Abstracts

RATIONALE: Understanding the cellular and molecular mechanisms that contribute to epilepsy is critical for the development of new therapeutic approaches. Cell signaling cascades provide an intriguing target for therapeutic intervention because of the potential for a host of upstream regulators and downstream effectors within these systems. We have recently demonstrated activation of the ERK MAPK cascade and identified the K+ channel subunit, Kv4.2, as a candidate effector for ERK in the kainate model. In this study we sought to further characterize ERK activation and phosphorylation of Kv4.2 in the kainate model and tested the hypothesis that these changes are necessary for the expression of kainate-induced limibic motor seizures. METHODS: Seizures were induced by kainate (KA)(IP). Experimental and control animals received the MEK inhibitor, SL327 , or vehicle 30 min prior to KA. Seizure activity was scored using the Racine scale. After 1 hr of limbic motor seizures (or 3 hr after KA) the animals were sacrificed and CA1, CA3, and dentate were prepared for immunoblotting. RESULTS: Following kainate-induced seizures there was a significant increase in ERK activation (p<0.001) and Kv4.2 phosphorylation (CA1 and CA3 p< 0.0001, den p<0.001). This effect was significantly attenuated by pretreatment with the MEK inhibitor, SL327. Furthermore, SL327 blocked the expression of motor seizures (100%, n=9). CONCLUSIONS: Our findings suggest that Kv4.2 is an effector of the ERK cascade in epilepsy and that ERK activation and Kv4.2 phosphorylation are necessary for the induction of seizures in the kainate model. These findings also suggest that inhibitors of ERK activation might represent a new category of potential therapies for the treatment of epilepsy in humans. Supported by NINDS.