Neurobiology of AIF and PARP in cerebral ischemia

Polyadenosine diphosphoribose polymerase-1 (PARP-1) is an important mediator of neuronal cell death following cerebral ischemia. Normally a guardian of the genome required for the proper cellular response to DNA damage following mild to moderate stress, this nuclear enzyme is overactivated following acute neuronal injury. The result is unregulated synthesis of polyadenosine diphosphoribose (PAR) followed by widespread neuronal cell death. Once thought to be a purely necrotic type of cell death, recent findings suggest that one underlying mechanism of this PARP-1-dependent neuronal cell death appears to involve the translocation of the mitochondrial flavoprotein apoptosis-inducing factor (AIF) to the nucleus, which triggers a caspase-independent form of cell death. Inhibition of PARP-1 activity results in decreased PAR synthesis, inhibition of AIF translocation, and extensive neuronal cell survival. Therefore, PARP-1 and AIF, two principal mediators of neuronal cell death following cerebral ischemia, are emerging as therapeutic targets in the treatment of stroke.