Regulation of Kindling Epileptogenesis by Hippocampal Galanin Type 1 and Type 2 Receptors: The Effects of Subtype-Selective Agonists and the Role of G-Protein-Mediated Signaling
- 12 May 2006
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 318 (2), 700-708
- https://doi.org/10.1124/jpet.106.104703
Abstract
The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. Wistar rats received 24-h-long intrahippocampal infusion of a GalR1/2 agonist galanin(1-29), GalR1 agonist M617 [galanin(1-13)-Gln14-bradykinin(2-9)-amide], or GalR2 agonist galanin(2-11). The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), Gq/11 protein inhibitor [d-Arg1,d-Trp5,7,9,Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling—60 electrical trains administered to ventral hippocampus every 5 min. M617 delayed epileptogenesis, whereas galanin(1-29) and galanin(2-11) completely prevented the occurrence of full kindled seizures. TPQ abolished anticonvulsant effect of M617 but not of galanin(2-11). PTX blocked anticonvulsant effects of M617 and inversed the action of galanin(1-29) and galanin(2-11) to proconvulsant. dSP and dantrolene did not modify seizure suppression through GalR1 and GalR2, but eliminated the proconvulsant effect of PTX + galanin(1-29) and PTX + galanin(2-11) combinations. We conclude that hippocampal GalR1 exert their disease-modifying effect through the Gi-GIRK pathway. GalR2 is antiepileptogenic through the Gi mechanism independent of GIRK. A secondary proconvulsant pathway coupled to GalR2 involves Gq/11 and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.Keywords
This publication has 38 references indexed in Scilit:
- Role of galanin receptor 1 and galanin receptor 2 activation in synaptic plasticity associated with 3′,5′-cyclic AMP response element-binding protein phosphorylation in the dentate gyrus: Studies with a galanin receptor 2 agonist and galanin receptor 1 knockout miceNeuroscience, 2005
- Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim testsProceedings of the National Academy of Sciences of the United States of America, 2004
- Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretionNature Medicine, 2003
- Critical role for GALR1 galanin receptor in galanin regulation of neuroendocrine function and seizure activityMolecular Brain Research, 2002
- Galanin inhibits tyrosine hydroxylase expression in midbrain dopaminergic neuronsJournal of Neurochemistry, 2002
- Temporal profile of CRE DNA-binding activity in the rat hippocampus following a kindling stimulationEpilepsy Research, 2000
- A Novel High-Affinity Inhibitor for Inward-Rectifier K+ ChannelsBiochemistry, 1998
- Binding and agonist/antagonist actions of M35, galanin(1-13)-bradykinin(2-9) amide chimeric peptide, in Rin m 5F insulinoma cellsRegulatory Peptides, 1995
- A Pertussis Toxin-Sensitive G Protein in Hippocampal Long-Term PotentiationScience, 1989
- Neuronal Supersensitivity to Acetylcholine Induced by Kindling in the Rat HippocampusScience, 1979