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(Stroke. 2002;33:1101.)
© 2002 American Heart Association, Inc.

Original Contributions

Poly(ADP-Ribose) Polymerase Impairs Early and Long-Term Experimental Stroke Recovery

Shozo Goto, MD; Rong Xue, PhD; Nobuo Sugo, MD; Masahiko Sawada, MD; Kathleen K. Blizzard, BS; Marc F. Poitras, PhD; David C. Johns, PhD; Ted M. Dawson, MD, PhD; Valina L. Dawson, PhD; Barbara J. Crain, MD, PhD; Richard J. Traystman, PhD; Susumu Mori, PhD Patricia D. Hurn, PhD

From the Departments of Anesthesiology and Critical Care Medicine (S.G., N.S., M.S., K.K.B., R.J.T., P.D.H.), Biomedical Engineering (R.X.), Radiology (R.X., S.M.), Neurology (M.F.P., T.M.D., V.L.D.), Neurosurgery (D.C.J.), and Pathology (B.J.C.), Johns Hopkins University Schools of Medicine, Baltimore, Md.

Correspondence to Patricia D. Hurn, PhD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N Wolfe St, Blalock 1414, Baltimore MD 21287. E-mail phurn{at}jhmi.edu

Background and Purpose— 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 ß-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.

Key Words: adenosine diphosphate ribose • cerebral ischemia • magnetic resonance imaging • Sindbis virus • mice

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