Mechanism of action of vigabatrin: correcting misperceptions

Abstract

Discovered more than three decades ago, vigabatrin is approved in more than 50 countries as adjunctive therapy for adult patients with refractory complex partial seizures who have responded inadequately to several alternative treatments and as monotherapy for pediatric patients aged 1 month to 2 years with infantile spasms. Contrary to a fairly common misperception, the compound's mechanism of action is very well-characterized in animal models and cell cultures. γ-Aminobutyric acid (GABA)-ergic synapses comprise approximately 30% of all synapses within the central nervous system, and therein underlies the primary mode of synaptic inhibition. Vigabatrin was rationally designed to have a specific effect on brain chemistry by inhibiting the GABA-degrading enzyme, GABA transaminase, resulting in a widespread increase in GABA concentrations in the brain. The increase in GABA functions as a brake on the excitatory processes that can initiate seizure activity. Despite the short half-life of vigabatrin in the body (5-7 h) and its relatively low concentration in cerebrospinal fluid (10% of the concentration observed in plasma), it has the profound effect of increasing GABA concentration in the brain for more than a week after a single dose in humans. This effect persists steadily over years of vigabatrin administration and results in significant and persistent decreases in seizure activity. Vigabatrin can be effective with once-daily dosing. Because of its specificity, vigabatrin has helped researchers explore the specific mechanisms within the brain that underlie seizure activity.