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

Authors
Gwag, BJ; Lee, YA; Ko, SY; Lee, MJ; Im, DS; Yun, BS; Lim, HR; Park, SM; Byun, HY; Son, SJ; Kwon, HJ; Lee, JY; Cho, JY; Won, SJ; Kim, KW; Ahn, YM; Moon, HS; Lee, HU; Yoon, SH; Noh, JH; Chung, JM,; Cho, SI
Citation
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 27(6):1142-1151, 2007
Journal Title
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
ISSN
0271-678X1559-7016
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 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.
MeSH terms
AnimalsAntioxidants/pharmacology*Aspirin/chemistryBenzoic Acids/pharmacology*Benzoic Acids/therapeutic useBrain Ischemia/drug therapyBrain Ischemia/prevention & control*Cells, CulturedExcitatory Amino Acid Antagonists/chemistryExcitatory Amino Acid Antagonists/pharmacologyInfarction, Middle Cerebral ArteryMiceN-Methylaspartate/antagonists & inhibitors*Oxidative Stress/drug effectsReceptors, N-Methyl-D-Aspartate/antagonists & inhibitorsSulfasalazine/chemistry
DOI
10.1038/sj.jcbfm.9600418
PMID
17106444
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Research Institute for Neural Science & Technology
AJOU Authors
곽, 병주조, 제영조, 성익
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