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 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.
Mandir
A S
AS
Departments of Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Poitras
M F
MF
Berliner
A R
AR
Herring
W J
WJ
Guastella
D B
DB
Feldman
A
A
Poirier
G G
GG
Wang
Z Q
ZQ
Dawson
T M
TM
Dawson
V L
VL
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008845:Microinjections; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000819:agonists / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012845:Sindbis Virus / Q000235:genetics; D014162:Transfection; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000378:metabolism
D011064:Poly Adenosine Diphosphate Ribose; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D011065:Poly(ADP-ribose) Polymerases