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.
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), G(q/11) 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-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 G(q/11) and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.
Mazarati
Andréy
A
Department of Pediatrics, Division of Pediatric Neurology, D. Geffen School of Medicine at UCLA, Box 951752, 22-474 MDCC, Los Angeles, CA 90095-1752, USA. mazarati@ucla.edu
Lundström
Linda
L
Sollenberg
Ulla
U
Shin
Don
D
Langel
Ulo
U
Sankar
Raman
R
D000818:Animals; D000927:Anticonvulsants; D001514:Bee Venoms / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology; D003620:Dantrolene / Q000494:pharmacology; D004558:Electric Stimulation; D004827:Epilepsy / Q000503:physiopathology*; D005456:Fluorescent Dyes / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D019004:Galanin / Q000494:pharmacology*; D006624:Hippocampus / Q000502:physiology; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008032:Limbic System / Q000502:physiology; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044091:Receptor, Galanin, Type 1 / Q000819:agonists* / Q000502:physiology*; D044092:Receptor, Galanin, Type 2 / Q000819:agonists* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000927:Anticonvulsants; D001514:Bee Venoms; D005456:Fluorescent Dyes; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D009125:Muscle Relaxants, Central; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; C029738:tertiapin; D019004:Galanin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D003620:Dantrolene