dizocilpine-maleate and Heat-Stroke

Dextromethorphan (DM) has been shown to protect against endotoxic shock in mice. Heatstroke resembles sepsis in many respects. The objective of this study was to examine the heat-induced acute lung inflammation and injury in rats with or without DM, and for comparison with those of the rats with MK-801 (an N-methyl-D-aspartate receptor antagonist), SA4503 (a sigma-1 receptor agonist), or fluoxetine (a serotonin reuptake inhibitor). Heatstroke was induced by exposing the anesthetized rats to heat stress (43°C for 68 min). At 68 minutes after start of heat stress, animals treated with vehicle medium, DM (10-30 mg/kg of body weight, intramuscular), MK-801 (1 mg/kg of body weight, intraperitoneal), SA4503 (1 mg/kg of body weight, intraperitoneal), or fluoxetine (5 mg/kg of body weight, intraperitoneal) were allowed to recover at room temperature (26°C). As compared with vehicle-treated heatstroke rats (25-31 min; n = 8), DM (30 mg/kg)-treated heatstroke rats and MK-801 (1 mg/kg)-treated heatstroke rats had significantly greater survival time (193-209 min [n = 7] and 121-133 min [n = 8], respectively). However, the survival times for the SA4503-treated heatstroke rats (28-34 min; n = 8) or the fluoxetine-treated heatstroke rats (20-26 min; n = 8) were not significantly different from the vehicle-treated heatstroke rats. DM treatment significantly: (1) reduced acute lung injury, including edema, neutrophils infiltration, and hemorrhage scores; (2) decreased acute pleurisy; and (3) decreased bronchoalveolar fluid levels of the proinflammatory cytokines, and ischemia and oxidative damage markers during heatstroke. Our results indicate that DM therapy may improve outcomes of heatstroke in rats by antagonizing the N-methyl-D-aspartate receptors.

Topics: Acute Lung Injury; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Dextromethorphan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluoxetine; Heat Stroke; Hemodynamics; Inflammation Mediators; Lung; Male; Piperazines; Pneumonia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Time Factors

This study attempted to ascertain whether heatstroke-induced ischemia is associated with augmented striatal glutamate release and can be attenuated by NMDA receptor antagonists. Mean arterial pressure (MAP), striatal cerebral blood flow (CBF), striatal glutamate release and striatal neuronal damage score were assessed in saline-treated rats and in rats treated with NMDA receptor antagonists. Heatstroke was induced by exposing the animals to a high ambient temperature; the moment at which MAP and CBF began to decrease from their peak levels was taken as the onset of heatstroke. During onset of heatstroke, rats displayed higher values of colonic temperature, striatal glutamate release and striatal neuronal damage score, and lower values of MAP and striatal blood flow compared with normothermic control rats. The decreased MAP, the diminished striatal blood flow, the augmented striatal glutamate release and the increased striatal neuronal damage score during onset of heatstroke were significantly attenuated by pretreatment with an NMDA receptor antagonist such as MK-801 or ketamine. In addition, the survival time (interval between onset of heatstroke and death) of the rats was extended by pretreatment with one of these two NMDA receptor antagonists. These results suggest that marked accumulation of glutamate in the striatum is important for the development of ischemic damage to striatal neurons during the onset of heatstroke.

Topics: Animals; Body Temperature; Brain Ischemia; Cerebrovascular Circulation; Corpus Striatum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Heat Stroke; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate