Fast, Non-Competitive and Reversible Inhibition of NMDA-Activated Currents by 2-BFI Confers Neuroprotection

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DOIResolve DOI: http://doi.org/10.1371/journal.pone.0064894
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TypeArticle
Journal titlePLoS ONE
ISSN1932-6203
Volume8
Issue5
Article numbere64894
Subject2 (2 benzofuranyl) 2 imidazoline; alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid; calcium; imidazoline derivative; memantine; n methyl dextro aspartic acid; n methyl dextro aspartic acid receptor; unclassified drug; animal cell; article; brain cell; calcium transport; concentration response; controlled study; drug mechanism; drug receptor binding; drug selectivity; embryo; excitotoxicity; in vitro study; male; nerve cell culture; nerve cell excitability; neuroprotection; nonhuman; rat
AbstractExcessive activation of the N-methyl-D-aspartic acid (NMDA) type glutamate receptors (NMDARs) causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca2+]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl)-2-imidazoline (2-BFI), an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10-9 M-1 sec-1) and off rate (Koff = 0.67±0.02 sec-1) than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment. © 2013 Han et al.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences (IBS-ISB)
Peer reviewedYes
NPARC number21269690
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Record identifiercafe3662-db1c-4641-a272-5eb6be83012b
Record created2013-12-13
Record modified2016-05-09
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