Gerald D. Williams

Modest hypothermia preserves cerebral energy metabolism during hypoxia-ischemia and correlates with brain damage : A 31P nuclear magnetic resonance study in unanesthetized neonatal rats

Recent studies have shown that mild to moderate (modest) hypothermia decreases the damage resulting from hypoxic-ischemic insult (HI) in the immature rat. To determine whether suppression of oxidative metabolism during HI is central to the mechanism of neuroprotection, 31P nuclear magnetic resonance (NMR) spectroscopy was used to measure high energy metabolites in 7-d postnatal rats under conditions of modest hypothermia during the HI. The rats underwent unilateral common carotid artery ligation followed by exposure to hypoxia in 8% oxygen for 3 h. Environmental temperature was decreased by 3 or 6 °C from the control temperature, 37 °C, which reliably produces hemispheric damage in over 90% of pups. The metabolite parameters and tissue swelling (edema) at 42 h recovery varied very significantly with the three temperatures. Tissue swelling was 26.9, 5.3, and 0.3% at 37, 34, and 31 °C, respectively. Core temperature and swelling were also measured, with similar results, in parallel experiments in glass jars. Multislice magnetic resonance imaging, histology, and triphenyltetrazolium chloride staining confirmed the fairly uniform damage, confined to the hemisphere ipsilateral to the ligation. The NMR metabolite levels were integrated over the last 2.0 h out of 3.0 h of HI, and were normalized to their baseline for all surviving animals (n = 25). ATP was 47.9, 69.0, and 83.0% of normal, whereas the estimator of phosphorylation potential (phosphocreatinine/inorganic phosphorus) was 16.9, 27.8, and 42.6% of normal at 37, 34, and 31 °C, respectively. There was a significant correlation of both phosphocreatinine/inorganic phosphorus (p < 0.0001) and ATP levels (p < 0.0001) with brain swelling. Abnormal brain swelling and thus damage can be reliably predicted from a threshold of these metabolite levels (p < 0.0001). Thus for all three temperatures, a large change in integrated high energy metabolism during HI is a prerequisite for brain damage. With a moderate hypothermia change of 6 °C, where there is an insufficient change in metabolites, there is no subsequent HI brain damage. In general, treatment for HI in our 7-d-old rat model should be aimed at preserving energy metabolism.

Increased plasma beta-hydroxybutyrate, preserved cerebral energy metabolism, and amelioration of brain damage during neonatal hypoxia ischemia with dexamethasone pretreatment.

Dexamethasone (DEX) pretreatment has been shown to be neuroprotective in a neonatal rat model of hypoxia ischemia (HI). The exact mechanism of this neuroprotection is still unknown. This study used 31P nuclear magnetic resonance spectroscopy to monitor energy metabolism during a 3-h episode of HI in 7-d-old rat pups in one of two groups. The first group was pretreated with 0.1 mL saline (i.p.) and the second group was treated with 0.1 mL of 0.1mg/kg DEX (i.p.) 22 h before HI. Animals pretreated with DEX had elevated nucleoside triphosphate and phosphocreatine levels during HI when compared with controls. Saline-treated animals had significant decreases in nucleoside triphosphate and phosphocreatine and increases in inorganic phosphate over this same period. 31P nuclear magnetic resonance data unequivocally demonstrate preservation of energy metabolism during HI in neonatal rats pretreated with DEX. Animals pretreated with DEX had little or no brain damage following 3 h of HI when compared with matched controls, which experienced severe neuronal loss and cortical infarction. These same pretreated animals had an increase in blood beta-hydroxybutyrate levels before ischemia, suggesting an increase in ketone bodies, which is the neonates primary energy source. Elevation of ketone bodies appears to be one of the mechanisms by which DEX pretreatment provides neuroprotection during HI in the neonatal rat.