〔Abstract〕 Objective To investigate the role and mechanism of mitochondrial permeability transition pore(MPTP) in the damage of hippocampal neurons in SD rats induced by exposure for 6 hours to sevoflurane. Methods The hippocampal neurons of primary cultured SD rats and fetal rats were randomly divided into control group(Con group), cyclosporin A group(CsA group, 0.1,0.5,1 μmol/L), 3% sevoflurane exposure for 6 h Group(Sevo group), cyclosporin A pretreatment+3% sevoflurane 6 h group(Sevo+CsA group, 0.1, 0.5, 1 μmol/L). CCK-8 kit was used to detect cell activity, TUNEL staining was used to detect neuron apoptosis, JC-1 kit was used to detect mitochondrial membrane potential, Calcein AM was used to detect MPTP opening degree, and Western blot was used to detect proteins expression of brain-derived neurotrophic factor(BDNF), postsynaptic compact protein(PSD-95), Snaptophysin, Snapsin-1, and Cyclophilin D(CypD).Results Compared with Con group, the cell viability of Sevo group was significantly reduced(P<0.05), the apoptosis rate of neurons increased(P<0.01),the expression of synapse proteins decreased(P<0.05), the mitochondrial membrane potential decreased(P<0.01), the opening degree of MPTP increased(P<0.01), and the expression of CypD protein increased(P<0.01). Cyclosporin A, a specific inhibitor of MPTP opening, could reduce hippocampal neuron apoptosis and synaptic damage caused by sevoflurane exposure, maintain mitochondrial membrane potential, and inhibit MPTP opening and CypD protein expression.Conclusion Prolonged exposure to sevoflurane can cause damage to hippocampal neurons in SD rats. The mechanism is related to the promotion of CypD-mediated MPTP opening.