PPAR-Alpha Agonist Used at the Acute Phase of Experimental Ischemic Stroke Reduces Occurrence of Thrombolysis-Induced Hemorrhage in Rats

Figure 1

Evaluation of the effects of the PPAR-α agonist fenofibrate administered during the acute phase of experimental stoke in combination with thrombolysis with tPA on neuronal and vascular compartments. Evaluation takes place 72 h after the induction of middle cerebral artery occlusion in the rat. Fenofibrate (50 mg/kg/day) or vehicle was administered by twice-daily gavage over 72 h. Values are means ± SEM. (a) Blinded, histological evaluation of the number of petechiae (as seen in the picture) in the infarct area revealed a significant decrease () in the hemorrhagic risk of tPA when fenofibrate had been administered (–9 per group). (b) The total, cortical, and striatal infarction volumes were clearly lower in fenofibrate-treated rats, compared with the vehicle group (–9 per group, ) as seen in the histological images for cresyl fast violet staining. (c) The application of increasing doses of acetylcholine led to endothelium-dependent relaxation, which was altered by ischemia and thrombolysis (). However, the postischemia dysfunction in relaxation was prevented by acute treatment with fenofibrate () (-6 per group). (d) Expression of ICAM-1 adhesion protein, a marker of leukocyte/endothelium interactions, was increased during ischemia and thrombolysis but was lowered by fenofibrate treatment ( per group; ); scale bar, 100 μm. (e) Neutrophil infiltration into the infarct area, quantified by counting the anti-myeloperoxidase-positive cells, was significantly decreased by fenofibrate treatment ( per group; ). Scale bar, 100 μm. (f) Expression of CD11b by Ox 42 antibody, a marker of microglial activation, was increased during ischemia and thrombolysis but was lowered by fenofibrate treatment ( per group; ); scale bar, 25 μm.

(a) Hemorrhages

(b) Infarct volume

(c) Cerebrovascular endothelium function

(d) Vascular ICAM-1

(e) Infiltrated PMN

(f) Activated microglial cells