Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappaB activation and apoptosis in rat striatum.
Oxidative stress has long been implicated in the pathogenesis of both the acute and chronic neurotoxic effects of glutamate acting through ionotrophic receptors of the N-methyl-d-aspartate (NMDA) subtype. To evaluate the contribution of oxidative stress to the NMDA receptor-mediated apoptotic death of rat striatal neurons in vivo, the effects of a novel, orally administered free radical scavenger, OPC-14117, was studied following intrastriatal infusion of the NMDA receptor agonist quinolinic acid (QA). Receptor autoradiography and in situ hybridization histochemistry showed that pretreatment with OPC-14117 (600 mg/kg) reduced the QA (120 nmol)-induced loss of striatal D1 dopamine receptors by about 20% (p<0.01) and NMDA receptors by 15% (p<0.01) as well as 67 kDa glutamic acid decarboxylase mRNA (34%; p<0.01) and proenkephalin mRNA (36%; p<0.01). OPC-14117 also decreased the apomorphine-induced ipsilateral rotational response in unilaterally QA-lesioned animals by about 70% (p<0.05). In addition, OPC-14117 pretreatment inhibited QA-induced internucleosomal DNA fragmentation. Western blot analysis and electrophoresis mobility shift assay further revealed that the free radical scavenger (300 and 600 mg/kg) blunted the QA-induced degradation of IkappaBalpha (increased IkappaBalpha levels from about 15% to 33 and 62% of control, respectively; p<0.01) as well as the ensuing activation of NF-kappaB by 25 to 34%, respectively (p<0. 01) and the augmentation in c-Myc (35 to 70%, respectively) and p53 expression by 50-80%, respectively (both p<0.01). In contrast, OPC-14117 had no significant effect on the QA-induced increase in AP-1 binding activity. These results suggest that the NMDA receptor-mediated generation of reactive oxygen species contributes to the QA-induced activation of NF-kappaB and further that orally administered OPC-14117 partially protects against excitotoxin-induced apoptosis of striatal neurons through inhibition of the NF-kappaB apoptotic cascade.
Nakai
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Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bldg 10, Rm. 5C103, 10 Center Drive, MSC 1406, Bethesda, MD 20892-1406, USA.
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D020672:I-kappa B Proteins; D007189:Indans / Q000494:pharmacology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D007189:Indans; D016328:NF-kappa B; D009498:Neurotoxins; C000606206:Nfkbia protein, rat; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D016194:Receptors, N-Methyl-D-Aspartate; D016159:Tumor Suppressor Protein p53; D000072000:NF-KappaB Inhibitor alpha; C074852:OPC 14117; D017378:Quinolinic Acid