YM872, A HIGHLY WATER-SOLUBLE AMPA RECEPTOR ANTAGONIST, PRESERVES THEHEMODYNAMIC PENUMBRA AND REDUCES BRAIN INJURY AFTER PERMANENT FOCAL ISCHEMIA IN RATS

Background and Purpose-We recently described an image analysis techniq ue based on the temporal correlation mapping (TCM) of injected contras t agents that can be used to distinguish the hemodynamic core and hemo dynamic penumbra after focal ischemia. In this study we used this tech nique for the first time to investigate the effects of the water-solub le AMPA receptor antagonist YM872 in permanent focal ischemia, Methods -Fischer 344 rats were subjected to permanent occlusion of the middle cerebral artery. Approximately 30 minutes after ischemia, functional C T images were collected with the use of a dynamic scanning protocol wi th bolus injections of nonionic contrast agent iohexol (1 mL/kg). TCM analysis defined the distributions of hemodynamic core and hemodynamic penumbra, Cerebral perfusion indices were calculated on the basis of the area under the first-pass transit curves. One hour after ischemia, animals were randomly treated with YM872 (n=8, 20 mg/kg per hour over 4 hours) or normal saline (n=10). Twenty-four hours later, neurologic al deficits were evaluated, and conventional CT and triphenyltetrazoli um chloride staining were used to define volumes of ischemic damage. R esults-At 24 hours after ischemia, hypodense lesions were visible on c onventional CT scans that were highly correlated with triphenyltetrazo lium chloride lesion volumes. YM872 improved neurological deficits and reduced volumes of ischemic damage in cortex (90+/-14 versus 170+/-16 mm(3) in controls) but not striatum (57+/-14 versus 79+/-6 mm3 in con trols). Comparison of early TCM images with conventional CT scans of i schemic injury showed that the hemodynamic core was always damaged in all rats. In controls, 54% of the tissue within the hemodynamic penumb ra evolved into ischemic damage compared with 24% in YM872-treated rat s. Furthermore, the perfusion index corresponding to the ischemic dama ge threshold was significantly reduced by YM872 (28+/-2% versus 37+/-2 % in controls). Conclusions-These results indicate that YM872 is a neu roprotective compound that ameliorates the deterioration of the hemody namic penumbra after focal ischemia.