Yoshiaki Ochi

Protective effect of a new prostacyclin analogue OP-2507 against cerebral anoxia and edema in experimental animals

Protective effects of OP-2507 [15-cis-(4-propylcyclohexyl)-16,17,18,19,20-pentanor-9-deoxy -9 alpha, 6-nitrilo-PGF1 methyl ester] against cerebral anoxia and edema were investigated in a variety of experimental models in mice and rats. OP-2507 given s.c. or p.o. led to a consistent and dose-dependent prolongation of survival time against cerebral anoxia in hypobaric and normobaric hypoxia, KCN-induced anoxia and decapitation-induced gasping. Furthermore, treatment with 0.03-0.1 mg/kg s.c. or 0.3 mg/kg p.o. of OP-2507 was found to be effective against the changes of cerebral energy metabolites and cyclic nucleotides in hypoxic brain. In brain ischemia induced by bilateral ligation of common carotid arteries of rats, a reduction in specific gravity of cortex and an increase in water content of brain were observed, in accordance with changes of cerebral energy metabolites. These edematous and biochemical changes were prevented by the treatment with 0.01-0.03 mg/kg s.c. of OP-2507. These results indicate a potential usefulness of OP-2507 in protecting the brain from oxygen insufficiency resulting from cerebral ischemia.

Protective effect of prostaglandins D2, E1, and I2 against cerebral hypoxia/anoxia in mice

Summary1.The protective effect of prostaglandins (PGs) against cerebral hypoxia/anoxia was investigated with a variety of experimental models in relation to their CNS depressant effects in mice. Furthermore, the effect of PGs on the changes of cerebral energy metabolites and cyclic nucleotide was examined in hypoxic mice. Mice were given s.c. doses of PGs 30 min before tests. Among the PGs tested, treatment with PGD2, PGE1 and PGI2 Na showed a consistent and dose-dependent protection against cerebral anoxia induced by all models studied: histotoxic anoxia by KCN, hypobaric hypoxia, normobaric hypoxia and decapitation-induced gasping. However, PGA1, PGA2, PGB1, PGB2, PGE2, PGF1α, PGF2α and 6-keto-PGF1α at a dose of 3mg/kg were without effect against normobaric hypoxia and gasping duration.2.The three PGs, i.e. PGD2, PGE1 and PGI2 which showed anti-hypoxic effects decreased locomotor activity and potentiated hexobarbital-induced sleep. On the other hand, PGE2, PGA1, PGA2 and PGB2 also caused a decrease in locomotor activity. Similarly, PGE2 and PGA1 caused a potentiation of hexobarbital-induced sleep, but interestingly they did not cause clear-cut increase in cerebral resistance to hypoxia, in contrast with the former three PGs. Thus general depression of CNS function appears not to be responsible for the PGD2-, PGE1- and PGI2-induced increase in cerebral resistance to hypoxia.3.The levels of Cr-P and ATP were significantly reduced and those of ADP and AMP were markedly elevated in hypoxic brain, resulting in a decrease in a calculated energy charge potential. The lactate level and lactate/pyruvate ratio increased and the glucose level decreased markedly. Also, an elevation in cyclic AMP was observed in hypoxic brain. Treatment with 1–3 mg/kg, s.c. of PGD2 or PGE1 and 0.1–3 mg/kg, s.c. of PGI2 Na was found to be effective against the changes of energy metabolites and cyclic nucleotide in hypoxic brain.4.Thus, PGD2, PGE1 and PGI2 possess a protective effect against cerebral hypoxia/anoxia by various causing, and it was suggested that these protective effect was related to an increase in the energy reserve available or a decrease in the cerebral energy demand.