The Potential Role of ATP-sensitive Potassium Channels in Treating Epileptic Disorders

Despite antiepileptic drug (AED) therapy, epilepsy remains uncontrolled in around one third of patients. The majority of current AEDs fall into two pharmacological classes, those that modulate neuronal voltage-gated sodium and calcium channels and those that modulate neurotransmitters. There is a need for new AEDs with novel mechanisms of action to serve as adjunct therapy for the treatment of intractable epilepsy. Among the diverse molecular targets, to selectively modify the excitability of neurons so that high frequency epileptic firing can be blocked without disturbing normal neuronal activity, potassium is a potential target. Potassium channels play a major role in the control of resting membrane potential, responsiveness to synaptic inputs, spike frequency adaptation and neurotransmitter release. Among them, the important metabolic coupler to electrical activityATP-sensitive potassium (KATP) channels provides a distinct link between the metabolic and electrical state of cells. We have demonstrated the role of KATP channels in epileptic seizures in diabetic hyperglycemia, providing the direct evidence that increases in extracellular glucose and intracellular ATP attenuate KATP channels, leading to a more excitable state. We also examined the KATP channel agonist mediating neuroprotection in diabetic individuals with status epilepticus. Here, we report how we investigated the diabetic hyperglycemia-related epileptic disorder from clinical observation to experimental studies, and review this potential novel mechanism underlying attenuating epileptic activities by opening KATP channels, especially related to metabolic syndrome.