RT Journal Article
SR Electronic
T1 NMDA But Not Non-NMDA Excitotoxicity is Mediated by Poly(ADP-Ribose) Polymerase
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8005
OP 8011
DO 10.1523/JNEUROSCI.20-21-08005.2000
VO 20
IS 21
A1 Allen S. Mandir
A1 Marc F. Poitras
A1 Adam R. Berliner
A1 William J. Herring
A1 Daniel B. Guastella
A1 Alicia Feldman
A1 Guy G. Poirier
A1 Zhao-Qi Wang
A1 Ted M. Dawson
A1 Valina L. Dawson
YR 2000
UL http://www.jneurosci.org/content/20/21/8005.abstract
AB 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 insults including, cerebral ischemia,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum 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 excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.