PMID- 17299028
OWN - NLM
STAT- MEDLINE
DCOM- 20070529
LR  - 20181201
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 71
IP  - 5
DP  - 2007 May
TI  - Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of 
      N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase.
PG  - 1258-67
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, 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 [(3)H]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 IC(50) values at 2.9 and 9.3 microM 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.
FAU - Li, Wenming
AU  - Li W
AD  - Department of Biochemistry, Hong Kong University of Science and Technology, Hong 
      Kong, China.
FAU - Xue, Jian
AU  - Xue J
FAU - Niu, Chunying
AU  - Niu C
FAU - Fu, Hongjun
AU  - Fu H
FAU - Lam, Colin S C
AU  - Lam CS
FAU - Luo, Jialie
AU  - Luo J
FAU - Chan, Hugh H N
AU  - Chan HH
FAU - Xue, Huaiguo
AU  - Xue H
FAU - Kan, Kelvin K W
AU  - Kan KK
FAU - Lee, Nelson T K
AU  - Lee NT
FAU - Li, Chaoying
AU  - Li C
FAU - Pang, Yuanping
AU  - Pang Y
FAU - Li, Mingtao
AU  - Li M
FAU - Tsim, Karl W K
AU  - Tsim KW
FAU - Jiang, Hualiang
AU  - Jiang H
FAU - Chen, Kaixian
AU  - Chen K
FAU - Li, Xiaoyuan
AU  - Li X
FAU - Han, Yifan
AU  - Han Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070213
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine)
RN  - 0 (Isoenzymes)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Neurotoxins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 27JT06E6GR (omega-N-Methylarginine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 4VX7YNB537 (Tacrine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - W8O17SJF3T (Memantine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding, Competitive/drug effects
MH  - Cells, Cultured
MH  - Computer Simulation
MH  - Drug Synergism
MH  - Glutamic Acid/toxicity
MH  - Isoenzymes/antagonists & inhibitors/metabolism
MH  - Memantine/pharmacology
MH  - Molecular Sequence Data
MH  - Neurons/drug effects/enzymology/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Neurotoxins
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type I/*antagonists & inhibitors/chemistry/metabolism
MH  - Nitric Oxide Synthase Type II/antagonists & inhibitors/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors
MH  - Tacrine/*analogs & derivatives/chemistry/pharmacology
MH  - Time Factors
MH  - omega-N-Methylarginine/pharmacology
EDAT- 2007/02/15 09:00
MHDA- 2007/05/30 09:00
CRDT- 2007/02/15 09:00
PHST- 2007/02/15 09:00 [pubmed]
PHST- 2007/05/30 09:00 [medline]
PHST- 2007/02/15 09:00 [entrez]
AID - mol.106.029108 [pii]
AID - 10.1124/mol.106.029108 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2007 May;71(5):1258-67. doi: 10.1124/mol.106.029108. Epub 2007 Feb 
      13.