The microtubule‐disrupting agent colchicine is known to be neurotoxic toward certain neuronal populations including cerebellar granule cells (CGCs). In this study we investigated the involvement of cytochrome c release and caspase‐3 activation during colchicine‐induced CGC apoptosis. Treatment of rat CGCs with 1 μm colchicine (for up to 24 h) caused high molecular weight DNA fragmentation and nuclear condensation. An involvement of group II caspases (which includes caspase‐3) was demonstrated by the proteolytic degradation of poly(ADP‐ribose) polymerase (PARP) after 18 h exposure to colchicine. Colchicine induced a time‐dependent increase in Ac‐Asp‐Glu‐Val‐Asp‐α‐(4‐methyl‐coumaryl‐7‐amide) (DEVD‐MCA) cleavage activity in CGCs, which was blocked with a specific, peptide‐based, aldehyde inhibitor of group II caspases, i.e. DEVD‐CHO. We also observed a time‐dependent proteolysis of caspase‐3 as judged by the appearance of p17 which is one of the subunits of active caspase‐3. Activation of caspase‐3 during colchicine‐induced apoptosis may be mediated by cytochrome c since there was a close correlation between the time courses of cytochrome c release from the mitochondria and of caspase‐3 activation. Furthermore, colchicine‐induced apoptosis, as assessed by propidium iodide visualization of the nuclei, could be blocked by the caspase inhibitor benzyloxycarbonyl‐Val‐Ala‐Asp (O‐methyl) fluoromethyl ketone.
European Journal of Neuroscience – Wiley
Published: Mar 1, 1999
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