RT Journal Article
SR Electronic
T1 Synergistic Neuroprotection by Bis(7)-tacrine via Concurrent Blockade of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptors and Neuronal Nitric-Oxide Synthase
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1258
OP 1267
DO 10.1124/mol.106.029108
VO 71
IS 5
A1 Wenming Li
A1 Jian Xue
A1 Chunying Niu
A1 Hongjun Fu
A1 Colin S. C. Lam
A1 Jialie Luo
A1 Hugh H. N. Chan
A1 Huaiguo Xue
A1 Kelvin K. W. Kan
A1 Nelson T. K. Lee
A1 Chaoying Li
A1 Yuanping Pang
A1 Mingtao Li
A1 Karl W. K. Tsim
A1 Hualiang Jiang
A1 Kaixian Chen
A1 Xiaoyuan Li
A1 Yifan Han
YR 2007
UL http://molpharm.aspetjournals.org/content/71/5/1258.abstract
AB 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, NG-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. The American Society for Pharmacology and Experimental Therapeutics