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Synergistic Neuroprotection by Bis(7)-tacrine via Concurrent Blockade of N-Methyl-D-aspartate Receptors and Neuronal Nitric-Oxide Synthase

Departments of Biochemistry (W.L., H.F., C.S.C.L., J.L., H.H.N.C., K.K.W.K., N.T.K.L., Y.H.), Chemistry (J.X., H.X., X.L.), and Biology (K.W.K.T.), Hong Kong University of Science and Technology, Hong Kong, China; Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Shanghai, China (C.N., H.J., K.C.); Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland (C.L.); Mayo Foundation for Medical Education and Research, Rochester, Minnesota (Y.P.) and Department of Pharmacology and Proteomics Lab, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, China (W.L., M.L.)

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 [³H]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 µM 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.

Received for publication July 23, 2006.

Accepted for publication February 13, 2007.

Address correspondence to: Dr. Yifan Han, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China. E-mail: bcyfhan{at}ust.hk

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