Carbohydrate and Energy Metabolism during the Evolution of Hypoxic-Ischemic Brain Damage in the Immature Rat

Abstract

Summary: The brain damage that evolves from perinatal cerebral hypoxia-ischemia may involve lingering distur bances in metabolic activity that proceed into the recov ery period. To clarify this issue, we determined the car bohydrate and energy status of cerebral tissue using en zymatic, fluorometric techniques in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37°C. This insult is known to produce tissue injury (selective neuronal necrosis or infarction) predominantly in the cerebral hemisphere ipsilateral to the carotid artery occlusion in 92% of the animals. Rat pups were quick-frozen in liquid nitrogen at 0, 1, 4, 12, 24, or 72 h of recovery; littermate controls underwent neither ligation nor hypoxia. Glucose in both cerebral hemi spheres was nearly completely exhausted during hypoxia ischemia, with concurrent increases in lactate to 10 mmoU kg. During recovery, glucose promptly increased above control values, suggesting an inhibition of glycolytic flux, as documented in the ipsilateral cerebral hemisphere by measurement of glucose utilization (CMRg1c) at 24 h. Tis sue lactate declined rapidly during recovery but remained slightly elevated in the ipsilateral hemisphere for 12 h.Cerebral hypoxia-ischemia is a frequent accom paniment to high-risk pregnancy and labor, and oc casionally culminates in brain damage with its as sociated neurologic impairment (F enichel, 1983;Volpe, 1987;Vannucci, 1989). The pathophysio- Abbreviations used: 2-DG, 2-deoxyglucose; MCA, middle ce rebral artery; NMR, nuclear magnetic resonance; PCA, perchlo ric acid; P-Cr, phosphocreatine. 227Phosphocreatine (P-Cr) and ATP in the ipsilateral cere bral hemisphere were 14 and 26% of control (p < 0.001) at the end of hypoxia-ischemia; total adenine nUcleotides (A TP + ADP + AMP) also were partially depleted (-46%). During the first hour of recovery, mean P-Cr was replenished to within 90% of baseline, whereas mean ATP was incompletely restored to 68-81 % of control (p < 0.05). Individual ATP and total adenine nucleotide values were >2 SD below control levels in 17/24 (71%) brains at all intervals of recovery. Both ATP and total adenine nu cleotides were inversely correlated with tissue water con tent, reflecting the extent of cerebral edema. No major alterations in the high-energy phosphate reserves oc curred in the contralateral cerebral hemisphere either during or following hypoxia-ischemia. Thus, following perinatal cerebral hypoxia-ischemia, ATP and total ade nine nUcleotides never recover completely in brains un dergoing damage but rather are permanently depleted to levels that reflect the severity of tissue injury. Recovery of P-Cr to near normal levels can occur despite evolving brain damage. The findings have relevance to the assess ment of asphyxiated newborn humans using magnetic res onance spectroscopy.

Delayed (“Secondary”) Cerebral Energy Failure after Acute Hypoxia-Ischemia in the Newborn Piglet: Continuous 48-Hour Studies by Phosphorus Magnetic Resonance Spectroscopy

“…2, Table 4) resembled those reported in previous studies, including those of newborn animals (8,9,(23)(24)(25). The profound decrease in pH, was attributable in part to production of lactic acid.…”

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

“…H-I causes severe metabolic perturbation in the brain (25). To investigate the metabolic status of the brain after H-I, we measured NAD and ATP levels in wild-type and cytNmnat1-Tg littermates 24 h after H-I.…”

Oxidative Stress of Newborn

“…At the cellular level, cerebral hypoxia-ischemia sets in motion a series of biochemical events commencing in a shift from oxidative to anaerobic metabolism; this leads to an accumulation of NADH, FADH, lactic acid and H+ ions [Palmer, C. et al (1990)]. If the asphyxic insult persists, the fetus is unable to maintain circulatory centralization, cardiac output and cerebral perfusion falls.…”