Neuroprotective effect of ATM/ATR inhibitor CGK733 on acrylamide-induced inhibition of cytotoxic effects and neurite outgrowth in PC12 cells

Acrylamide is a neurological and reproductive toxicant for both humans and laboratory animals. It inhibits cellular differentiations in variant cells in vitro. We investigated whether the DNA damage response (DDR) pathway is involved in the inhibition of neurite outgrowth and the induction of cytotoxicity by acrylamide in PC12 cells. In this study, CGK733 (ataxia telangiectasia mutated kinase (ATM) and ATM-related kinase (ATR) inhibitor) was used in inhibition of the DDR pathway, which was induced by acrylamide exposure. The results showed that NGF triggered neurite outgrowth and proliferation of PC12 cells. Both neurite outgrowth and cell proliferation induced by NGF were attenuated after acrylamide exposure. The acrylamide-decreased neurite outgrowth and cell proliferation were increased in the administrations of CGK733. In the NGF-stimulated PC12 cells, CGK733 attenuated acrylamide-induced cell cycle alterations and cellular apoptosis. Moreover, the DDR-related molecules were estimated by Western blotting. The results showed that CGK733 can reverse not only acrylamide-induced expressions of ATM, ATR, and p21 but also acrylamide-decreased expression of cyclin D₁ in the NGF-stimulated PC12 cells. These results demonstrated that acrylamide exposure induced the DDR pathway in the NGF-stimulated neurite outgrowth of PC12 cells. Acrylamide-induced inhibition of neurite outgrowth and cytotoxicity in NGF-stimulated PC12 cells can be attenuated by CGK733.