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

Byoung Joo Gwag, Young Ae Lee, Sun Young Ko, Moon Jung Lee, Doo Soon Im, Bok Sun Yun, Hyang Ran Lim, Sun Mi Park, Han Yeol Byun, Sun Ju Son, Hye Jin Kwon, Ji Yoon Lee, Jae Young Cho, Seok Joon Won, Kee Won Kim, Young Min Ahn, Ho Sang Moon, Hae Un Lee, Sung Hwa Yoon, Ji Hyun NohJun Mo Chung, Sung Ig Cho

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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 μmol/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.

Original languageEnglish
Pages (from-to)1142-1151
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number6
DOIs
StatePublished - Jun 2007

Keywords

  • Aspirin
  • Ischemia
  • NMDA
  • Neuronal death
  • Oxidative stress

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