Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors

TY - JOUR

T1 - Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors

AU - Woldbye, David P D

AU - Nanobashvili, Avtandil

AU - Sørensen, Andreas Vehus

AU - Husum, Henriette

AU - Bolwig, Tom G

AU - Sørensen, Gunnar

AU - Ernfors, Patrik

AU - Kokaia, Merab

AU - Sørensen, Gunnar

PY - 2005/12/1

Y1 - 2005/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Convulsants

KW - Cyclohexanes

KW - Disease Models, Animal

KW - Epilepsy

KW - Epilepsy, Temporal Lobe

KW - Excitatory Amino Acid Agonists

KW - Female

KW - Gene Expression Regulation

KW - Genetic Predisposition to Disease

KW - Hippocampus

KW - Kainic Acid

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Knockout

KW - Neurons

KW - Neuropeptide Y

KW - Organ Culture Techniques

KW - Receptors, Neuropeptide Y

KW - Synaptic Transmission

KW - Xanthenes

U2 - 10.1016/j.nbd.2005.05.010

DO - 10.1016/j.nbd.2005.05.010

M3 - Journal article

C2 - 15979311

SN - 0969-9961

VL - 20

SP - 760

EP - 772

JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - 3

ER -