P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Although its pathogenesis remains unclear, mitochondrial dysfunction plays a vital role in the pathology of PD. P7C3, an aminopropyl carbazole, possesses a significant neuroprotective ability in several neurodegenerative disorders, including PD. Here, we showed that P7C3 stabilized mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited cytochrome c release in MES23.5 cells (a dopaminergic (DA) cell line) exposed to 1-methyl-4-phenylpyridinium (MPP + ). In MES23.5 cells, P7C3 inhibited glycogen synthase kinase-3 beta (GSK3 β ) activation induced by MPP + . P7C3 also inhibited p53 activity and repressed Bax upregulation to protect cells from MPP + toxicity. In addition, the activation of p53 was significantly attenuated with the inhibition of GSK3 β activity by P7C3. Furthermore, P7C3 blocked GSK3 β and p53 activation in the midbrain, and prevented DA neuronal loss in the substantia nigra in 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine mice. Thus, our study demonstrates that P7C3 protects DA neurons from neurotoxin-induced cell death by repressing the GSK3 β -p53-Bax pathway both in vitro and in vivo , thus providing a theoretical basis for P7C3 in the potential clinical treatment of PD.