NMDA But Not Non-NMDA Excitotoxicity is Mediated by Poly(ADP-Ribose) Polymerase

摘要: Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these other toxic models death. Different glutamate agonists trigger different downstream pathways toward neurotoxicity. We examine the role PARP-1 NMDA- non-NMDA-mediated excitotoxicity. NMDA non-NMDA were stereotactically delivered into striatum mice lacking control (48 hr) chronic (3 week) toxicity paradigms. Mice are highly resistant excitoxicity induced by but as equally susceptible AMPA excitotoxicity wild-type mice. Restoring protein viral transfection restored susceptibility NMDA, supporting requirement Furthermore, Western blot analyses demonstrate activated after delivery not administration. Consistent with theory nitric oxide (NO) peroxynitrite prominent NMDA-induced neurotoxicity, was gene for NO synthase These results suggest selective excitoxicity, strategies inhibiting NMDA-mediated neurotoxicity offer substantial neuroprotection.