OBJECTIVE To investigated the variation of apoptosis rate, necrosis rate and cell cycle in SH-SY5Y cells after they exposed to MnCl2 directly, or preconditioned with agonist (pyrroloquinoline quinine, PQQ) and suppressant (LY294002), respectively, and then exposed to MnCl2, which provided theoretical basis for the mechanism of Mn neurotoxicity and its possible interventions.METHODS The SH-SY5Y cells were cultured in Dulbeccos modification of Eagles medium (Hyclone) supplemented with 10% fetal bovine serum (Gibco), penicillin 50 mg·L-1 and streptomycin 100 mg· L-1 at 37℃ in a humidified air atmosphere containing 5%CO2.They were divided into three groups, a non-pretreatment group and two intervention groups.In non-preconditioning group, SH-SY5Y cells were directly exposed to different concentrations of MnCl2 (0, 0.5, 1.0, 2.0 and 4.0 mmol· L-1) for 12 h, and the control was treated with 0.9% NaCl solution.In the two intervention groups, SH-SY5Y cells were preconditioned with 0.1 μmol·L-1 PQQ and 10 μmol·L-1 LY294002 for 1 h, respectively, and then treated with MnCl2 in the same way with non-preconditioning group.After treatment, the cell viability, apoptosis rate, necrosis rate and every phases of cell cycle were detected by MTT and flow cytometry, severally.RESULTS The cell viability decreased in three groups compared to the control (P < 0.01), and it dropped much more in LY294002 group than in non-preconditioning group.The rate of cell apoptosis and necrosis showed obvious dose-response relationships, which significantly increased in three groups with concentrations of MnCl2 rising.And the increment in LY294002 group was much more than in non-preconditioning group, while the increment was less in PQQ group than in non-preconditioning group.The ratio of G0/G1 and G2/M were significantly decreased but the percentage of S phase was obviously increased in three groups versus the control (P<0.01).And the decrements of G0/G1 and G2/M ratio and increment of the percentage of S phase in LY294002 group were much more than in non-preconditioning group,while they were less in PQQ group than in non-preconditioning group.CONCLUSION Mn can promote apoptosis and necrosis, and vary cell cycle of SH-SY5Y cells.PQQ or LY294002 can protect or enhance, respectively, the neurotoxicity of Mn by regulating apoptosis, necrosis, and cell cycle of SHSY5Y cells.Our findings provide reliable evidences that Mn-induced cells apoptosis and necrosis of may underlie crucial mechanisms of Mn-induced degenerative neuropathy.Furthermore, it is reasonable to speculate that PQQ may be an effective intervention in the process of Mn-induced degenerative neuropathy by reducing apoptosis rate and necrosis rate caused by Mn.