A caspase-3-like protease is involved in NF-kappaB activation induced by stimulation of N-methyl-D-aspartate receptors in rat striatum.

Glutamate receptor stimulation reportedly activates NF-kappaB in vitro and in vivo, although underlying mechanisms remain to be elucidated. Here we evaluated the role of proteases in mediating N-methyl-D-aspartate (NMDA) receptor agonist-induced NF-kappaB activation and apoptosis in rat striatum. The intrastriatal infusion of quinolinic acid (QA, 60 nmol) had no effect on levels of NF-kappaB family proteins, including p65, p50, p52, c-Rel and Rel B. In contrast, QA decreased IkappaB-alpha protein levels by 60% (P<0. 05); other members of the IkappaB family, including IkappaB-beta, IkappaB-gamma, IkappaB-epsilon and Bcl-3, were not altered. The QA-stimulated degradation of IkappaB-alpha was completely blocked by the NMDA receptor antagonist MK-801. QA-induced IkappaB-alpha degradation and NF-kappaB activation were not affected by the proteasome inhibitor MG-132 (1-4 microg). On the other hand, the caspase-3 inhibitor Ac-DEVD.CHO (2-8 microgram) blocked QA-induced IkappaB-alpha degradation in a dose-dependent manner (P<0.05). Ac-DEVD.CHO (4 microgram) also substantially reduced QA-induced NF-kappaB activation (P<0.05), but had no effect on QA-induced AP-1 activation. Furthermore, Ac-DEVD.CHO, but not MG-132, dose-dependently attenuated QA-induced internucleosomal DNA fragmentation. These findings suggest that NF-kappaB activation by NMDA receptor stimulation involves IkappaB-alpha degradation by a caspase-3-like cysteine protease dependent mechanism. Caspase-3 thus appears to contribute to the excitotoxin-induced apoptosis in rat striatal neurons occurring at least partially as a consequence of NF-kappaB activation.