title: Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole.
abstract: Nitric oxide (NO) is known to affect synaptic plasticity in various regions of the brain via the cGMP-cGMP-dependent protein kinase (PKG) pathway. We found that a novel compound 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole (YC-1), a drug known to modulate the response of soluble guanylyl cyclase to NO, greatly potentiates long-term potentiation (LTP). This compound markedly enhanced the induction of LTP in rat hippocampal and amygdala slices by weak tetanic stimulation. The potentiation of LTP by YC-1 was greatly reduced by NO synthase inhibitor Ng-nitro-l-arginine-methylester, guanylyl cyclase inhibitor 1 H-[1,2,4]-oxadiazolo(4,3-a)-quinoxalin-1-one, and PKG inhibitor (9S,10R,12R)-2,3,9,10,11,12, hexahydro-10-methoxy-2,9-dimethyl-1-ox0-9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT5823). In addition, mitogen-activated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) also markedly inhibited LTP potentiating action of YC-1. Intracellular increase of Ca2+ concentration derived from N-methyl-d-aspartate and glutamate metabotropic receptors contributes to the potentiating action of YC-1. Concurrent perfusion of YC-1 and NO donor sodium nitroprusside for a short time period resulted in the induction of LTP by stimuli at a frequency as low as 0.02 Hz. Incubation of unstimulated hippocampal slices with YC-1 plus nitroprusside increased the immunofluorescence of phospho-extracellular signal-regulated kinase (ERK) and phospho-cAMP response element binding protein (CREB). Furthermore, the Western blot shows that the phosphorylation of ERKs 1 and 2 and CREB of unstimulated hippocampal slices was increased by YC-1 plus nitroprusside, which was inhibited by KT5823. The NO-cGMP-PKG-ERK signaling pathway thus plays important role in the potentiation of LTP by YC-1.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Chien
authors.forename: Keng-Chen
authors.initials: KC
authors.lastname: Liang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Lee
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Fu
mesh_terms: D000818:Animals; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission
chemical_list: D020536:Enzyme Activators; D007191:Indazoles; D020030:Nitric Oxide Donors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase