Search

Heat shock protein 70 (Hsp70) preconditioning induces thermotolerance, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a role in the process of autophagy. Here, we investigated whether 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) protected against heat stroke (HS) in rats by up-regulation of Hsp70 and phosphorylated AMPK (pAMPK). To produce HS, male Sprague-Dawley rats were placed in a chamber with an ambient temperature of 42°C. Physiological function (mean arterial pressure, heart rate and core temperature), hepatic and intestinal injury, inflammatory mediators and levels of Hsp70, pAMPK and light chain 3 (LC3B) in hepatic tissue were measured in HS rats or/and rats pre-treated with 17-DMAG. 17-DMAG pre-treatment significantly attenuated hypotension and organ dysfunction induced by HS in rats. The survival time during HS was also prolonged by 17-DMAG treatment. Hsp70 expression was increased, whereas pAMPK levels in the liver were significantly decreased in HS rats. Following pre-treatment with 17-DMAG, Hsp70 protein levels increased further, and pAMPK levels were enhanced. Treatment with an AMPK activator significantly increased the LC3BII/LC3BI ratio as a marker of autophagy in HS rats. Treatment with quercetin significantly suppressed Hsp70 and pAMPK levels and reduced the protective effects of 17-DMAG in HS rats. Both of Hsp70 and AMPK are involved in the 17-DMAG-mediated protection against HS. 17-DMAG may be a promising candidate drug in the clinical setting., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

1. There is evidence that hydroxyl radicals are accumulated and oxidative stress is produced in multiple organs, including the brain, of rats with heat stroke. Herein, we investigated the effect on heat stroke-induced circulatory shock and cerebral ischaemic injury of two free radical scavengers, namely mannitol and alpha-tocopherol. 2. Urethane-anaesthetized rats were exposed to heat stress (ambient temperature 42 degrees C) to induce heat stroke. Control rats were exposed to 24 degrees C. Mean arterial pressure and cerebral blood flow after the onset of heat stroke were significantly lower in heat stroke rats than in control rats. However, cerebral free radicals, lipid peroxidation and the neuronal damage score were greater in heat stroke rats compared with control rats. Similarly, plasma cytokines, including tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6, were significantly higher in heat stroke rats compared with their normothermic controls. 3. Pretreatment with alpha-tocopherol (20 mg/kg, i.v.) or mannitol (10%, i.v.) 30 min before the onset of heat exposure significantly attenuated heat stroke-induced arterial hypotension, cerebral ischaemia and neuronal damage, the increased free radical formation and lipid peroxidation in the brain and the increased plasma levels of cytokines. Pretreatment with alpha-tocopherol or mannitol resulted in a prolongation of survival time in heat stroke. 4. These results demonstrate that although pretreatment with alpha-tocopherol and mannitol does not prevent the heat stroke syndrome entirely, an attenuation of the syndrome is observed.

1. Free radicals mediate cerebral ischaemic injury associated with heatstroke. Magnolol, an active component of Magnolia officinalis, is 1000-fold more potent than alpha-tocopherol in inhibiting lipid peroxidation in rat mitochondria. The aim of the present study was to ascertain whether magnolol attenuated cerebral ischaemic injury and free radical formation associated with heatstroke. 2. Urethane-anaesthetized rats were exposed to heat stress (ambient temperature 42 degrees C) to induce heatstroke. Controlled rats were exposed to 24 degrees C. Mean arterial pressure, cerebral perfusion pressure and cerebral blood flow after the onset of heatstroke were all significantly lower than in control rats. However, colonic temperature, intracranial pressure, heart rate, cerebral free radicals, lipid peroxidation and the neuronal damage score were greater after the onset of heatstroke. 3. Magnolol (20 or 40 mg/kg, i.v.) significantly attenuated the heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral ischaemia and neuronal damage and increased free radical formation and lipid peroxidation in the brain. The extracellular concentrations of ischaemic (e.g. glutamate and lactate/pyruvate ratio) and damage (e.g. glycerol) markers in the corpus striatum were increased after the onset of heatstroke. Magnolol significantly attenuated the increase in striatal ischaemia and damage markers associated with heatstroke. 4. Thus, it appears that magnolol has impressive effects against heatstroke reactions.

1. Heatstroke was induced by exposure under general anaesthesia to a high ambient temperature. The moment in which the mean arterial pressure (MAP) began to decrease from its peak level was taken as the onset of heatstroke. 2. Compared with normothermic controls, rats with heatstroke had higher values for colon temperature, neuronal damage score and heart rate, but lower MAP and cerebral blood flow. 3. Induction of heat shock protein, antagonism of interleukin-1 or N-methyl-D-aspartate receptors or depletion of brain monoamines protects against the heatstroke-induced arterial hypotension and cerebral ischaemic injury. 4. Thus, it appears that arterial hypotension and cerebral ischaemic damage is the main reason for development of heatstroke syndromes.