Abstract
The hypothalamus may be involved in regulating homeostasis, motivation, and emotional behavior by controlling autonomic and endocrine activity. The hypothalamus communicates input from the thalamus to the pituitary gland, reticular activating substance, limbic system, and neocortex. This allows the output of pituitary hormones to respond to changes in autonomic nervous system activity. Environmental heat stress increases cutaneous blood flow and metabolism, and progressively decreases splanchnic blood flow. Severe heat exposure also decreases mean arterial pressure (MAP), increases intracranial pressure (ICP), and decreases cerebral perfusion pressure (CPP = MAP – ICP), all of which lead to cerebral ischemia and hypoxia. Compared with normothermic controls, rodents with heatstroke have higher hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), proinflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α), inducible nitric oxide synthase-dependent nitric oxide, and an indicator for the accumulation of polymorphonuclear leukocytes (e.g., myeloperoxidase activity), as well as neuronal damage (e.g., apoptosis, necrosis, and autophagy) after heatstroke. Hypothalamic values of antioxidant defenses (e.g., glutathione peroxidase and glutathione reductase), however, are lower. The ischemic, hypoxic, and oxidative damage to the hypothalamus during heatstroke may cause multiple organ dysfunction or failure through hypothalamic-pituitary-adrenal axis mechanisms. Finding the link between the signaling and heatstroke-induced hypothalamic oxidative and ischemic damage might allow us to clinically attenuate heatstroke. In particular, free radical scavengers, heat shock protein-70 inducers, hypervolemic hemodilution, inducible nitric oxide synthase inhibitors, progenitor stem cells, flutamide, estrogen, interleukin-1 receptor antagonists, glucocorticoid, activated protein C, and baicalin mitigate preclinical heatstroke levels.
Highlights
Heatstroke is a form of hyperthermia associated with a systemic inflammatory response that leads to multiorgan dysfunction syndrome (MODS), in which central nervous system (CNS) disorders predominate [1]
Brain cooling significantly reduced the ischemic and oxidative damage to the hypothalamus during heatstroke [35]. These findings suggest that whole-body or brain cooling may resuscitate patients with heatstroke by decreasing the overproduction of RNS, TNF, and ROS that occurs in the hypothalamus and during cerebrovascular dysfunction
We evaluated the effect of melatonin, a versatile molecule synthesized in the pineal gland and in many organs, in heatstroke and showed that melatonin significantly (i) attenuated hyperthermia, hypotension, and hypothalamic ischemia and hypoxia; (ii) reduced the plasma index of the toxic oxidizing radicals like nitric oxide (NO) metabolites and hydroxyl radicals; (iii) diminished the plasma index of hepatic and renal dysfunction, such as creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase; (iv) attenuated plasma systemic inflammation response molecules such as soluble intracellular and lesion molecule-1, E-selectin, TNF, IL-1, and IL-6; (v) promoted plasma levels of IL-10; (vi) reduced myeloperoxidase activity in the lung, an index of infiltration of polymorphonuclear neutrophils; and (vii) quadrupled survival time compared with the heatstrokealone group
Summary
Heatstroke is a form of hyperthermia associated with a systemic inflammatory response that leads to multiorgan dysfunction syndrome (MODS), in which central nervous system (CNS) disorders (e.g., delirium, convulsion, and coma) predominate [1]. Passive heatstroke is experienced primarily by the very young or the elderly during annual heat waves [2]. The hypothalamus is believed to be involved in regulating homeostasis, motivation, and emotional behavior These functions are mediated through hypothalamic control of autonomic and endocrine activity [16, 17]. The hypothalamus receives input from the thalamus, reticular activating substance, limbic system, eyes, and neocortex; it transmits this input to the pituitary gland This allows the output of pituitary hormones to respond to changes in the autonomic nervous system activity and to the needs of temperature regulation, water balance, and energy requirements [16]. The hypothalamic PVN has been described as the “autonomic master controller” [17] It coordinates critical physiological responses by controlling the HPA axis. This review will provide current evidence and discuss the hypothesis that ischemic and oxidative damage to the hypothalamus is responsible for the occurrence of MODS in heatstroke via the mechanisms of the HPA axis
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