Abstract
We examined the efficacy of the liposoluble iron chelator 2,2′-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1α (HIF-1α) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (+100%) and HIF-1α (–50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia.
Footnotes
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This study was supported by a research grant supplied by the Conseil Régional de Bourgogne.
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doi:10.1124/jpet.104.072744.
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ABBREVIATIONS: ROS, radical oxygen species; DP, 2,2′-dipyridyl; HO-1, heme oxygenase-1; HIF-1α, hypoxia-inducible factor-1α; CBF, cerebral blood flow; NAA, N-acetylaspartate; GSH, glutathione; GSSG, oxidized form of GSH; BBB, blood-brain barrier.
- The American Society for Pharmacology and Experimental Therapeutics
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