Abstracts

Galanin is a neuropeptide with well established anticonvulsant effects in acute seizure models. No data are available onto whether galanin might inhibit epileptogenesis. In the hippocampus, galanin acts at two G protein-coupled receptor types - GalR1 and GalR2. We examined antiepileptogenic potential of selective GalR1 and GalR2 agonist to in kindling model, and examined putative downstream pathway that mediate anticonvulsant effects of galanin., Adult male Wistar rats received 24 hour long intrahippocampal infusion of a non - selective GalR1/GalR2 agonist galanin(1-29), selective GalR1 agonist synthetic peptide M617, or selective GalR2 agonist galanin(2-11). The peptides were administered alone, or combined with an inhibitor of G[sub]i/o[/sub] protein pertussis toxin (PTX); blocker of G-protein coupled inwardly rectifying K⁺ channels (GIRK) - tertiapin Q (TPQ); G[sub]q/11 [/sub]protein inhibitor [D-Arg¹,D-Trp^5,7,9,Leu¹¹]-substance P (dSP); or an inhibitor of intracellular Ca²⁺ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling - sixty electrical trains administered to ventral hippocampus every 5 minutes. Hippocampal afterdischarge properties before and after treatment, as well as before and after kindling, and the number of stimulations required to reach each consecutive behavioral seizure score (1 through 4) were analyzed., Activation of hippocampal GalR1 delayed, but did not prevent kindling progression. Twenty four hours after kindling, M617 - treated animals exhibited the decrease of afterdischarge threshold and developed stage 4-5 seizures in response to threshold stimulation, similar to control. GalR1/GalR2 and GalR2 agonists completely prevented both the development of full motor seizures in the course of kindling, and the decrease of afterdischarge threshold 24 hours after kindling procedure. Anticonvulsant effect of GalR1 was not observed in the presence of G[sub]i/o [/sub]and GIRK inhibitors. Antiepileptogenic action of GalR2 agonist was PTX- sensitive, but GIRK - independent. Furthermore, inhibition of G[sub]i/o [/sub]by PTX changed antiepileptogenic effects of galanin(1-29) and of galanin(2-11) to proconvulsant. Inhibition of G[sub]q/11[/sub] and of intracellular Ca⁺⁺ release eliminated proconvulsant effect of PTX+galanin(1-29) and PTX+galanin(2-11) combinations., We conclude that hippocampal GalR1 exert disease - modifying effect through G[sub]i[/sub]-GIRK pathway. GalR2 is antiepileptogenic through G[sub]i [/sub]mechanism, which does not involve GIRK. Our studies also revealed a secondary proconvulsant pathway coupled to GalR2, which involves G[sub]q/11 [/sub]and intracellular Ca²⁺. The data are important for understanding endogenous mechanisms regulating epileptogenesis, and for the development of novel antiepileptogenic drugs., (Supported by NIH/NINDS grants NS043409 (AM) and NS046516 (RS).)