VOLTAGE-ACTIVATED CALCIUM CHANNELS - TARGETS OF ANTIEPILEPTIC DRUG-THERAPY

Voltage-gated calcium currents play important roles in controlling neu ronal excitability. They also contribute to the epileptogenic discharg e, including seizure maintenance and propagation. In the past decade, selective calcium channel blockers have been synthesized, aiding in th e analysis of calcium channel subtypes by patch-clamp recordings. It i s still a matter of debate whether whether any of the currently availa ble antiepileptic drugs (AEDs) inhibit these conductances as part of t heir mechanism of action. We tested oxcarbazepine, lamotrigine, and fe lbamate and found that they consistently inhibited voltage-activated c alcium currents in cortical and striatal neurons at clinically relevan t concentrations. Low micromolar concentrations of GP 47779 (the activ e metabolite of oxcarbazepine) and lamotrigine reduced calcium conduct ances involved in the regulation of transmitter release. In contrast, felbamate blocked nifedipine-sensitive conductances at concentrations significantly lower than those required to modify N-methyl-D-aspartate (NMDA) responses or sodium currents. Aside from contributing to AED e fficacy, this mechanism of action may have profound implications for p reventing fast-developing cellular damage related to ischemic and trau matic brain injuries. Moreover, the effects of AEDs on voltage-gated c alcium signals may lead to new therapeutic strategies for the treatmen t of neurodegenerative disorders.