Title : The role of branched-chain amino acids in the epileptic brain: recent advances and controversies
Epilepsy is a heterogeneous group of chronic neurological disorders characterized by recurrent, spontaneous seizures. Epilepsy affects approximately 1% of the population worldwide and carries a significant societal burden. The treatment of epilepsy is focused on reducing the frequency and severity of seizures, minimizing side effects of treatment, and restoring quality of life. Seizures are commonly treated with antiepileptic drugs, either as monotherapy or in combination with other agents. Up to 40% of patients however are refractory to currently available medications or cannot tolerate their side effects. Many patients thereby seek alternative, more invasive approaches such as surgical resection or deep brain stimulation, with varying degrees of success. In many cases, the underlying causes for how epilepsy develops in the brain after an acute insult are largely unknown. Therefore, there is much need to better understand the pathophysiology of seizure disorders, and to develop novel therapeutic targets to reduce the seizure burden.
In recent years, the essential branched-chain amino acids valine, leucine, and isoleucine have been shown to have numerous effects in the brain, and can both stimulate and inhibit seizures. Although the mechanistic link between branched-chain amino acids and seizure activity has not been fully elucidated, their effects on seizure activity likely reflect the numerous and complex cellular pathways by which they are thought to act (e.g., glutamate, GABA, and ammonia homeostasis) in the brain. Moreover, the different effects of branched-chain amino acids on seizures might reflect differences in the complex pathophysiological mechanisms of the underlying seizure disorder. In exploring the effects of branched-chain amino acids on seizures in various types of epilepsies, we will discuss several themes that have emerged that provide insights into the mechanisms by which branched-chain amino acids might impact seizures. This is significant because a better understanding of these mechanisms might advance research in the field and facilitate the development of novel treatments for epilepsy.