Molecular Basis of GABA Aminotransferase Inhibition in Epilepsy: Structure, Mechanisms, and Drug Development

Epilepsy affects approximately 50 million people worldwide, with nearly one-third of patients experiencing inadequate seizure control with conventional anti-epileptic drugs. The GABAergic system, responsible for inhibitory neurotransmission in the central nervous system, represents a critical target for seizure management. GABA aminotransferase (GABA-T), the enzyme responsible for GABA catabolism, has emerged as a particularly attractive therapeutic target. Inhibition of GABA-T increases synaptic GABA availability, enhancing inhibitory neurotransmission and raising the seizure threshold. Vigabatrin, an irreversible GABA-T inhibitor, has demonstrated remarkable efficacy in specific epilepsy syndromes, particularly infantile spasms and refractory partial seizures. However, its clinical utility is tempered by the risk of irreversible visual field defects, necessitating careful patient selection and monitoring. This review examines the molecular biology of GABA-T, the mechanisms of action of its inhibitors, clinical applications, safety considerations, and emerging developments in this therapeutic area. We discuss the structure-function relationships of GABA-T, the pharmacology of vigabatrin and experimental inhibitors, clinical efficacy across various epilepsy syndromes, adverse effect profiles, and future directions including novel inhibitors with improved safety profiles. Understanding the role of GABA-T in epilepsy pathophysiology and the therapeutic potential of its inhibitors provides insights into rational drug design and personalized treatment strategies for epilepsy management.