Kainic acid-induced neuronal cell death in cerebellar granule cells is not prevented by caspase inhibitors

1 We examined the role of non-NMDA receptors in kainic acid (KA)-induced apoptosis in cultures of rat cerebellar granule cells (CGCs). KA (1 - 500 mum) induced cell death in a concentration-dependent manner, which was prevented by NBQX and GYKI 52466, non-NMDA receptor antagonists. Moreover, AMPA blocked KA-induced excitotoxicity, through desensitization of AMPA receptors. 2 Similarly, KA raised the intracellular calcium concentration of CGCs, which was inhibited by NBQX and GYKI 52466. Again, AMPA (100 mum) abolished the KA (100 mum)-induced increase in intracellular calcium concentration. 3 KA-induced cell death in CGCs had apoptotic features, which were determined morphologically, by DNA fragmentation, and by expression of the prostate apoptosis response-4 protein (Par-4). 4 KA (500 mum) slightly (18%) increased caspase-3 activity, which was strongly enhanced by colchicine (1 mum), an apoptotic stimulus. However, neither z-VAD.fmk, a pan-caspase inhibitor, nor the more specific caspase-3 inhibitor, Ac-DEVD-CHO, prevented KA-induced cell death or apoptosis. In contrast, both drugs inhibited colchicine-induced apoptosis. 5 The calpain inhibitor ALLN had no effect on KA or colchicine-induced neurotoxicity. 6 Our findings indicate that colchicine-induced apoptosis in CGCs is mediated by caspase-3 activation, unlike KA-induced apoptosis. British Journal of Pharmacology (2002).