Marked prevention of ischemic brain injury by Neu2000, an NMDA antagonist and antioxidant derived from aspirin and sulfasalazine.
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.
Gwag
Byoung Joo
BJ
Neurotech Pharmaceuticals Co., Ajou University School of Medicine, Suwon, Gyeonggido, South Korea. bjgwag@ajou.ac.kr
Lee
Young Ae
YA
Ko
Sun Young
SY
Lee
Moon Jung
MJ
Im
Doo Soon
DS
Yun
Bok Sun
BS
Lim
Hyang Ran
HR
Park
Sun Mi
SM
Byun
Han Yeol
HY
Son
Sun Ju
SJ
Kwon
Hye Jin
HJ
Lee
Ji Yoon
JY
Cho
Jae-Young
JY
Won
Seok Joon
SJ
Kim
Kee-Won
KW
Ahn
Young Min
YM
Moon
Ho Sang
HS
Lee
Hae Un
HU
Yoon
Sung Hwa
SH
Noh
Ji-Hyun
JH
Chung
Jun-Mo
JM
Cho
Sung Ig
SI
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
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