Antiapoptotic Agents

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in stroke injury. Caspases, a family of cysteine-aspartate proteases that include at least 14 members divided into three groups (I, II, and III), are essential players in apoptotic death. Many groups have studied the effects of caspase inhibition on cerebral ischemia-induced neurodegeneration by using the broad spectrum caspase inhibitor z-VAD, either in the fluoromethylketone (fmk) or dichlorobenzoylox-opentanoic acid (dcb) form and z-DVED-fmk. Both inhibitors were neuroprotective in mouse models of transient cerebral ischemia, and z-VAD was neuroprotec-tive also in transient and permanent models in the rat (Hara et al., 1997). Ac-YVAD-cmk (Ac-Tyr-Val-Ala-Asp-cmk), a caspase group I (caspase-1-like) inhibitor also was shown to be neuroprotective in a mouse transient model of cerebral ischemia (Hara et al., 1997). Peptide-based caspase inhibitors also have been shown to prevent neuronal loss in animal models of stroke. A protein identified as having anti-apoptotic activity in many different cell types, including neurons, is Bcl-2. Bcl-2 is one of a family of related proteins, some of which have anti-apoptotic properties (e.g., Bcl-xL, Mcl-1), whereas others are pro-apoptotic (e.g., Bax, Bid, and Bad) (Mattson et al., 2000). The efficacy of anti-apoptotic agents in human stroke patients has not been tested.

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