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  • Title: Poly(ADP-ribose) polymerase impairs early and long-term experimental stroke recovery.
    Author: Goto S, Xue R, Sugo N, Sawada M, Blizzard KK, Poitras MF, Johns DC, Dawson TM, Dawson VL, Crain BJ, Traystman RJ, Mori S, Hurn PD.
    Journal: Stroke; 2002 Apr; 33(4):1101-6. PubMed ID: 11935067.
    Abstract:
    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 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.
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