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.
Footnotes
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This work was supported by National Institutes of Health/National Institute of Neurological Diseases and Stroke Grants NS043409 (to A.M.) and NS046516 (to R.S.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.104703.
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ABBREVIATIONS: GalR1, type 1 galanin receptor(s); GalR2, type 2 galanin receptor(s); GIRK, G-protein-coupled inwardly rectifying K+ channel(s); CREB, cyclic AMP-responsive element-binding protein; PTX, pertussis toxin; TPQ, tertiapin Q; dSP, [d-Arg1,d-Trp5,7,9,Leu11]-substance P; M35, [galanin(1-13)-bradykinin(2-9) amide]; M617, galanin(1-13)-Gln14-bradykinin(2-9)-amide; ANOVA, analysis of variance.
- Received March 22, 2006.
- Accepted May 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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