Energy requirement for caspase activation and neuronal cell death

Recent work has shown that execution of the apoptotic program involves a re latively limited number of pathways. According to a general view, these wou ld converge to activate the caspase family of proteases. However, there is increasing evidence that apoptotic-like features can be found also when cel ls are treated with inhibitors of caspases as the cell permeable tripeptide , Z-Val-Ala-Asp-fluoromethyl-ketone (Z-VAD-fmk), or analogous compounds. Th is has posed the question as to whether apoptosis may occur in a caspase in dependent way, and whether caspase inhibitors may then be used to treat dis eases characterised by an excess apoptosis. It is also becoming clear, that ATP depletion during the early phases of apoptosis can preclude caspase ac tivation, and consequently switch execution of cell death towards necrosis, In vivo, a block or partial inhibition of the typical apoptotic demise may have profound implications, as persistence of damaged but "undead" cells w ithin the nervous system, followed by delayed lysis may favour neuroinflamm atory reactions, In this review, we discuss some recent findings, which sug gest that cells may use diverging execution pathways, with different implic ations in neuropathology and therapy.