CHANGES IN THE BIOENERGETIC STATE OF RAT HIPPOCAMPUS DURING 2.5 MIN OF ISCHEMIA, AND PREVENTION OF CELL-DAMAGE BY CYCLOSPORINE-A IN HYPERGLYCEMIC SUBJECTS

A recent study from this laboratory has shown that brief transient isc hemia (2 min 30 s) in normo- and hyperglycemic rats leads to moderate neuronal necrosis in CAI cells of the hippocampus, of equal density in the two groups. However, hyperglycemic animals failed to depolarize d uring tile ischemia, nor did they show a decrease in extracellular cal cium concentration. The present study was undertaken to study the meta bolic correlates to these unexpected findings. Normoglycemic (plasma g lucose similar to 6 mM) and hyperglycemic (similar to 20 mM) rats were subjected to ischemic periods of 1 min and 2 min 15 a (2 min 30 s wit h freezing delay considered), and their brains were frozen in Situ. Sa mples of dorsal hippocampus were dissected at -22 degrees C and extrac ted for the measurement of phosphocreatine (PCr), creatine. ATP, ADP, AMP, glucose, glycogen, and lactate. Normoglycemic animals showed rapi d depletion of PCr, ATP, glucose, and glycogen, and a rise in lactate content to 10-12 mM.kg(-1) during the ischemia. Hyperglycemic animals displayed a more moderate rate of fall of PCr and ATP, with ATP values exceeding 50% of control after 2 min 30 s. Glycogen stores were large ly maintained, but degradation of glucose somewhat enhanced the lactic ac idosis. The results demonstrate that hyperglycemic rats maintained ATP at levels sufficient to prevent cell depolarization and calcium i nflux during the ischemic period. However, the metabolic perturbation observed must have been responsible for tile delayed neuronal damage. We speculate that lowered ATP, increased inorganic P, and oxidative st ress triggered a delayed mitochondrial permeability transition (MPT), which led to delayed neuronal necrosis. This assumption was supported by a second series of experiments in which CAI damage in hyperglycemic rats was prevented by cyclosporin At a virtually specific inhibitor o f tile MPT.