Effect of Mild Hypothermia on Cerebral Energy Metabolism During the Evolution of Hypoxic-Ischemic Brain Damage in the Immature Rat

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Abstract
Background and Purpose Intraischemic hypothermia (34°C and 31°C) has a profound neuroprotective effect on the brain of the immature rat. Hypothermia immediately after hypoxia-ischemia is not beneficial. To determine the mechanisms by which mild to moderate hypothermia affects cerebral energy metabolism of the brain of the newborn rat pup, we examined alterations in cerebral glycolytic intermediates and high-energy phosphate compounds during intraischemic and postischemic hypothermia and correlated these findings with known neuropathologic injury. Methods Seven-day-old rat pups underwent unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen at either 37°C, 34°C, or 31°C for 3.0 hours. Separate groups were exposed to hypoxia-ischemia at 37°C for 3 hours but recovered at either 37°C, 34°C, or 31°C. At 60, 120, and 180 minutes of intraischemic hypothermia and at 10, 30, 60, and 240 minutes of postischemic hypothermia, individual rat pups were quick-frozen in liquid nitrogen for later determination of cerebral concentrations of glucose, lactate, ATP, and phosphocreatine. Results Cerebral glucose was significantly higher and lactate significantly lower in the 31°C animals during hypoxia-ischemia than either the 34°C or 37°C groups. Brain ATP concentrations were completely preserved during hypoxia-ischemia at 31°C, whereas 34°C of hypothermia had no effect on preserving high-energy phosphate compounds compared with those animals in the 37°C group. Postischemic hypothermia of either 34°C or 31°C had no effect on the rate or extent of recovery of glycolytic intermediates or high-energy phosphate compounds compared with the normothermic 37°C rat pups. Conclusions Moderate hypothermia of 31°C completely inhibits the depletion of ATP during hypoxia-ischemia, a mechanism that likely accounts for its neuroprotective effect. No preservation of ATP was seen, however, during intraischemic mild hypothermia of 34°C despite the relatively profound neuroprotective effect of this degree of temperature reduction. Thus, the mechanisms by which mild hypothermia is neuroprotective are temperature dependent and may act at more than one point along the cascade of events eventually leading to hypoxic-ischemic brain damage in the immature rat.