POLY(ADP-RIBOSE) POLYMERASE GENE DISRUPTION RENDERS MICE RESISTANT TOCEREBRAL-ISCHEMIA

Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide ani on, have been implicated as mediators of neuronal damage following foc al ischemia, but their molecular targets have not been defined. One ca ndidate pathway is DNA damage leading to activation of the nuclear enz yme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. E xcessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection aga inst glutamate-NO-mediated ischemic insults in vitro and major decreas es in infarct volume after reversible middle cerebral artery occlusion . These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and sug gest that therapies designed towards inhibiting PARP may provide benef it in the treatment of cerebrovascular disease.