NMDA but not non-NMDA excitotoxicity is mediated by poly(ADP-ribose) polymerase

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of i nsults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropy ridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to u nderlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. W e examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striat um of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the e xcitoxicity induced by NMDA but are as equally susceptible to AMPA excitoto xicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 b y viral transfection restored susceptibility to NMDA, supporting the requir ement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses d emonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and perox ynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activa ted in mice lacking the gene for neuronal NO synthase after NMDA administra tion. These results suggest a selective role of PARP-1 in glutamate excitox icity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity m ay offer substantial acute and chronic neuroprotection.