Caspase Regulation

Caspase-3 is markedly activated after HI in the immature rat brain (Zhu et al., 2000; Wang et al., 2001; Benjelloun et al., 2003) compared to ischemia in the adult brain (Namura et al., 1998). In P7 rat brain, caspase-3 activation contributes substantially to cell death after ischemia with reperfusion not only in the penumbra but also in the core (Benjelloun et al., 2003; Manabat et al., 2003), and cells with the cleaved active form of caspase-3 colocalize with markers of DNA fragmentation in injured brain regions (Zhu et al., 2000). There is also a good correlation between the downregulation of procaspase-3 expression and a decline of procaspase-3 activation in the maturing rat brain (Hu et al, 2000; Blomgren et al, 2001) as well as for Apaf-1 and caspase-3 genes (Yakovlev et al., 2001). Considering these results together, it has been proposed that, in the brain, the cytochrome c-dependent mitochon-drial pathway is abrogated within two to four weeks after birth, whereas this pathway is still observed in other adult tissues such as the liver (Ota et al., 2002). Caspase-3 activity was the most repeatedly detected enzyme activation after synthetic acetyl-Asp-Glu-Val-Asp-7-amino-4-trifluoromethyl-coumarin (ac-DEVD-AMC) substrate cleavage. As shown in Table 42.2, caspase-3 activity was reported in several but not all studies following ischemia in the adult rats or mice, but sometimes authors were unable to detect it. In contrast, DEVDase activity was found in all the studies in neonatal HI, peaking at 24 hours. This DEVDase activity appeared to be 10- to 20-fold higher in the P7 compared to adult rat and 31- and 25-fold in P5 and P9 mice, respectively, whereas it increases by only about 40% in P21 and P60 mice (Zhu et al., 2005). In the mitochondrial apoptotic pathway, caspase-9 activity precedes caspase-3 activity as reported in the P7 rat brain, after stroke (Benjelloun et al., 2003). Caspase-9 activity was reported only in two studies in adult rodents, but the peak of its activity was shown to follow, and not to precede, that of caspase-3 activity. In addition, caspase-9 activity was demonstrated in the penumbra and not in the core of the infarct (Benchoua et al., 2001).

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