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

Neurotech Pharmaceuticals Co., Ajou University School of Medicine, Suwon, Gyeonggido, South Korea.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.4). 07/2007; 27(6):1142-51. DOI: 10.1038/sj.jcbfm.9600418
Source: PubMed

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.

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    ABSTRACT: Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI.
    Experimental and Molecular Medicine 01/2011; 43(2):121-8. · 2.57 Impact Factor
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    ABSTRACT: Both oxidative stress and excessive activation of glutamate receptors are implicated as major causes of ischemic brain injury. However, the existing N-methyl-D-aspartate (NMDA) receptor antagonists have not exerted good clinical outcome, most likely because they do not protect neurons against oxidative stress. Thus, more effective glutamate antagonists and antioxidants are needed for the treatment of ischemic stroke. In previous study, SP-8203, derived from earth worms, showed the blocking effect of NMDA receptor. We provided evidence that SP-8203 could also suppress the oxidative stress in this study. In vitro, 250 μM H2O2 was treated to SH-SY5Y cells after the pre-treatment of SP-8203 (2, 20 and 200 μM). SP-8203 significantly suppressed H2O2-induced cell death and reactive oxygen species production. In addition, we investigated the effects of SP-8203 in middle cerebral artery (MCA) occluded rat model. SP-8203 (5 and 10 mg/kg) was administered intraperitoneally to rats before and after the MCA occlusion and was injected daily for 10 days. After 10 days, SP-8203 remarkably reduced brain infarct volume and lipid peroxidation products in the MCA-occluded rats but MK-801 didn't. Moreover, SP-8203 significantly improved neurological deficits such as shortening of latency time in Rota rod performance. However, MK-801 didn't improve behavioral deficits. Therefore, SP-8203 may be more effective for multiple-target mechanisms of ischemic stroke.
    Pharmacology Biochemistry and Behavior 03/2011; 98(1):150-4. · 2.82 Impact Factor
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    ABSTRACT: Neu2000 (NEU; 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid), a recently developed derivative of acetylsalicylic acid and sulfasalazine, potently protects against neuronal cell death following ischemic brain injury by antagonizing NMDA receptor-mediated neuronal toxicity and oxidative stress. However, it has yet to be determined whether NEU can attenuate hypoxia-induced impairment of neuronal electrical activity. In this study, we carried out extracellular recordings of hippocampal slices in order to investigate the effects of NEU on the electrical activity of neurons exposed to a hypoxic insult (oxygen and glucose deprivation). NEU prominently suppressed hypoxia-induced impairment of neuronal activity in a concentration-dependent manner. NEU, at a low dose (1 μM), competently depressed the hypoxia-induced convulsive activity in a manner similar to trolox. Furthermore, high concentrations of NEU (50 μM) markedly abolished all hypoxia-mediated impairment of neuronal activity and accelerated the slow recovery of neuronal activity more efficiently than ifenprodil and APV. These results suggest that NEU attenuates hypoxia-induced impairment of neuronal activity more potently than the antioxidant, trolox, and the NMDA receptor antagonists, ifenprodil and APV. We propose that NEU is a striking pharmacological candidate for neuroprotection against hypoxia because of its defensive action on hypoxia-mediated impairment of electrical neurotransmission as well as its neuroprotective action against neuronal cell death induced by exposure to pathological hypoxic conditions.
    Archives of Pharmacal Research 06/2013; · 1.54 Impact Factor

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