Metformin alleviates neuronal injury in MK-801-Induced Schizophrenia-Like mice by inhibiting neuronal ferroptosis

BACKGROUND AND OBJECTIVE: Schizophrenia (SCZ) is a severe mental disorder, and its pathological mechanism is closely associated with neuronal ferroptosis. Metformin (Met) has a well-defined anti-ferroptotic effect. Therefore, this study aimed to investigate whether Met improves neuronal injury and behavioral abnormalities in MK-801-induced SCZ-like mice by inhibiting neuronal ferroptosis. METHODS: Mice received dizocilpine (MK-801) to induce a SCZ-like phenotype. The behavioral activities of mice were evaluated using the open field test, Morris water maze test, and forced swim test. Neuronal injury in the hippocampus was evaluated by Nissl staining. The mitochondrial structure in the hippocampal tissue was observed using transmission electron microscopy. Ferroptosis was assessed by measuring the levels of glutathione (GSH), malondialdehyde (MDA), and Fe²⁺; lipid peroxidation; mitochondrial membrane potential; and p53, SLC7A11, and GPX4 expression in the hippocampus. RESULTS: Hippocampal neurons in MK-801-induced SCZ-like mice exhibited typical ferroptotic characteristics, including obvious neuronal injury; reduced mitochondrial membrane potential, GSH, SLC7A11, and GPX4 levels; and elevated lipid peroxidation, MDA, Fe²⁺, and p53 levels. Met intervention significantly reversed these ferroptosis-related indicators and inhibited hippocampal neuronal ferroptosis. Furthermore, Met alleviated MK-801-induced ferroptosis in HT22 cells. Behavioral results revealed that Met ameliorated behavioral abnormalities in the MK-801-treated mice. The ferroptosis inducer RSL3 partially reversed the behavioral improvements induced by Met. Further studies demonstrated that risperidone (RIS) or Met alone alleviated behavioral abnormalities in MK-801-induced SCZ-like mice, whereas their combined treatment produced greater improvement than either monotherapy. CONCLUSION: Met can alleviate neuronal damage and cognitive dysfunction in MK-801-induced SCZ-like mice, at least in part, by inhibiting neuronal ferroptosis. Moreover, combined treatment with Met and RIS is more effective.