CDK5 inhibitors prevent astroglial apoptosis and reactive astrogliosis by regulating PKA and DRP1 phosphorylations in the rat hippocampus.

ABSTRACT

Status epilepticus (SE) results in the unique pattern of dynamin-related protein 1 (DRP1)-mediated mitochondrial dynamics, which is associated with astroglial apoptosis and reactive astrogliosis in the regional-specific pattern representing the differential astroglial properties. However, less defined are the epiphenomena/upstream effecters for DRP1 phosphorylation in this process. Since cyclin-dependent kinase 5 (CDK5) is involved in reactive astrogliosis, CDK5 is one of the possible upstream regulators for DRP1 phosphorylation. In the present study, both olomoucine and roscovitine (CDK5 inhibitors) effectively ameliorated SE-induced astroglial apoptosis in the dentate gyrus without changed seizure susceptibility. In addition, they inhibited reactive astrogliosis in the CA1 region independent of neuronal death induced by SE. These effects of CDK5 inhibitors were relevant to abrogation of altered DRP1 phosphorylation ratio and mitochondrial length induced by SE. CDK5 inhibitors also negatively regulated protein kinase A (PKA) activity in astrocytes. Therefore, our findings suggest that CDK5 inhibitors may mitigate astroglial apoptosis and reactive astrogliosis accompanied by modulations of DRP1-mediated mitochondrial dynamics.