ抑制了PGRMC1/GLP-1R/Mfn2信号通路，而LIRA治疗的组合逆转了抑制性变化，对CLZ诱导的线粒体功能障碍和能量代谢紊乱具有恢复作用。相反，进一步添加Ex9可消除LIRA的保护作用。本研究强调了PGRMC1/GLP-1R/Mfn2信号在抗精神病药物诱导的线粒体神经毒性中的重要性，表明通过GLP-1R激动剂上调该通路可能为SCZ提供一种新的辅助治疗方法。
