Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappa B activation and apoptosis in rat striatum

Oxidative stress has long been implicated in the pathogenesis of both the a cute and chronic neurotoxic effects of glutamate acting through ionotrophic receptors of the N-methyl-D-aspartate (NMDA) subtype. To evaluate the cont ribution of oxidative stress to the NMDA receptor-mediated apoptotic death of rat striatal neurons in vivo, the effects of a novel, orally administere d free radical scavenger, OPC-14117, was studied following intrastriatal in fusion of the NMDA receptor agonist quinolinic acid (QA). Receptor autoradi ography and in situ hybridization histochemistry showed that pretreatment w ith OPC-14117 (600 mg/kg) reduced the QA (120 nmol)-induced loss of striata l D-1 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 < 0.0 1) and proenkephalin mRNA (36%; p < 0.01). OPC-14117 also decreased the apo morphine-induced ipsilateral rotational response in unilaterally QA-lesione d animals by about 70% (p < 0.05). In addition, OPC-14117 pretreatment inhi bited QA-induced internucleosomal DNA fragmentation. Western blot analysis and electrophoresis mobility shift assay further revealed that the free rad ical scavenger (300 and 600 mg/kg) blunted the QA-induced degradation of I kappa B alpha (increased I kappa B alpha levels from about 15% to 33 and 62 % of control, respectively; p < 0.01) as well as the ensuing activation of NF-kappa B 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 (b oth p < 0.01). In contrast, OPC-14117 had no significant effect on the QA-i nduced increase in AP-1 binding activity. These results suggest that the NM DA receptor-mediated generation of reactive oxygen species contributes to t he QA-induced activation of NF-kappa B and further that orally administered OPC-14117 partially protects against excitotoxin-induced apoptosis of stri atal neurons through inhibition of the NF-kappa B apoptotic cascade. (C) 19 99 Elsevier Science B.V. All rights reserved.