Poly(ADP-ribose) polymerase impairs early and long-term experimental stroke recovery.
OBJECTIVE
Poly(ADP-ribose) polymerase (PARP-1; Enzyme Commission 2.4.30) is a nuclear DNA repair enzyme that mediates early neuronal ischemic injury. Using novel 3-dimensional, fast spin-echo-based diffusion-weighted imaging, we compared acute (21 hours) and long-term (3 days) ischemic volume after middle cerebral artery (MCA) occlusion in PARP-1-null mutants (PARP-/-) versus genetically matched wild-type mice (WT mice). PARP-/- mice were also treated with viral transfection of wild-type PARP-1 to determine whether protection from MCA occlusion is lost with restoration of the gene product.


METHODS
Halothane-anesthetized mice were treated with reversible MCA occlusion via intraluminal suture technique. Ischemic volumes were delineated by diffusion-weighted imaging with high spatial and temporal resolution during MCA occlusion and reperfusion. Recombinant Sindbis virus carrying beta-galactosidase (lacZ) or PARP-1 was injected into ipsilateral striatum, then animals underwent MCA occlusion 3 days later. Infarction volume was measured at 22 hours of reperfusion (2,3,5-triphenyltetrazolium chloride histology).


RESULTS
Reduction in regional water apparent diffusion coefficient (ADC) during occlusion or secondary ADC decline during reperfusion was not different between groups. Ischemic volume was smaller early in occlusion in PARP-/- versus WT mice and remained less at 21 hours of reperfusion. Ischemic volume then increased from 1 to 2 days in all mice, then stabilized without further change. Ischemic damage was smaller in PARP-/- than in WT mice at 3 days. Transfection of PARP-1 into PARP-/- mice increased stroke damage relative to lacZ-injected PARP-/- and increased damage to that of the WT mice. Intraischemic laser-Doppler flowmetry and physiological variables were not different among groups.


CONCLUSIONS
PARP-1 deficiency provides both early and prolonged protection from experimental focal stroke. The mechanism is not linked to preservation of ADC and mitigation of secondary energy depletion during early reperfusion.
Goto
Shozo
S
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University Schools of Medicine, Baltimore, Md 21287, USA.
Xue
Rong
R
Sugo
Nobuo
N
Sawada
Masahiko
M
Blizzard
Kathleen K
KK
Poitras
Marc F
MF
Johns
David C
DC
Dawson
Ted M
TM
Dawson
Valina L
VL
Crain
Barbara J
BJ
Traystman
Richard J
RJ
Mori
Susumu
S
Hurn
Patricia D
PD
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002544:Cerebral Infarction / Q000209:etiology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004058:Diffusion; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects* / Q000235:genetics; D015424:Reperfusion; D012845:Sindbis Virus / Q000235:genetics; D020521:Stroke / Q000209:etiology / Q000503:physiopathology*; D013995:Time; D014162:Transfection; D014867:Water / Q000378:metabolism
D014867:Water; D011065:Poly(ADP-ribose) Polymerases