One possibility is that the differential
effect of caspase inhibitors might reflect the use of different excitotoxic
stimuli. Alternatively, it has been suggested that caspase inhibitors might
prevent the internucleosomal DNA degradation and morphologic manifestations
of apoptosis without preventing death by a caspase-independent
pathway.188 This latter explanation is highly reminiscent of results of McCarthy
et al., who demonstrated that caspase inhibitors prevent apoptotic
changes without inhibiting cell death after a variety of treatments in Rat-1
fibroblasts.192 Further studies are required to distinguish between these two
possibilities. As is the case with neurotrophin withdrawal-induced apoptosis,
the pathways that lead to caspase activation and the roles of individual
caspases in excitotoxic PCD also remain to be clarified.