Targeting The Gaba(B) Receptor For The Treatment Of Epilepsy

Epilepsy is a disorder of neural networks that is characterized by spontaneous recurrent seizures. The role of GABA(B) receptor-mediated mechanisms in the pathogenesis of seizures depends upon neural networks involved, which determine the seizure type. Generalized seizures involve diffuse, bi-hemispheric neuronal networks, while focal seizures involve regional brain networks. GABA(B) receptor agonists have been shown to diminish seizure activity in mouse models of both generalized convulsive and focal seizures. However, generalized non-convulsive seizures such as typical and atypical absence seizures (AASs) characteristically are exacerbated by GABA(B) receptor agonists and blocked by GABA(B) receptor antagonists. The reason for this dichotomy is the involvement of thalamic circuitry in both typical and atypical absence seizures. Thalamocortical circuitry underpins typical absence seizures (TASs) and hippocampal-thalamocortical circuitry is involved in AASs. In addition, high doses of GABA(B) receptor agonists active at the GABA(B) receptor/G-protein coupled inwardly rectifying potassium 2 (GIRK2) channel recently have been shown to induce the phenotype of a specifi c catastrophic epilepsy syndrome of childhood, infantile spasms, in mice. Therefore, GABA(B) receptor-mediated mechanisms can be pro-or anti-convulsant depending on the nature of the pathological neuronal networks involved. Although there are pre-clinical data in support of the efficacy of GABA(B) receptor agonists and antagonists in specific experimental models of seizures, these data have not been translated into the clinical arena because of the potential for downstream adverse effects. The therapeutic goal for the use of these compounds in epilepsy awaits a strategy that targets only those GABA(B) receptor for specific networks that are involved in a given pathological state.