Energy depletion in seizures: anaplerosis as a strategy for future therapies

Seizure activity can lead to energy failure and neuronal injury, resulting in neurological and cognitive sequelae. Moreover, mutations affecting genes encoding for proteins that maintain energy homeostasis within the cell often result in an epileptic phenotype, implying that energy failure can contribute to epileptogenesis. Indeed, there is evidence to indicate that the efficacy of the ketogenic diet, a treatment for refractory epilepsy, can be partly explained by its effect on increasing energetic substrates. The ATP level, reflecting the energy level of a cell, is maintained by the potential gradient across the mitochondrial membrane. This potential gradient is maintained by NADH/H(+) equivalents, produced by reactions within the tricarboxylic acid cycle (TCA-cycle). Anaplerosis, the replenishment of TCA-cycle substrates, therefore represents an appealing strategy to address energy failure such as occurs in seizures. There is accumulating evidence that pyruvate, a classical anaplerotic substrate, has seizure suppressive effects and protects against seizure induced cell death. This review summarizes the evidence for the contribution of TCA cycle deficits in generating seizures. We highlight the role for TCA substrate supplementation in protecting against seizures and seizure induced cell death, and propose that these are important targets for future translational research addressing energy depletion in seizures. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.