Ischemic and oxidative damage to the hypothalamus may be responsible for heat stroke

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.

Keywords: Hypothalamus; antioxidants; cytokines; heatstroke; hypotension; hypoxia; inflammation; ischemia; oxidative stress; pharmacology..

Fig. (1)

A flowchart of the proposed pathogenic sequence in the hypothalamus during heatstroke. Environmental heat stress increases cutaneous blood flow and metabolism, and progressively decreases splanchnic blood flow. Severe heat exposure also decreases mean arterial pressure, increases intracranial pressure, and results in decreased cerebral perfusion pressure, which leads to cerebral ischemia and hypoxia. Compared with normothermic controls, rodents with heatstroke have more hypothalamic markers of cellular ischemia and damage, pro-oxidant enzymes, and higher hypothalamic values of proinflammatory cytokines, iNOS-dependent NO, and an indicator of the accumulation of polymorphonuclear leukocytes, as well as more neuronal damage after heatstroke. In contrast, they have fewer antioxidants in the hypothalamus. The ischemic, hypoxic, and oxidative damage to the hypothalamus during heatstroke may lead to MODS.