NMDA and non-NMDA receptor-stimulated IκB-α degradation:: differential effects of the caspase-3 inhibitor DEVD • CHO, ethanol and free radical scavenger OPC-14117

The excitotoxic response of striatal neurons to NMDA and non-NMDA receptor agonists involves the nuclear translocation of transcription factor nuclear factor-kappa B (NF-kappa B) due to I kappa B-alpha degradation. Resultant augmentation in c-Myc, p53 and cyclin D1 expression presages the apoptotic-like destruction of these cells in vivo. To differentiate molecular events triggered by intrastriatally injected quinolinic acid (QA, 60 nmol) and kainic acid (KA, 2.5 nmol), we compared the effects of a caspase-3 inhibitor (DEVD . CHO, 8 mu g intrastriatally), a free radical scavenger (OPC-14117; 600 mg/kg, orally) and ethanol (2.14-8.6 mu mol, intrastriatally or 25-100 mmol/kg, orally) on changes induced by these glutamatergic agonists on NF-kappa B cascade components and the apoptotic death of rat striatal neurons in vivo. The results indicated that the QA induced degradation of I kappa B-alpha is almost totally mediated by a caspase-3-dependent mechanism, while KA-induced I kappa B-alpha degradation is only partially dependent on caspase-3. OPC-14117 attenuated the effects of QA but not KA on I kappa B-alpha degradation, suggesting that oxidative stress contributes to the QA- but not the KA-induced degradation of I kappa B-alpha. In contrast, ethanol inhibited the KA- but not the QA-induced degradation of I kappa B-alpha and the ensuing DNA fragmentation and loss of striatal GABAergic neurons. It would now appear that NF-kappa B activation in striatal neurons induced by NMDA or KA receptor stimulation involves different biochemical mechanisms. Since excitotoxicity associated with NF-kappa B activation may contribute to neuronal degenerative disorders such as Huntington's disease, a more detailed understanding of biochemical events underlying ionotrophic glutamate receptor-stimulated cell death may assist in the discovery of alternative approaches to interdicting the deleterious consequences of excitotoxic insult. (C) 2000 Published by Elsevier Science B.V. All rights reserved.