N-TERT-BUTYL-ALPHA-PHENYLNITRONE IMPROVES RECOVERY OF BRAIN ENERGY-STATE IN RATS FOLLOWING TRANSIENT FOCAL ISCHEMIA

Recent results have demonstrated that the spin trapping agent N-tert-b utyl-alpha-phenylnitrone (PBN) reduces infarct size due to middle cere bral artery occlusion (MCAO), even when given after ischemia. The obje ctive of the present study was to explore whether PEN influences recov ery of energy metabolism. MCAO of 2-hr duration was induced in rats by an intraluminal filament technique. Brains were frozen in situ at the end of ischemia and after 1, 2, and 4 hr of recirculation. PEN was gi ven 1 hr after recirculation. Neocortical focal and perifocal (''penum bra'') areas were sampled for analyses of phosphocreatine (PCr). Creat ine, ATP, ADP, AMP, glycogen, glucose, and lactate. The penumbra showe d a moderate-to-marked decrease and the focus showed a marked decrease in PCr and ATP concentrations, a decline in the sum of adenine nucleo tides, near-depletion df glycogen, and an increase in lactate concentr ation after 2 hr of ischemia. Recirculation for 1 hr led to only a par tial recovery of energy state, with little further improvement after 2 hr and signs of secondary deterioration after 4 hr, particularly in t he focus. After 4 hr of recirculation, PBN-treated animals showed pron ounced recovery of energy state, with ATP and lactate contents in both focus and penumbra approaching normal values. Although an effect of P EN on mitochondria cannot be excluded, the results suggest that PEN ac ts by preventing a gradual compromise of microcirculation. The results justify a reevaluation of current views on the pathophysiology of foc al ischemic damage and suggest that a therapeutic window of many hours exists in stroke.