INHIBITION OF DEPOLARIZATION-INDUCED NITRIC-OXIDE SYNTHASE ACTIVATIONBY NS-7, A PHENYLPYRIMIDINE DERIVATIVE, IN PRIMARY NEURONAL CULTURE

Citation
S. Tatsumi et al., INHIBITION OF DEPOLARIZATION-INDUCED NITRIC-OXIDE SYNTHASE ACTIVATIONBY NS-7, A PHENYLPYRIMIDINE DERIVATIVE, IN PRIMARY NEURONAL CULTURE, Journal of neurochemistry, 70(1), 1998, pp. 59-65
Citations number
41
Categorie Soggetti
Biology,Neurosciences
Journal title
ISSN journal
00223042
Volume
70
Issue
1
Year of publication
1998
Pages
59 - 65
Database
ISI
SICI code
0022-3042(1998)70:1<59:IODNSA>2.0.ZU;2-R
Abstract
Neuronal nitric oxide synthase (NOS) is considered to be involved in t he pathogenesis of ischemic brain damage. In the present study, the ef fect of a novel neuroprotective phenylpyrimidine derivative, enyl)-2-m ethyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride (NS-7), on dep olarization-stimulated NOS activity was examined in cultured neurons o f mouse cerebral cortex. Various depolarizing stimuli such as veratrid ine, KCl, and N-methyl-D-aspartate increased the NOS activity determin ed by cyclic GMP formation. NS-7 concentration-dependently inhibited b oth the veratridine- and KCl-induced NOS activation with IC50 values o f 9.3 and 9.6 mu M, respectively. The reversal of KCl-evoked NOS activ ity by NS-7 was also observed under blockade of both ionotropic glutam ate receptors and the Na+ channel with MK-801, 6-cyano-7-nitroquinoxal ine-2,3-dione, and tetrodotoxin. In contrast, NS-7, even at 100 mu M, did not affect N-methyl-D-aspartate-stimulated NOS activity, nor did i t have any influence on NOS activity determined in the soluble fractio n of rat hippocampus. Because NS-7 has already been shown to block bot h Na+ and Ca2+ channels, the present findings suggest that this compou nd inhibits depolarization-induced NOS activation by reducing Ca2+ inf lux through blockade of Na+ and Ca2+ channels in primary neuronal cult ure.