RESUMO
Developments in the molecular biology and pharmacology of GLU(K5), a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU(K5)-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU(K5)-containing kainate receptors prevented development of epileptiform activity--evoked by the muscarinic agonist, pilocarpine--and inhibited the activity when it was pre-established. In conscious rats, these GLU(K5) antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU(K5) antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU(K5) kainate receptor antagonists offer a potential new therapy for epilepsy.
Assuntos
Epilepsia/prevenção & controle , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sistema Límbico/efeitos dos fármacos , Pilocarpina , Receptores de Ácido Caínico/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Eletrochoque , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Humanos , Técnicas In Vitro , Isoquinolinas/farmacologia , Ácido Caínico/farmacologia , Sistema Límbico/fisiopatologia , Masculino , Camundongos , Ratos , Ratos Wistar , Especificidade por Substrato , Resultado do TratamentoRESUMO
BACKGROUND: The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics. OBJECTIVE/METHODS: We review the advances in the field in recent years, focusing on a rationale for pain therapy and potential challenges associated with these targets. RESULTS/CONCLUSIONS: Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 - 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets.