Caspase Inhibition

The pharmacology of caspase inhibition is a rapidly expanding field, and effectiveness of blocking caspase activity is still largely debated (Loetscher et al., 2001). Small peptides that irreversibly inactivate the active enzyme site by alkylating the cysteine residue in the consensus sequence QACXG have recently been synthesized, and block caspases and apoptosis in vitro as well as in vivo. Initially, the involvement of caspases in ischemia-induced cell death was inferred from studies demonstrating that administration of zVAD-fmk, Boc-aspartyl-(Ome)fluoromethyl-ketone (BAF) or z-DEVD-fmk, which are broad-spectrum caspase-inhibitors, before ischemia were neuroprotective in animal models of focal and global ischemia (Loddick et al., 1996; Adachi et al., 2001; Gill et al., 2002). However, the efficacy of these inhibitors in focal ischemia was less clear in later studies. z-DEVD-fmk also has been tested in a transient ischemic model, and, although some reduction in neuronal death was observed, impairment of motor function and long-term potentiation was not prevented (Gillardon et al., 1999), suggesting that caspase inhibition alone does not preserve neuronal function. Intracerebroventricular injections of the same caspase-3 inhibitor promoted cell survival when administered 30 minutes before or two hours after transient ischemia in adult mice (Fink et al., 1998). Another pan-caspase inhibitor, benzyloxycarbonyl-Asp-CH2-dichlorobenzene (zD), also was shown to have neuroprotective effects in a transient ischemia model in gerbils (Himi et al., 1998). The discrepancy between these results may, in part, be due to the different models of ischemia used (global or focal) and the severity of the insult (mild or severe). Administration of a broad-spectrum inhibitor BAF was significantly neuroprotective in P7 rat pups subjected to HI (Rice-Vannucci model) when given by intracerebroventricular injection three hours after cerebral hypoxia-ischemia. In addition, systemic injection of BAF significantly protected brain tissue (Cheng et al., 1998). A combination of systemic hypothermia and BAF produced a strong protective effect against neuronal damage in the same model used (Adachi et al., 2001). These results were not confirmed in the previous model used (Zhu et al., 2003) and in a model of unilateral focal ischemia with reperfusion in 7-day-old-rats, in which systemic BAF administration did not induce a significant reduction in infarct volume (see Figure 42.4A).

However, two populations of animals were found, one of which had no apparent infarct (Joly et al., 2004). A general trend to reduce size lesion was observed after a delayed second dose of BAF administration (Joly et al., 2004). Very recently, a potent nontoxic (due to its carboxy-terminal O-phenoxy group) pan-caspase inhibitor with enhanced cell-permeant properties (due to its amino-terminal quinoline), quinoline-Val-Asp(Ome)-CH2-O-Phenoxy (Q-VD-OPh), was shown to significantly reduce neuronal damage and conferred long-lasting neuroprotection (see Figure 42.4B) and appears as a wider caspase inhibitor than BAF, especially against caspases 2 and 6 (Charriaut-Marlangue et al., 2004). These data were in agreement with a role of mitochon-drially derived cytochrome c and pro-caspase-3 activation in ischemia-induced cell death in neonatal but not in adult brain (Gill et al., 2002; Blomgren et al., 2003).

It is now well known that distinct mechanisms of cell protection (i.e., anti-excitotoxic and anti-apoptotic) may be effective in animal models of stroke, suggesting that, when combined, these treatments could act in synergy.

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