Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection

PLoS One. 2013 May 31;8(5):e64894. doi: 10.1371/journal.pone.0064894. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzofurans / metabolism
  • Benzofurans / pharmacology*
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Imidazoles / metabolism
  • Imidazoles / pharmacology*
  • Kinetics
  • Male
  • Membrane Potentials / drug effects*
  • N-Methylaspartate / metabolism
  • N-Methylaspartate / pharmacology*
  • N-Methylaspartate / toxicity
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Patch-Clamp Techniques
  • Protein Binding
  • Rats
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Benzofurans
  • Imidazoles
  • Neuroprotective Agents
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • 2-(2-benzofuranyl)-2-imidazoline
  • Calcium

Grants and funding

This work was supported by grants from the Chinese National Natural Science Foundation (81070960), partly supported by Zhejiang Provincial Natural Science Funding (Y2090932) and the Building Funding of Zhejiang Key Subjects (Pharmacology and Biochemical Pharmaceutics). STH’s contribution to this work was supported by a 3010 grant from Wenzhou Medical College. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.