platonin and Shock

The aim of this study was to investigate the therapeutic effect of platonin, a cyanine photosensitizing dye as well as an inhibitor of proinflammatory cytokines, in an animal model of heat stroke. Anesthetized rats, immediately after the onset of heat stroke, were divided into two major groups and given the following: normal saline (1 mL per kg body weight) intravenously, or platonin (12.5-50 microg/mL per kg body weight) intravenously. They were exposed to ambient temperature of 43 degrees C to induce heat stroke. Another group of rats was exposed to room temperature (26 degrees C) and used as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 18 to 22 min. Resuscitation with intravenous doses of platonin, but not normal saline, immediately at the onset of heat stroke, significantly improved survival during heat stroke (41-147 min). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, fibrinogen degradation products, and D-dimer, and decreased platelet count and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase, and striatal levels of partial pressure of oxygen, local cerebral blood flow, glycerol, glutamate, and lactate/pyruvate were all elevated during heat stroke. The systemic inflammation, hypercoagulable state, and cerebral ischemia and injury during heat stroke were all significantly suppressed by platonin. The data demonstrate that platonin therapy may resuscitate heat stroke victims by reducing circulatory shock, systemic inflammation, hypercoagulable state, and tissue ischemia and injury.

Topics: Animals; Blood Coagulation; Cell Hypoxia; Heat Stroke; Inflammation; Injections, Intravenous; Ischemia; Photosensitizing Agents; Rats; Rats, Sprague-Dawley; Shock; Thiazoles

Platonin, a cyanine photosensitizing dye, is a potent macrophage-activating agent and an immunomodulator. In this study, we compare the inhibitory effects of platonin with those of the three clinical drugs minocycline, clindamycin, and cyclosporin, on hypotension, tachycardia, and nitric oxide (NO) formation in a rat model of circulatory shock induced by Escherichia coli lipopolysaccharide (LPS). We also evaluate the effect of drugs on the 6 h survival rate in LPS-treated rats. Administration of LPS (15 mg/kg) caused a rapid drop in mean arterial blood pressure (MAP). Minocycline (10 mg/kg, i.v.) significantly prevented the fall of MAP at 3 h, and platonin (100 microg/kg, i.v.) markedly prevented the fall of MAP within the 0-3 h period after LPS administration. However, neither clindamycin (10 mg/kg, i.v.) nor cyclosporin (15 mg/kg, i.v.) had any effects in this study. On the other hand, an inducible NO synthase inhibitor, NG-nitro-L-arginine ester (L-NAME), caused a significantly increase in MAP and a moderate bradycardia after LPS administration. In addition, an increase in plasma nitrate formation elicited by endotoxemia was significantly reduced by pretreatment with either minocycline (10 mg/kg) or platonin (100 microg/kg). However, only platonin (100 microg/kg) markedly reduced the mortality and prolonged the mean survival time in LPS-treated rats. Minocycline, clindamycin, and cyclosporin had no effects under the same conditions. Further studies using an electron spin resonance (ESR) method were conducted on the scavenging activity of platonin on the free radicals formed. Platonin (10 microm) greatly reduced the ESR signal intensity of superoxide anion, hydroxyl radical, and methyl radical formation. In conclusion, platonin has beneficial effects on ameliorating endotoxaemia. This protective effect of platonin may be mediated, at least partly, by the reduced drop in MAP and the inhibition of NO and free radical formation in rat models of endotoxemia.

Topics: Animals; Endotoxemia; Lipopolysaccharides; Male; Photosensitizing Agents; Rats; Rats, Inbred WKY; Shock; Thiazoles