β-Hydroxybutyrate, a Cerebral Function Improving Agent, Protects Rat Brain Against Ischemic Damage Caused by Permanent and Transient Focal Cerebral Ischemia

Abstract

ABSTRACT-In our previous study, b-hydroxybutyrate (BHB) was found to prolong survival time and to inhibit cerebral edema by improving energy metabolism in the hypoxia, anoxia and global cerebral ischemia models. In this study, the cerebroprotective effect of BHB was examined in rats with permanent (p)-occlusion and transient (t)-occlusion of middle cerebral artery (MCA). BHB (30 mg × kg -1 × h -1 ) was continuously administered through the femoral vein. In rats with p-MCA occlusion, BHB significantly reduced infarct area at 24 h after the occlusion, but not at 72 h after the occlusion. In rats with 2-h t-MCA occlusion followed by 22-h reperfusion, BHB significantly reduced cerebral infarct area, edema formation, lipid peroxidation and neurological deficits. Moreover, in the t-MCA occlusion model, delayed administration of BHB started at 1 h after the initiation of the MCA occlusion also significantly reduced cerebral infarct area. Taking together the results obtained in our previous study into account, these results indicate that BHB decreased cerebral edema formation and infarct area by improving of the cerebral energy metabolism during ischemia and by inhibition of lipid peroxidation after reperfusion.Keywords: b -Hydroxybutyrate, Permanent ischemia, Transient ischemia, Middle cerebral artery occlusion, CerebroprotectionIn the previous study, we have shown b-hydroxybutyrate (BHB), one of the ketone bodies, demonstrated cerebral protective activity in experimental screening models for evaluating ischemic brain damage. BHB (50 mg × kg -1 × h -1 ) prolonged the survival time against N 2 gas-induced hypoxia, KCN-induced anoxia and decapitation-induced complete ischemia (1). BHB at a dose of 30 mg × kg -1 × h -1 also inhibited cerebral edema formation, maintained high tissue ATP level, and reduced lactate accumulation without affecting cerebral blood flow in rats subjected to incomplete global cerebral ischemia by bilateral common carotid artery ligation (1). BHB was reported to suppress lactic acidemia and hyperglycemia via alleviation of glycolysis during hemorrhagic shock in rats (2). BHB is converted to acetyl-CoA through pathways other than glycolysis before entering the tricarboxylic acid. These results suggest that preferential utilization of BHB rather than glucose as an energy substrate might reduce the deleterious accumulation of lactate during ischemia.Cerebral edema and infarction are serious clinical complications in acute human cerebrovascular diseases. Recently, several cerebral ischemic models similar to human cerebrovascular diseases have been developed using rats subjected to middle cerebral artery (MCA) occlusion. Tamura et al. developed the electrocauterization model of MCA occlusion in rats (3), and this model has widely been used to investigate therapeutic approach in permanent cerebral ischemia because of its advantages to produce limited cerebral infarction and to be chronically available. There is another model, the intraluminal suture model in rats, in which a nylon suture is inserted into...

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