NMDA and non-NMDA receptor-stimulated IkappaB-alpha 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-kappaB) due to IkappaB-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 microgram intrastriatally), a free radical scavenger (OPC-14117; 600 mg/kg, orally) and ethanol (2.14-8.6 micromol, intrastriatally or 25-100 mmol/kg, orally) on changes induced by these glutamatergic agonists on NF-kappaB cascade components and the apoptotic death of rat striatal neurons in vivo. The results indicated that the QA-induced degradation of IkappaB-alpha is almost totally mediated by a caspase-3-dependent mechanism, while KA-induced IkappaB-alpha degradation is only partially dependent on caspase-3. OPC-14117 attenuated the effects of QA but not KA on IkappaB-alpha degradation, suggesting that oxidative stress contributes to the QA- but not the KA-induced degradation of IkappaB-alpha. In contrast, ethanol inhibited the KA- but not the QA-induced degradation of IkappaB-alpha and the ensuing DNA fragmentation and loss of striatal GABAergic neurons. It would now appear that NF-kappaB activation in striatal neurons induced by NMDA or KA receptor stimulation involves different biochemical mechanisms. Since excitotoxicity associated with NF-kappaB 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.
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, USA.
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Wang
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
D061945:Caspase Inhibitors; D002492:Central Nervous System Depressants; D015853:Cysteine Proteinase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D007189:Indans; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D018808:Transcription Factor AP-1; C108637:aspartyl-glutamyl-valyl-aspartal; D000431:Ethanol; C074852:OPC 14117; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D017378:Quinolinic Acid; D007608:Kainic Acid