Insight into mitochondrial dysfunction mediated by clozapine-induced inhibition of PGRMC1 in PC12 cells.

Apr 24, 2023

Experts: Liwei Wang,Qian Chen,Rui Ma,Bikui Zhang,Ping Yang,Ting Cao,Shimeng Jiao,Hui Chen,Chenquan Lin,Hualin Cai

Clozapine is usually considered as the last resort for treatment-resistant schizophrenia (TRS). However, it shows limited efficacy in cognition improvement. Moreover, the metabolic side effects induced by clozapine can aggravate cognitive impairment, which is closely related to its neurotoxicity. Nevertheless, the mechanisms underlying clozapine’s neurotoxicity remain largely elusive. In this study, PC12 cells were simultaneously treated with different concentrations (0μM, 10μM, 20μM, 40μM and 80μM) of clozapine and AG205 which functions as a blocking reagent of progesterone receptor membrane component 1 (PGRMC1). In addition, we examined the effect of PGRMC1 in clozapine-induced neurotoxicity through overexpressing or downregulating PGRMC1. Molecular docking and surface plasmon resonance (SPR) analysis indicated that clozapine and AG205 inhibited the binding of endogenous progesterone to PGRMC1. The results showed that high concentration of clozapine and AG205 induced a significant increase in cytotoxicity, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse, all of which were worsened as concentration increases, while overexpression of PGRMC1 reverted the above toxic effect of clozapine on PC12 cells. Furthermore, clozapine and AG205 also downregulated the expression of PGRMC1, glucagon-like peptide-1 receptor (GLP-1R) and mitofusin2 (Mfn2). Interestingly, overexpression of PGRMC1 could revert these effects. Our data suggest that overexpression of PGRMC1 in PC12 cells prevents and restores clozapine-induced oxidative and mitochondrial damage. We propose PGRMC1 activation as a promising therapeutic strategy for clozapine-induced neurotoxicity to facilitate the relief of neuronal damage.
Copyright © 2023 Elsevier B.V. All rights reserved.

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ABOUT THE EXPERTS

Liwei Wang,Qian Chen,Rui Ma,Bikui Zhang,Ping Yang,Ting Cao,Shimeng Jiao,Hui Chen,Chenquan Lin,Hualin Cai

Liwei Wang

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Qian Chen

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Rui Ma

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Bikui Zhang

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Ping Yang

Department of Psychiatry, Hunan Brain Hospital, 427# Furong Road, Changsha, Hunan 410000, China.

Ting Cao

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Shimeng Jiao

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Hui Chen

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Chenquan Lin

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China.

Hualin Cai

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China; Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, China; International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China. Electronic address: hualincai@csu.edu.cn.