Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase
文献类型：期刊论文
| 作者 | 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
 |
| 出版日期 | 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 |
| WOS记录号 | WOS:000245974900011 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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