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...

l-Carnitine significantly increased the number of CFU-E colonies in mouse bone marrow cell cultures. This finding suggests that l-carnitine stimulates erythropoiesis, partially accounting for its mitigating effect on renal anaemia.

To analyze specific genes related to radiation-induced apoptosis, 12 apoptosis-resistant clones were isolated from cells of the radiosensitive mouse thymic lymphoma 3SB line after treatment with ethyl methanesulfonate. Five of 12 clonal cell lines were recloned and were examined for their susceptibility to X-ray-induced apoptosis. A cell survival assay showed that all five secondary cell lines were two to three times more resistant to X rays than 3SB cells. When 3SB cells were exposed to 5 Gy of X rays, the fraction of cells stained with erythrosin B increased quickly within 8 h of incubation after irradiation. However, no apoptosis occurred in these secondary mutant cells. In particular, the percentage of cells undergoing apoptosis in one clone, 1B1C4, was low even after incubation for 48 h. In contrast to X rays, after exposure to 20 J/m2 UV radiation, the proportion of apoptotic cells in these mutant cells increased and reached about 60 to 100% at 24 h, indicating a difference in the ability of X rays and UV radiation to induce apoptosis. A similar radioresistance was observed using agarose gel electrophoresis of DNA from cells of all X-irradiated secondary lines. Western blot analysis and a sequence-specific DNA-binding assay demonstrated that 1B1C4 cells had a functional defect in p53 protein, but the other four cell lines displayed wild-type p53 after X irradiation. Our results suggest the existence of separate radiation-specific p53-dependent and independent apoptosis in thymic lymphoma cells. Thus these apoptosis-resistant cell lines provide a useful tool to identify the genes involved in the signaling pathways leading to X-ray-specific apoptosis.

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