Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole

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 N-G-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 phosphoextracellular 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.