Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase

doi:10.1124/mol.106.029108

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 新药研究国家重点实验室

	Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase
	Li, Wenming ; Xue, Jian ; Niu, Chunying ; Fu, Hongjun ; Lam, Colin S. C.; Luo, Jialie ; Chan, Hugh H. N.; Xue, Huaiguo ; Kan, Kelvin K. W.; Lee, Nelson T. K.
刊名	MOLECULAR PHARMACOLOGY
	2007-05
卷号	71 期号:5 页码:1258-1267
ISSN号	0026-895X
DOI	10.1124/mol.106.029108
文献子类	Article
英文摘要	The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide ( NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase ( NOS) inhibitor, N-G-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis( 7)tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate. Moreover, like L-NMMA but not like 5H-dibenzo[a, d] cyclohepten-5,10- imine (MK-801) and memantine, bis( 7)-tacrine showed greater neuroprotection and inhibition on NO release when neurons were pretreated for a prolonged time between 0 and 24 h and remained quite potent even when neurons were post-treated 1 h after the glutamate challenge. Bis(7)-tacrine was additionally found to be as moderately potent as memantine in competing with [H-3] MK-801, inhibiting NMDA-evoked currents and reducing glutamate-triggered calcium influx, which eventually reduced neuronal NOS activity. More importantly, at neuroprotective concentrations, bis(7)-tacrine substantially reversed the overactivation of neuronal NOS caused by glutamate without interfering with the basal activity of NOS. Furthermore, in vitro pattern analysis demonstrated that bis( 7)tacrine competitively inhibited both purified neuronal and inducible NOS with IC50 values at 2.9 and 9.3 mu M but not endothelial NOS. This result was further supported by molecular docking simulations that showed hydrophobic interactions between bis( 7)-tacrine and three NOS isozymes. Taken together, these results strongly suggest that the substantial neuroprotection against glutamate by bis( 7)-tacrine might be mediated synergistically through the moderate blockade of NMDAR and selective inhibition of neuronal NOS.
WOS关键词	ANTI-ALZHEIMERS AGENT ; ACETYLCHOLINESTERASE INHIBITOR ; NEURODEGENERATIVE DISORDERS ; MULTIFUNCTIONAL DRUGS ; CEREBRAL-ISCHEMIA ; CNS TARGETS ; DISEASE ; NMDA ; APOPTOSIS ; PROTEIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000245974900011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273277]
专题	新药研究国家重点实验室中科院受体结构与功能重点实验室
通讯作者	Han, Yifan
作者单位	1.Hong Kong Univ Sci & Technol, Dept Biochem, Hong Kong, Peoples R China 2.Sun Yat Sen Univ, Zhongshan Med Coll, Dept Pharmacol & Proteom Lab, Guangzhou, Peoples R China 3.Mayo Fdn Med Educ & Res, Rochester, MN USA 4.NIAAA, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD USA 5.Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Discovery & Design, Shanghai, Peoples R China 6.Hong Kong Univ Sci & Technol, Dept Biol, Hong Kong, Peoples R China 7.Hong Kong Univ Sci & Technol, Dept Chem, Hong Kong, Peoples R China
推荐引用方式 GB/T 7714	Li, Wenming,Xue, Jian,Niu, Chunying,et al. Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase[J]. MOLECULAR PHARMACOLOGY,2007,71(5):1258-1267.
APA	Li, Wenming.,Xue, Jian.,Niu, Chunying.,Fu, Hongjun.,Lam, Colin S. C..,...&Han, Yifan.(2007).Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase.MOLECULAR PHARMACOLOGY,71(5),1258-1267.
MLA	Li, Wenming,et al."Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase".MOLECULAR PHARMACOLOGY 71.5(2007):1258-1267.