ozagrel and Brain-Edema

Topics: Anticoagulants; Antipyrine; Arginine; Aspirin; Brain Edema; Edaravone; Fibrinolytic Agents; Free Radical Scavengers; Glycerol; Humans; Hyperlipidemias; Hypertension; Japan; Methacrylates; Pipecolic Acids; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Risk Factors; Stroke; Sulfonamides; Thrombolytic Therapy; Time Factors; Warfarin

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.

Topics: Animals; Antithrombins; Arginine; Aspirin; Blood Pressure; Brain Edema; Cerebrovascular Circulation; Fibrinolytic Agents; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Methacrylates; Microcirculation; Nerve Degeneration; Neurons; Pipecolic Acids; Sulfonamides; Survival Rate; Thrombin

Effects of thromboxane A2 (TXA2) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.

Topics: Animals; Aspirin; Brain Chemistry; Brain Edema; Cerebral Arteries; Cerebral Infarction; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Fibrinolytic Agents; Guinea Pigs; Intracranial Embolism and Thrombosis; Lactates; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Methacrylates; Photochemistry; Potassium; Pyridines; Rabbits; Rats; Rats, Sprague-Dawley; Rose Bengal; Sodium; Thromboxane A2; Ticlopidine

Head trauma (HT) was induced in the left hemisphere of rats by a weight drop device. Edema was maximal 24 h after HT in the injured zone, and PGE2, TXB2 and 6-keto-PGF1 alpha were elevated in both the injured and remote areas. The effect of a specific thromboxane synthetase inhibitor, OKY-046, on the outcome of HT was studied. OKY-046, 100 mg/kg, was given to rats immediately and 8 h after HT. The neurological severity score (NSS) was evaluated at 1 h after HT, and at 24 h, just prior to sacrifice. Specific gravity (SG) of both hemispheres was measured after decapitation. Prostaglandins (PGs) were extracted from the site of injury and from the frontal lobes, remote from the injury, and assayed by RIA. Basal levels of PGE2 and 6-keto-PGF1 alpha were not reduced by the drug while basal TXB2 levels were lowered. However, the increased production due to HT of all PGs, was inhibited by OKY-046, especially that of TXB2. The ratio of TXB2/6-keto-PGF1 alpha, known to affect vascular tone, was reduced by OKY-046 treatment as a result of TXA2 synthesis inhibition. Still, no effect was found on the neurological outcome (as evaluated by the NSS), or on edema formation (expressed by reduced SG). Thus, based on the present findings increased TXA2 synthesis cannot be implicated in the pathophysiology of cerebral edema or dysfunction following HT.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Brain Edema; Brain Injuries; Dinoprostone; Male; Methacrylates; Rats; Specific Gravity; Thromboxane B2; Thromboxane-A Synthase

The involvements of arachidonic acid metabolites in the development of ischemic brain edema and cerebral energy metabolism were investigated on the experimental ischemia and reperfusion model. The level of arachidonic acid in brain tissue increases especially on the ischemic insult, which is rapidly converted to prostaglandins and leukotrienes after the reperfusion. The drugs which modify the arachidonic acid metabolism were administrated to clarify the effect on ischemic brain edema and cerebral energy metabolism. Male stroke resistant spontaneously hypertensive rats (SHRSR) were subjected to incomplete ischemia for two hours by occlusion of both common carotid arteries with vascular clips, and reperfused for two hours. The drugs used are dexamethasone, indomethacin, trapidil and OKY-046. Indomethacin inhibits cyclooxygenase. Dexamethasone inhibits phospholipases by the production of lipocortin. OKY-046 inhibits thromboxane A2 synthetase. Trapidil inhibits thromboxane A2 synthetase and increases the level of 6-keto-PGF1 alpha. These drugs were administered 18 hours before, just after clipping on (1/2) and off (1/2). Brain water content, cerebral ATP and lactic acid levels were examined. In the saline treated group, the cerebral water content was increased after the reperfusion and reached its maximal level after two hours of the reperfusion. The development of brain edema was prevented by the administration of dexamethasone or trapidil, but not by indomethacin and OKY-046. Administration of trapidil or dexamethasone was found to prevent the decrease in ATP and the increase of lactic acid. In the indomethacin administrated group, only the increase of lactic acid was prevented. 6-keto-PGF1 alpha was high in the trapidil administrated group and low in the indomethacin administrated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Arachidonic Acids; Body Water; Brain; Brain Edema; Dexamethasone; Energy Metabolism; Indomethacin; Lactates; Lactic Acid; Male; Methacrylates; Perfusion; Rats; Rats, Inbred SHR; Trapidil