Antiepileptic effects of levetiracetam related to the regulation of cell cycle reentry in the parietal cortex of EL mouse brain

Abstract

We have reported that cyclins and the corresponding cyclin-dependent kinase (CDK) family are related to cell proliferation during development as well as epileptogenesis. In the present study, we used EL mice to examine how levetiracetam (Lev) controls the altered expressions of cyclins and the CDK family during development, and further, the epileptogenesis as well in the parietal cortex, the seizure initiation site of EL. Developmental changes in the expression of cyclin and the corresponding CDK families (cyclin D/CDK-4, cyclin E/CDK-2, cyclin A/CDK-2, cyclin A/ CDK-1, and cyclin B/CDK-1) in the parietal cortex of EL mice and the control DDY mice were examined by Western blotting. At different ages, one group of mice (n = 6) were administered a single dose of Lev 160 mg/kg Lev p.o. and a treatment naïve group (n = 6) was administered vehicle, three days before sacrifice. Compared with the control DDY mice, treatment naïve EL mice showed upregulations of cell cycle-specific cyclins/ CDK during the early developmental stages, suggesting that reentry into cell cycle is promoted prior to the beginning of seizures. Lev abolished these effects and Lev-treated EL mice showed no seizures at all. These results suggest that cyclins/CDK may be activated during early stages of development before exhibiting seizures, suggesting that reentry into cell cycle in the parietal cortex is a candidate mechanism for the seizure predisposition of EL mice. The antiepileptic effects of Lev may be related to regulation of cell cycle reentry.

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“…The active form of CDK is dephosphorylated on Thr14/Tyr15 and phosphorylated in the T loop; Thr161 (ATP binding site). The molecules that control the cell cycle and act as the driving force are: CDK as the enzyme, cyclin as the accelerator, and CKI as the brake [3].…”