ataprost and Brain-Ischemia

A PGI2 derivative, OP-41483, and a hyperosmotic agent, glycerol, were tested for possible beneficial effects on brain edema, metabolism and pathological changes in cerebral ischemia. Combination treatment with these agents was also tested. Cerebral ischemia was produced in spontaneously hypertensive rats, using bilateral common carotid artery ligation (BLCL). OP-41483 was administered four times, hourly (500 ng/kg x 4, i.p.). Ten percent glycerol was administered intravenously (6.6 ml/kg). And, for the combination treatment, OP-41483 was administered three times, hourly (500 ng/kg x 3, i.p.), and 10% glycerol was administered intravenously (6.6 ml/kg) in the same manner as the glycerol treated group. In ischemic controls, saline was administered intravenously (6.6 ml/kg). After 3 h of ischemia, brain water content and metabolites were determined and pathological observation was conducted using electron microscopy. OP-41483 treated animals maintained higher levels of ATP concentration and reduced accumulation of lactate, but showed no difference in brain water content compared to saline treated controls. Glycerol treated animals showed significance in terms of reduction of brain water content and accumulation of lactate. Glycerol abated the depletion of ATP concentration. OP-41483+glycerol treated animals showed the most significant effect on the reduction of brain water content and accumulation of lactate. The combination treatment also maintained higher levels of ATP concentration. Additionally, swelling of astrocytic foot processes and mitochondria with destroyed crista were not observed pathologically in the combination treated animals. These results show that OP-41483, glycerol and combination treatment are beneficial in the treatment of cerebral ischemia. They also indicate that the combination treatment significantly enhances the protective effects compared to individual treatment.

Topics: Animals; Body Water; Brain; Brain Edema; Brain Ischemia; Cerebral Cortex; Drug Therapy, Combination; Epoprostenol; Glycerol; Male; Microscopy, Electron; Rats; Rats, Inbred SHR

In order to clarify the role of platelets as a factor aggravating cerebral ischemia, an experimental model of ischemia was investigated using thrombocytopenic rats. In addition, the prostacyclin derivative (OP-41483) and the thromboxane A2 synthetase inhibitor (OKY-046), both of which inhibit platelet aggregation, were tested for possible beneficial effects on cerebral ischemia. Cerebral ischemia was produced in spontaneously hypertensive male rats using bilateral common carotid artery ligation (BLCL). Thrombocytopenia was produced with an antiplatelet antiserum which reduced the platelet count to less than 6 x 10(4)/microliters by 24 h. OP-41483 was administered four times hourly (500 ng/kg x 4, i.p.), beginning 1 h prior to BLCL. Similarly, OKY-046 was injected four times hourly (10 mg/kg x 4, i.p.). Brain metabolites such as ATP, lactate and pyruvate and water content were determined after 3 h of cerebral ischemia. Brain levels of ATP in the ischemic rats with thrombocytopenia were higher than those of the ischemic rats without thrombocytopenia. In addition, thrombocytopenia reduced the increase of lactate and water content in the ischemic brain. Animals treated with OP-41483 also maintained higher levels of ATP and lower levels of lactate and water compared to animals given a vehicle. OKY-046 significantly reduced brain water content, but had no effect on the ischemic alteration of brain metabolite levels. These results indicate that platelets play an important role in the progression of metabolic change during ischemia.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Body Water; Brain; Brain Ischemia; Epoprostenol; Immune Sera; Lactates; Male; Methacrylates; Platelet Aggregation Inhibitors; Platelet Count; Pyruvates; Rats; Rats, Inbred SHR; Reference Values; Thrombocytopenia; Thromboxane-A Synthase

Arachidonic acid is liberated from damaged cell membranes during ischemia and is the source of vasoactive prostanoids. In this study, specific drugs that influence AA metabolism were investigated for their effects on brain edema and energy metabolites during ischemia. The agents tested were: methylprednisolone (phospholipase A2 inhibition), indomethacin (cyclooxygenase inhibitor), trapidil (TXA2 synthetase inhibitor), and OP-41483 (prostacyclin derivative). Cerebral ischemia was produced using bilateral common carotid artery occlusion in spontaneously hypertensive rats. Brain water content and concentrations of ATP, pyruvate, and lactate were determined 3 hr after occlusion. Compared with its vehicle, methylprednisolone significantly reduced water content and lactate concentration and maintained high levels of ATP. Indomethacin had no effect on brain water content nor metabolite levels. Trapidil decreased water content and lactate levels and increased levels of ATP and pyruvate. OP-41483 had no effect on water content and lactate, but maintained ATP and pyruvate at high levels. These results indicate that some of the AA metabolites may play an important role in the development of brain edema and in the impairment of energy metabolism.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain Chemistry; Brain Edema; Brain Ischemia; Energy Metabolism; Epoprostenol; Hypertension; Indomethacin; Male; Membrane Lipids; Methylprednisolone; Rats; Rats, Inbred SHR; Trapidil