Future Perspectives

To date, the considerable amount of information on poly(ADP-ribosyl)ation and stroke undoubtedly indicates a pathogenetic role of PAR formation in ischemic brain injury. Also, a battery of compounds displaying high inhibitory potency toward PARP-1 has been developed and looks promising for ischemic neuroprotection. However, critical issues still wait to be resolved. For instance, current drugs do not exhibit significant selectivity toward PARP-1. This is of particular significance given the role of PARP-2 in DNA repair (Schreiber et al. 2002), and the mutagenic potential of non-selective PARP-1 inhibitors (Tong et al. 2001; Virag and Szabo 2002). Also, acceptable water solubility with satisfactory blood-brain barrier penetrability is an important feature of PARP-1 inhibitors to be optimized. Finally, research aimed at identifying mechanisms underpinning ischemic neuroprotection by inhibition of poly(ADP-ribosyl)ation may also disclose novel players involved in post-ischemic brain damage and provide innovative targets of therapeutic relevance to treatment of cerebral ischemia.

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