GABAergic mechanisms in epilepsy

gamma -Aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tone that counterbalances neuronal excitation. When this balance is perturbed, seizures may ensue. GABA is formed within GABAergic axon terminals and released into the synapse, where it acts at one of two types of receptor: GABA(A), which controls chloride entry into the cell, and GABA(B), which increases potassium conductance, decreases calcium entry, and inhibits the presynaptic release of other transmitters. GABA(A)-receptor binding influences the early portion of the GABA-mediated inhibitory postsynaptic potential, whereas GABA(B) binding influences the late portion. GABA is rapidly removed by uptake into both glia and presynaptic nerve terminals and then catabolized by GABA transaminase. Experimental and clinical study evidence indicates that GABA has an important role in the mechanism and treatment of epilepsy: (a) Abnormalities of GABAergic function have been observed in genetic and acquired animal models of epilepsy; (b) Reductions of GABA-mediated inhibition, activity of glutamate decarboxylase, binding to GABA(A) and benzodiazepine sites, GABA in cerebrospinal fluid and brain tissue, and GABA detected during microdialysis studies have been reported in studies of human epileptic brain tissue; (c) GABA agonists suppress seizures, and GABA antagonists produce seizures; (d) Drugs that inhibit GABA synthesis cause seizures', and (e) Benzodiazepines and barbiturates work by enhancing GABA-mediated inhibition. Finally, drugs that increase synaptic GABA are potent anticonvulsants. Two recently developed antiepileptic drugs (AEDs), vigabatrin (VGB) and tiagabine (TGB), are examples of such agents. However, their mechanisms of action are quite different (VGB is an irreversible suicide inhibitor of GABA transaminase, whereas TGB blocks GABA reuptake into neurons and glia), which may account for observed differences in drug side-effect profile.