Regulation of limbic status epilepticus by hippocampal galanin type 1 and type 2 receptors

被引:48
作者
Mazarati, A
Lu, XY
机构
[1] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA
[2] Univ Calif Los Angeles, D Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
[3] Scripps Res Inst, Harold L Dorris Neurol Res Ctr, Dept Neuropharmacol, La Jolla, CA 92037 USA
关键词
neuropeptide; galanin; seizures; G protein-coupled receptor; knockout mouse; peptide nucleic acid antisense;
D O I
10.1016/j.npep.2004.12.003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
It has been well established that galanin is a potent endogenous anticonvulsant peptide. However, the role of galanin receptor subtypes in mediating anticonvulsant effects of the peptide is poorly understood. Using pharmacological, transgenic and antisense approaches, we examined the involvement of galanin receptors GalR1 and GalR2 in regulating seizures and associated neuronal degenerative changes. In the rat model of status epilepticus (SE) induced by electrical stimulation of perforant path, in vivo uncoupling of G protein coupled receptors (GPCR) through intrahippocampal administration of pertussis toxin (PTX) facilitated the initiation of SE, and increased the severity of the established SE. Injection of a non-selective GalR1/GalR2 agonist galanin (1-29) and a preferential GalR2 agonist galanin (2-11) into the hippocampus of PTX-pretreated rats revealed that while during early phase of SE galanin inhibited seizures predominantly through GalR1, GalR2 mediated anticonvulsant effects of the peptide during advanced stage of SE. GalR1 knockout mice showed increased severity of both pilocarpine- and perforant path stimulation-induced SE, compared to wild type (WT) littermates. In GalR1 knockout animals SE led to more severe and wider-spread hippocampal injury, than in WT. Focal downregulation of GalR2, which had been achieved in rats by intrahippocampal infusion of anti-GalR2 peptide nucleic acid (PNA) antisense, significantly increased the severity of perforant path stimulation- induced SE. Downregulation of GalR2 led to mild injury to hilar interneurons and potentiated seizure-induced hippocampal damage. In conclusion, both GalR1 and GalR2 mediate anticonvulsant effects of galanin. GalR1 and GalR2 exhibit differential effects on the initiation and the maintenance phases of SE. Activation of both galanin receptor subtypes exerts neuro protective effects under conditions of excitotoxic injury. (c) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:277 / 280
页数:4
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