We report here that when untreated mice underwent heat stress, they displayed thermoregulatory deficit (e.g., animals display hypothermia during room temperature exposure), brain (or hypothalamic) inflammation, ischemia, oxidative damage, hypothalamic-pituitary-adrenal axis impairment (e.g., decreased plasma levels of both adrenocorticotrophic hormone and corticosterone during heat stress), multiple organ dysfunction or failure, and lethality. Melatonin therapy significantly reduced the thermoregulatory deficit, brain inflammation, ischemia, oxidative damage, hypothalamic-pituitary-adrenal axis impairment, multiple organ dysfunction, and lethality caused by heat stroke. Our data indicate that melatonin may improve outcomes of heat stroke by reducing brain inflammation, oxidative damage, and multiple organ dysfunction. 1. Introduction Melatonin, the main product of the pineal gland, is found in high concentrations in other body fluids and tissues [1, 2] and possesses anti-inflammatory and antioxidant actions [3–6]. We have evaluated the prophylactic [7] as well as the therapeutic [8] effect of melatonin in heatstroke rats under general anesthesia and showed the therapeutic effects of melatonin on heatstroke-induced multiple organ dysfunction syndrome. According to a more recent review [9], the ischemic and oxidative damage to the hypothalamus during heatstroke may cause multiple organ dysfunction or failure through hypothalamic-pituitary-adrenal (HPA) axis mechanisms. Studies are warranted to know whether the heatstroke-induced brain (or hypothalamic) inflammation and damage, thermoregulatory deficits, and multiple organ dysfunction can be affected by melatonin therapy in an unanesthetized and unrestrained mouse model [10–12]. To deal with the hypothesis, we assessed the temporal profiles of cellular markers of ischemia (e.g., glutamate and lactate/pyruvate ratio), damage (e.g., glycerol), inflammation (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1β), IL-10, and myeloperoxidase (MPO) activity), and oxidative damage (e.g., prooxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), anti-oxidant defenses (e.g., glutathione peroxidase (GPx), and glutathione reductase (GR), oxidant radicals, nitric oxide metabolites (NOx), and dihydroxybenzoic acid (DHBA)) in the hypothalamus that occurred after heat regimen in mice treated with or without melatonin therapy. In addition, the influence of melatonin therapy on the heatstroke-induced thermoregulatory deficits as well as increased plasma levels of multiple organ dysfunction or
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