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which indirectly influences receptor function by blocking its negative allosteric modulation
by beta-carbolines and zinc.

GABA turnover. Vigabatrin and tiagabine are modern antiepileptic agents that exert their
actions by selective neurochemical effects at the inhibitory synapse, resulting in altered
GABA turnover. Vigabatrin is an irreversible inhibitor of the mitochondrial enzyme GABA-
transaminase which is responsible for the catabolism of GABA, whereas tiagabine prevents
the removal of GABA from the synaptic cleft by blockade of GABA transport. These distinct
mechanisms result in the global elevation of brain GABA concentrations and the temporarily
prolonged presence of neuronally released GABA in the synapse, respectively. Although
these drugs target both neurones and glial cells, vigabatrin has marginally higher affinity for
neuronal GABA-transaminase, whereas tiagabine is slightly more effective in reducing glial
GABA uptake. Furthermore, tiagabine is selective for the GAT-1 GABA transporter and its
pharmacological effects mirror the regional distribution of this protein, with a more
pronounced action in hippocampus and neocortex. Other antiepileptic agents, including
sodium valproate, gabapentin and topiramate have also been reported to influence GABA
turnover by increasing neurotransmitter synthesis and/or release.

Glutamate receptors. Perampanel is the only current AED with selective effects at glutamate
receptors. It is a non-competitive AMPA receptor antagonist, which binds to a site on the
extracellular domain of the channel protein distinct from the glutamate recognition site.
Binding of perampanel induces a conformational change in AMPA receptor subunits that
limits their ability to translate agonist (i.e. glutamate) binding into channel opening. The
effect is to reduce fast excitatory neurotransmission and thereby limit the ability of seizure
discharges to spread. Several other antiepileptic agents exert their effects, in part, by an action
on glutamatergic neurotransmission. Blockade of the NMDA subtype of glutamate receptor
is believed to contribute to the pharmacological profile of felbamate, topiramate has an
inhibitory action on kainate receptors, and phenobarbital has been reported to block AMPA
receptors, albeit at concentrations towards the upper end of its clinical range. Although the
literature contains reports that several AEDs, most notably lamotrigine, can selectively
reduce glutamate release, this phenomenon is more likely related to an inhibitory action on
pre-synaptic sodium and calcium channels than any direct effect on the glutamate system.

Synaptic vesicle protein 2A. Levetiracetam was developed for the treatment of epilepsy with
no clear indication of how it worked at the cellular level. The identification of a specific
binding site for the drug in mammalian brain and its later classification as synaptic vesicle
protein 2A (SV2A) has resulted in claims that levetiracetam represents the first in a new class
of antiepileptic agents. To some extent, this remains a speculative assertion. Despite intense
investigation, the precise physiological role of SV2A is still unclear and important details of
the interaction between drug and protein remain to be defined. Indeed, there is still no
convincing evidence to suggest whether the interaction is facilitatory or inhibitory or if it
results in altered packaging, trafficking, membrane fusion or recycling of synaptic vesicles
within the nerve terminal. There is, however, credible evidence to support selective binding
of levetiracetam to SV2A, with little or no affinity for other members of the same protein
family, and an impressive correlation between SV2A binding affinity and the anticonvulsant
efficacy of a series of levetiracetam analogues in audiogenic seizure sensitive mice.

Carbonic anhydrase. The acid-base balance and maintenance of local pH is critical to normal
functioning of the nervous system. Various isoenzymes of carbonic anhydrase play an
important role in this regard. They are responsible for catalysing the bi-directional conversion
of carbon dioxide and water to bicarbonate and hydrogen ions (CO2 + H2O ↔ HCO3- + H+).
The forward reaction is rapid, whereas the rate of the reverse reaction is more modest. As a
result, inhibition of carbonic anhydrase influences the latter more significantly, producing a
localised acidosis and increased bicarbonate ion concentration. This, in turn, attenuates