Effects of retigabine on the neurodegeneration and extracellular glutamate changes induced by 4-aminopyridine in rat hippocampus in vivo.
We have previously shown that microdialysis perfusion of the K+ channel blocker 4-aminopyridine (4-AP) in rat hippocampus induces convulsions and neurodegeneration, due to the stimulation of glutamate release from synaptic terminals. Retigabine is an opener of the KCNQ2/Q3-type K+ channel that possesses antiepileptic action and may be neuroprotective, and we have therefore studied its effect on the hyperexcitation, the neuronal damage and the changes in extracellular glutamate induced by 4-AP. Retigabine and 4-AP were co-administered by microdialysis in the hippocampus of anesthetized rats, with simultaneous recording of the EEG, and the extracellular concentration of glutamate was measured in the microdialysis fractions. In 70-80% of the rats tested retigabine reduced the 4-AP-induced stimulation of glutamate release and prevented the neuronal damage observed at 24 h in the CA1 hippocampal region. However, retigabine did not block the EEG epileptic discharges and their duration was reduced in only 20-25% of the tested animals. We conclude that the neuroprotective action of retigabine is probably due to the blockade of the 4-AP-induced stimulation of glutamate release. This inhibition, however, was not sufficient to block the epileptic activity.
Mora
Gabriela
G
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, 04510, México, D. F., México.
Tapia
Ricardo
R
D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004347:Drug Interactions; D004569:Electroencephalography; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D017551:Microdialysis; D019636:Neurodegenerative Diseases / Q000139:chemically induced; D010655:Phenylenediamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine; D018698:Glutamic Acid; D015761:4-Aminopyridine