Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.
Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive 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 against glutamate-NO-mediated ischemic insults in vitro and major decreases 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 suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.
Eliasson
M J
MJ
Department of Pharmacology & Molecular Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Sampei
K
K
Mandir
A S
AS
Hurn
P D
PD
Traystman
R J
RJ
Bao
J
J
Pieper
A
A
Wang
Z Q
ZQ
Dawson
T M
TM
Snyder
S H
SH
Dawson
V L
VL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001921:Brain / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002560:Cerebrovascular Circulation; D004249:DNA Damage; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D007113:Immunity, Innate; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D009566:Nitrates / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009498:Neurotoxins; D009566:Nitrates; D010880:Piperidines; D009243:NAD; C039642:peroxynitric acid; D009569:Nitric Oxide; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D016202:N-Methylaspartate; C037689:benzamide; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases