Activated protein C improves heatstroke outcomes through restoration of normal hypothalamic and thermoregulatory function

Background: Human recombinant activated protein C (APC) has been found to be beneficial in treating heatstroke in both humans and rats. Here, we further investigated the possible mechanism underlying the therapeutic action exerted by APC in experimental heatstroke. Methods: Unanesthetized and unrestrained mice were exposed to an ambient temperature of 42.4°C for 1 hour to induce heatstroke. They were given normal saline or APC (5 mg/kg of body weight, intravenously) 1 hour after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored for 4 hours after cessation of heat stress. Mice that survived on day 4 of heat treatment were considered survivors. Results: When the vehicle-treated mice underwent heat treatment, the fraction survival and core temperature at 4 hours of body heating were found to be 0 of 12 and 33.8 ± 0.6°C, respectively. Administration of APC 1 hour after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12 of 12) and reduced hypothermia (core temperature, 37.4 ± 0.2°C). Heat-induced apoptosis in the hypothalamus was significantly reduced by APC. The increased levels of cellular ischemia (eg, glutamate, lactate-to-pyruvate ratio, nitrite, and dihydroxybenzoic acid) and damage (eg, glycerol) markers in the hypothalamus during heatstroke were also decreased significantly by APC therapy. The hypothalamic levels of tumor necrosis factor-α (a proinflammatory cytokine) that are upregulated in heat-stressed mice were significantly lower in APC-administered mice. Conclusions: Our results show that human recombinant APC improves heatstroke through restoration of normal hypothalamic and thermoregulatory function.