POLYNITROXYL ALBUMIN REDUCES INFARCT SIZE IN TRANSIENT FOCAL CEREBRAL-ISCHEMIA IN THE RAT - POTENTIAL MECHANISMS STUDIED BY MAGNETIC-RESONANCE-IMAGING

Nitroxide free radicals are known to protect cells from oxidative dama ge. Diffusion-weighted and perfusion-weighted magnetic resonance imagi ng was used to evaluate the effects of polynitroxyl albumin (PNA) in a middle cerebral artery intraluminal suture model of transient focal c erebral ischemia in the rat. Three groups of Sprague-Dawley rats were investigated: (1) PNA (N = 6), (2) human serum albumin (N = 6), and (3 ) saline (N = 7). The middle cerebral artery was occluded for 2 hours. Treatment was started 30 minutes after induction of ischemia. A total dose of 1% body weight (volume/weight) of PNA (23.5 mg/dL protein and 110 mmol/L nitroxide), albumin (23.5 mg/dL), or saline was injected i ntravenously at three time points: 0.5% at 0.5 hours, 0.25% at 2 hours (i.e., just before reperfusion), and 0.25% at 4 hours after occlusion . Six sets of diffusion- and perfusion-weighted magnetic resonance ima ges were acquired throughout the 2 hours of ischemia and the 2 hours o f reperfusion. The rats were killed at 24 hours, and the brains were s tained with 2,3,5-triphenyltetrazolium chloride (TTC). Diffusion-weigh ted imaging showed that the growth of the ischemic lesion was suppress ed in the PNA-treated group. The 4 hours diffusion-weighted imaging-de rived hemispheric lesion volume in the PNA-treated group (25% +/- 9%) was significantly smaller than that in the saline-treated (43% +/- 13% ; P = 0.016) or albumin-treated groups (38% +/- 6%; P = 0.017). A larg er difference was observed for the 24-hour TTC-derived lesion volumes in the PNA (8% +/- 7%), saline (35% +/- 8%; P < 0.001), and albumin (3 1% +/- 6%; P < 0.001) groups. Perfusion-weighted imaging demonstrated a marked improvement in cerebral perfusion in the PNA-treated group du ring ischemia and reperfusion. In conclusion, treatment with PNA resul ts in an improvement in perfusion and a reduction of infarct volume in a model of transient focal cerebral ischemia in the rat.