title: Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappaB activation and apoptosis in rat striatum.
abstract: 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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Nakai
authors.forename: Z H
authors.initials: ZH
authors.lastname: Qin
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: T N
authors.initials: TN
authors.lastname: Chase
mesh_terms: 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
chemical_list: 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