title: Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
abstract: Excessive 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 [Ca(2+)]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.
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang Province, P. R. China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Han
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Yang
authors.forename: Susan X
authors.initials: SX
authors.lastname: Jiang
authors.forename: Sheng-Tao
authors.initials: ST
authors.lastname: Hou
authors.forename: Rong-Yuan
authors.initials: RY
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001572:Benzofurans; D007093:Imidazoles; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; C103723:2-(2-benzofuranyl)-2-imidazoline; D002118:Calcium