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.