Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine

J Cereb Blood Flow Metab. 2007 Jun;27(6):1142-51. doi: 10.1038/sj.jcbfm.9600418. Epub 2006 Nov 15.


Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxic-ischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 micromol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Aspirin / chemistry
  • Benzoates / pharmacology*
  • Benzoates / therapeutic use
  • Brain Ischemia / drug therapy
  • Brain Ischemia / prevention & control*
  • Cells, Cultured
  • Excitatory Amino Acid Antagonists / chemistry
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fluorobenzenes
  • Infarction, Middle Cerebral Artery
  • Mice
  • N-Methylaspartate / antagonists & inhibitors*
  • Oxidative Stress / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Salicylates
  • Sulfasalazine / chemistry
  • meta-Aminobenzoates


  • 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid
  • Antioxidants
  • Benzoates
  • Excitatory Amino Acid Antagonists
  • Fluorobenzenes
  • Receptors, N-Methyl-D-Aspartate
  • Salicylates
  • meta-Aminobenzoates
  • Sulfasalazine
  • N-Methylaspartate
  • Aspirin