Focal and Perifocal Changes in Tissue Energy State during Middle Cerebral Artery Occlusion in Normo- and Hyperglycemic Rats

Abstract

The objective of the present study was to assess changes in cellular energy metabolism in focal and perifocal areas of a stroke lesion and to explore how these changes are modulated by preischemic hyperglycemia. A model for reversible occlusion of the middle cerebral artery (MCA) in rats was used to study changes in energy metabolism. Following MCA occlusion for 5, 15, or 30 min in normoglycemic rats, the tissue was frozen in situ, and samples from the lateral caudoputamen and from two neocortical areas were collected for metabolite analyses, together with a control sample from the contralateral, nonischemic hemisphere. Two other groups, subjected to 30 min of MCA occlusion, were made hyperglycemic by acute glucose infusion or by prior injection of streptozotocin. Enzymatic techniques were used for measurements of phosphocreatine, creatine, ATP, ADP, AMP, glycogen, glucose, pyruvate, and lactate. The neocortex of the contralateral, nonischemic hemisphere had labile metabolites that were similar to those measured in control animals. Ipsilateral neocortex bordering the focus, and thus constituting the “penumbra,” showed mild to moderate ischemic changes. In the “focus” (lateral caudoputamen plus the overlying neocortex), deterioration of energy state was rapid and relatively extensive (ATP content 20–40% of control). After 5 min of occlusion, no further deterioration of metabolic parameters was observed. Substrate levels were markedly reduced, and lactate content rose to ∼10 mM kg−1. In the animals with the most severe energy depletion, no additional accumulation of lactate occurred, suggesting substrate depletion. This was confirmed by the results obtained in the hyperglycemic subjects whose tissue lactate contents rose to ∼20 m M kg−1. However, the energy state of the focus was better preserved in both hyperglycemic groups as compared with the normoglycemic group. It has been shown, in this model, that relatively brief occlusion periods are required to induce infarction. The present results demonstrate that this can occur in spite of the absence of pronounced depletion of energy reserves. After 30 min of MCA occlusion, infarction developed in the lateral caudoputamen, but not in the neocortex. Since a similar perturbation in metabolic state was demonstrated here, other factors must contribute to the degree of tissue damage. The present results suggest that damage is exaggerated by hyperglycemia because it allows additional lactate to accumulate in the partially substrate-depleted tissue.