gamma-Aminobutyric acid (
GABA) is considered to be the major inhibitory
neurotransmitter in the brain and loss of
GABA inhibition has been clearly implicated in epileptogenesis.
GABA interacts with 3 types of receptor: GABAA, GABAB and GABAC. The GABAA receptor has provided an excellent target for the development of drugs with an
anticonvulsant action. Some clinically useful
anticonvulsants, such as the
benzodiazepines and
barbiturates and possibly
valproic acid (
sodium valproate), act at this receptor. In recent years 4 new
anticonvulsants, namely
vigabatrin,
tiagabine,
gabapentin and
topiramate, with a mechanism of action considered to be primarily via an effect on
GABA, have been licensed.
Vigabatrin elevates brain
GABA levels by inhibiting the
enzyme GABA transaminase which is responsible for intracellular
GABA catabolism. In contrast,
tiagabine elevates synaptic
GABA levels by inhibiting the
GABA uptake transporter, GAT1, and preventing the uptake of
GABA into neurons and glia.
Gabapentin, a cyclic analogue of
GABA, acts by enhancing
GABA synthesis and also by decreasing neuronal
calcium influx via a specific subunit of
voltage-dependent calcium channels.
Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with
intractable epilepsy. Despite this, additional
GABA enhancing
anticonvulsants are presently under development.
Ganaxolone,
retigabine and
pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed
GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing
GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally,
CGP 36742, a GABAB receptor antagonist, may prove to be particularly useful in the management of primary generalised absence
seizures. The exact impact of these new
GABA-enhancing drugs in the treatment of
epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of
epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other
anticonvulsants.