title: Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice.
abstract: Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.
authors.affiliation: The Institute of Basic Medical Sciences, National Cheng Kung University School of Medicine, Tainan, Taiwan.
authors.forename: Chian-Yuh
authors.initials: CY
authors.lastname: Lin
authors.forename: Chuan-Chih
authors.initials: CC
authors.lastname: Hsu
authors.forename: Mao-Tsun
authors.initials: MT
authors.lastname: Lin
authors.forename: Sheng-Hsien
authors.initials: SH
authors.lastname: Chen
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D002369:Castration; D016207:Cytokines / Q000097:blood; D005485:Flutamide / Q000494:pharmacology* / Q000627:therapeutic use; D018883:Heat Stroke / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D062385:Hydroxybenzoates / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D059002:Androgen Receptor Antagonists; D016207:Cytokines; D062385:Hydroxybenzoates; D011944:Receptors, Androgen; D009569:Nitric Oxide; C009135:2,3-dihydroxybenzoic acid; D005485:Flutamide; D007770:L-Lactate Dehydrogenase