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.
