Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors.
Neuropeptide Y (NPY) prominently inhibits epileptic seizures in different animal models. The NPY receptors mediating this effect remain controversial partially due to lack of highly selective agonists and antagonists. To circumvent this problem, we used various NPY receptor knockout mice with the same genetic background and explored anti-epileptic action of NPY in vitro and in vivo. In Y2 (Y2-/-) and Y5 (Y5-/-) receptor knockouts, NPY partially inhibited 0 Mg2+-induced epileptiform activity in hippocampal slices. In contrast, in double knockouts (Y2Y5-/-), NPY had no effect, suggesting that in the hippocampus in vitro both receptors mediate anti-epileptiform action of NPY in an additive manner. Systemic kainate induced more severe seizures in Y5-/- and Y2Y5-/-, but not in Y2-/- mice, as compared to wild-type mice. Moreover, kainate seizures were aggravated by administration of the Y5 antagonist L-152,804 in wild-type mice. In Y5-/- mice, hippocampal kindling progressed faster, and afterdischarge durations were longer in amygdala, but not in hippocampus, as compared to wild-type controls. Taken together, these data suggest that, in mice, both Y2 and Y5 receptors regulate hippocampal seizures in vitro, while activation of Y5 receptors in extra-hippocampal regions reduces generalized seizures in vivo.
Woldbye
David P D
DP
Section of Restorative Neurology, Wallenberg Neuroscience Center, BMC A-11, Lund University Hospital, S-221 84 Lund, Sweden.
Nanobashvili
Avtandil
A
Sørensen
Andreas T
AT
Husum
Henriette
H
Bolwig
Tom G
TG
Sørensen
Gunnar
G
Ernfors
Patrik
P
Kokaia
Merab
M
D000818:Animals; D002478:Cells, Cultured; D003292:Convulsants / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism* / Q000494:pharmacology; D009924:Organ Culture Techniques; D017476:Receptors, Neuropeptide Y / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014966:Xanthenes / Q000494:pharmacology
D003292:Convulsants; D003510:Cyclohexanes; D018690:Excitatory Amino Acid Agonists; C410588:L 152804; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D014966:Xanthenes; C095889:neuropeptide Y2 receptor; C100568:neuropeptide Y5 receptor; D007608:Kainic Acid