title: Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine.
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.
authors.affiliation: Neurotech Pharmaceuticals Co., Ajou University School of Medicine, Suwon, Gyeonggido, South Korea. bjgwag@ajou.ac.kr
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Ko
authors.forename: Moon Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Doo Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Bok Sun
authors.initials: BS
authors.lastname: Yun
authors.forename: Hyang Ran
authors.initials: HR
authors.lastname: Lim
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Han Yeol
authors.initials: HY
authors.lastname: Byun
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Son
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Lee
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Cho
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Kee-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Ho Sang
authors.initials: HS
authors.lastname: Moon
authors.forename: Hae Un
authors.initials: HU
authors.lastname: Lee
authors.forename: Sung Hwa
authors.initials: SH
authors.lastname: Yoon
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Noh
authors.forename: Jun-Mo
authors.initials: JM
authors.lastname: Chung
authors.forename: Sung Ig
authors.initials: SI
authors.lastname: Cho
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001241:Aspirin / Q000737:chemistry; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000188:drug therapy / Q000517:prevention & control*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology; D005464:Fluorobenzenes; D020244:Infarction, Middle Cerebral Artery; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012459:Salicylates; D012460:Sulfasalazine / Q000737:chemistry; D062368:meta-Aminobenzoates
chemical_list: C519903:2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)benzoic acid; D000975:Antioxidants; D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D005464:Fluorobenzenes; D016194:Receptors, N-Methyl-D-Aspartate; D012459:Salicylates; D062368:meta-Aminobenzoates; D012460:Sulfasalazine; D016202:N-Methylaspartate; D001241:Aspirin