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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.

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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