| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 107 === As the global warming, the rising average temperature and greenhouse effects bring a great threat to the human and animal health. The damage from global warming is directly reflected on the illness such as heat stroke. Pathological changes of heat stroke include hyperthermia (> 40°C) and CNS dysfunction accompanied with multiple organ failure. Autophagy is a cellular process of lysosomal degradation for removing damaged organelles and misfolded proteins, emerging as a major regulator of cellular homeostasis. The AMP-activated protein kinase (AMPK) is activated by ATP depletion or glucose starvation that activates autophagy via phosphorylation of ULK1 or inhibition of the mammalian target of rapamycin (mTOR). Ethyl pyruvate (EP) is a derivative of pyruvic acid and important endogenous metabolite that exerts antiinflammation ability. Previous studies had indicated that treatment with EP is able to ameliorate multiple organ dysfunctions in septic animal models. However, no study evaluates the beneficial effects of EP on heat stress-induced multiple organ dysfunction. Thus, the aim of the present study was to investigate the protective effect of EP on multiple organ dysfunctions in heat stroke rats and explore the associated mechanism involving autophagy and AMPK pathway. Male Wistar rats were divided into four groups：(1) Control group; (2) EP group (60 mg/kg); (3) Heat stroke (HS) group: rats were placed in a heating chamber (42℃) for 60 mins; (4) EP + HS group: EP (60 mg/kg) was administered 30 mins prior to heat exposure. Rats were monitored for 6 hours after heatstroke induction and sacrificed for further analysis. Previous results in our lab had indicated that EP significantly reduced the elevation of CPK, LDH, GPT levels caused by HS. Platelet counts were also reversed by EP administration. Histology of ileum section showed that EP alleviated HS-induced intestinal mucosal damage. In this experiment, the protective mechanism of EP was evidenced by the inhibition of the inflammatory protein expression of TNF-a, IL-6, IL-1b, HMGB1 and iNOS in the liver. Induction of HO-1 by EP possessing the anti-inflammatory and anti-oxidative effects and this effect might not mediate through Nrf2. EP also induced the protein expression of heat shock protein 90 and heat shock protein 70. As tracing the upstream transcription factor HSF1, administration of EP in HS rats showed significantly higher levels of HSF1 than that of HS group. In addition, EP activated p-AMPK, ULK1 to inhibit p-AKT, p-mTOR, p62 and induced expression of Atg7, Atg12, LC3-II, indicating EP activates autophagy to maintain cell survival and homeostasis. The findings suggest that EP could be a potential prophylactic agent against heat stroke.
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