thromboxane-a2 and Brain-Edema

Mild to moderate hypothermia (32-35 degrees C) is the first treatment with proven efficacy for postischemic neurological injury. In recent years important insights have been gained into the mechanisms underlying hypothermia's protective effects; in addition, physiological and pathophysiological changes associated with cooling have become better understood.. To discuss hypothermia's mechanisms of action, to review (patho)physiological changes associated with cooling, and to discuss potential side effects.. Review article.. None.. A myriad of destructive processes unfold in injured tissue following ischemia-reperfusion. These include excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage, cerebral thermopooling, and numerous others. The severity of this destructive cascade determines whether injured cells will survive or die. Hypothermia can inhibit or mitigate all of these mechanisms, while stimulating protective systems such as early gene activation. Hypothermia is also effective in mitigating intracranial hypertension and reducing brain edema. Side effects include immunosuppression with increased infection risk, cold diuresis and hypovolemia, electrolyte disorders, insulin resistance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (

Topics: Acidosis; Apoptosis; Body Temperature Regulation; Brain Edema; Brain Ischemia; Calpain; Critical Care; Epilepsy; Free Radicals; Genes, Immediate-Early; Humans; Hypothermia, Induced; Infections; Inflammation; Ion Pumps; Mitochondria; Reperfusion Injury; Thrombosis; Thromboxane A2

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