Failure Of Energy Metabolism Research Articles

Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain.

The objective of this study was to determine whether administration of dichloroacetate (DCA), an activator of pyruvate dehydrogenase (PDH), improves recovery of energy metabolites following transient cerebral ischemia. Gerbils were pretreated with DCA, and cerebral ischemia was produced using bilateral carotid artery occlusion for 20 min, followed by reperfusion up to 4 h. DCA had no effect on the accumulation of lactic acid and the decrease in ATP and phosphocreatine (PCr) during the 20-min insult, nor on the recovery of these metabolites measured at 20 and 60 min reperfusion. However, at 4 h reperfusion, levels of ATP and PCr were significantly higher in DCA-treated animals than in controls, as PCr exhibited a secondary decrease in caudate nucleus of control animals. PDH was markedly inhibited at 20 min reperfusion in both groups, but was reactivated to a greater extent in DCA-treated animals at 60 min and 4 h reperfusion. These results demonstrate that DCA had no effect on the initial recovery of metabolites following transient ischemia. However, later in reperfusion, DCA enhanced the postischemic reactivation of PDH and prevented the secondary failure of energy metabolism in caudate nucleus. Thus, inhibition of PDH may limit the recovery of energy metabolism following cerebral ischemia.

Acute metabolic encephalopathy: A review of causes, mechanisms and treatment

Acute encephalopathy is a relatively common problem: one of the causes is metabolic disorders. A detailed history, examination and investigations performed during the acute illness (blood sugar, blood gases, plasma ammonia, blood lactate, plasma ketones, plasma amino acids, liver function tests, and urinary organic acids) should identify those patients in whom a metabolic disorder is likely. More detailed studies may be needed to establish a precise diagnosis. The mechanism of the acute brain dysfunction is multifactorial. Factors that contribute include changes in blood flow and, initially, a disturbance in neurotransmitter function followed by failure of energy metabolism and cellular depolarization. Treatment of these conditions is largely supportive, with special attention to the management of cerebral perfusion pressure.

Energy metabolism in delayed neuronal death of CA1 neurons of the hippocampus following transient ischemia in the gerbil.

The delayed death of CA1 neurons in the gerbil has been reported to occur at 4 days of reflow following 5 min of bilateral ischemia. Samples of the CA1 and CA3 somal region of the hippocampus, as well as of the parietal cortex, were dissected from frozen dried sections of gerbil brains frozen in situ between 1.5 and 96 hr of reflow following 5 min of bilateral ischemia and the concentrations of the adenylates, P-creatine, glucose, glycogen, and lactate were determined. The values for high-energy phosphates were restored by 1.5 hr of recirculation in all three regions and remained at or above control in the CA3 region and cortex for up to 96 hr. In contrast, the P-creatine and ATP decreased in the CA1 region at 48 and 96 hr of reflow, respectively. The total adenylates also decreased in the CA1 region at 96 h, but the normal energy charge in this area indicated that the surviving tissue was metabolically viable. A glucose overshoot was exhibited in the three regions at all time periods except 6 and 96 hr. At 6 hr of reflow, there was a transient return of glucose levels toward those of control. By 96 hr, the glucose in the CA3 region and cortex was not significantly different from control but was elevated in the CA1 region. The lactate levels were depressed from 1.5 to 12 hr of recirculation in all areas, but the decrease was significant only in the cerebral cortex. The concentration of glycogen was significantly elevated at 6 hr in all regions, then was restored by 24 to 48 hr, only to increase once again in the affected CA1 region. The results clearly indicate that metabolic perturbations persist for long periods of time after ischemic durations that are compatible with the survival of the animal but that the loss of the CA1 neurons cannot be attributed to a failure in energy metabolism.

Excitatory amino acids and anoxic/ischaemic brain damage

The selective pattern of brain damage that follows cerebral anoxia or ischaemia is usually explained in terms of a failure of energy metabolism, or secondary disturbances of local blood flow, and the possible toxicity of free radicals. However, recent experiments suggest that neurotoxic actions of synaptically-released excitatory amino acids play a crucial role in the development of such damage. Antagonists of excitation due to acidic amino acids protect against anoxic/ischaemic damage in test systems in vitro and in vivo. This suggests a novel therapeutic or prophylactic approach to such conditions as stroke, perinatal asphyxia and the postoperative complications of cardiothoracic surgery.

Correlation between cerebral blood flow and ATP content following tourniquet-induced ischemia in cat brain.

Cerebral ischemia was produced in anesthetized cats using a neck tourniquet, which diminished cortical blood flow to less than 2 ml/100 g/min and depleted levels of ATP throughout the brain. Following a 30-min insult, cortical flow measured with H2 electrodes returned nearly to control, but subsequently decreased to 14-47% of control values. Despite this secondary hypoperfusion, ATP levels adjacent to the H2 electrode were restored to 75% of normal during the 2-h recirculation period. Therefore, this degree of hypoperfusion did not cause a secondary failure of energy metabolism. Following a 60-min insult, impaired reperfusion prevented the regeneration of brain ATP. However, preischemic bilateral craniectomies significantly improved recovery of blood flow and ATP levels following 60 min of ischemia. Therefore, in the present model, insufficient reflow is a primary factor limiting recovery of energy metabolism. Further, surgical decompression prevented the occurrence of "no reflow" caused by 60 min of ischemia.

Neurophysiological recovery after hypoglycemic coma in the rat: correlation with cerebral metabolism.

Recovery of electroencephalographic activity and somatosensory evoked responses was studied in paralyzed and lightly anesthetized (70% N2O) rats in which profound hypoglycemia had been induced by insulin administration. The duration of severe hypoglycemia was defined as the duration of a flat electroencephalogram (EEG) recording (5, 30, and 60 min, respectively) before restitution with glucose. The restitution period was followed by continuous EEG monitoring and repeated tests for evoked potentials. After 180 min of recovery, the brains were frozen in situ with liquid nitrogen and analyzed for energy metabolism. In accordance with earlier metabolic studies from this laboratory, the recovery after 60 min of severe hypoglycemia was incomplete, with signs of permanent failure of energy metabolism. There was persistent ATP reduction proportional to the duration of the hypoglycemia. The short-term recovery of EEG and sensory evoked responses was proportional to the duration of severe hypoglycemia. The neurophysiological recovery after 5 min of severe hypoglycemia was complete. After 30 min of severe hypoglycemia, the evoked responses recovered but showed a significant prolongation of latency, compared with normal. After 60 min of severe hypoglycemia, no early evoked response and scanty EEG activity were observed. The neurophysiological observations indicate a persistent deficit of synaptic transmission in the somatosensory pathway, including the cortical projection. This can be correlated with neuropathologic changes that are particularly prominent in intermediate cortical layers, as previously shown.

Pathophysiology of ischemic cell death: III. Role of extracellular factors.

The purpose of this study was to determine the effect on cell survival of extracellular changes that occur during ischemia, over and above the depletion of O2 and substrate. Rabbit retinas were deprived in vitro of both O2 and substrate, and then returned to control medium for 4 h before recovery was assessed by measuring protein synthesis, glucose utilization, and tissue water. Experimental conditions were altered in various ways during the period of O2 and substrate deprivation in order to modify the changes taking place in the interstitial fluid as a result of the failure of energy metabolism. When O2-free, substrate-free extracellular electrolyte solution was added to the retinas to reduce the ischemia-induced changes in the interstitial fluid, there was marked reduction in irreversible damage. But when energy-deprived retinas were exposed to retinas that had already been ischemic, or to interstitial fluid from ischemic retinas, there was an increase in irreversible damage. Removing Ca++ from the extracellular fluid during the period of energy deprivation increased the damage due to short deprivations in a restricted volume of extracellular fluid, but reduced the damage from longer deprivations in a large volume of extracellular fluid. The results demonstrate that several changes occur in the extracellular fluid during ischemia that significantly affect recovery.

Arterial acid--base changes and brain energy metabolism in unanaesthetized rats in mild hypoxia.

Abstract The behaviour of acid-base balance in the blood and of glycolytic pathway intermediates (glucose, glucose 6-phosphate, pyruvate, lactate, ATP, ADP, AMP and phosphocreatine) in the brains of rats was studied in animals breathing 7.5% O 2 in N 2 for 2 h. In the blood, a progressive non-respiratory acidosis reduced the initial shift of pH towards the alkaline direction; however, the concomitant decrease of P a,C0 2 maintained its value still above control values. The accumulation of lactate was followed by a rise in pyruvate concentration and resulted in relatively stable values for lactate excess and lactate/pyruvate ratios. The observed fall in blood pressure probably reflected the cardiac response to hypoxia and did not exceed 20 mmHg during 2 h of experiment. This decrease, however, was probably not limiting for brain perfusion, stimulated by hypoxia, since we observed no failure of energy metabolism in the brain. The triggering factors for the activation of glycolysis in the brain, under circumstances of unchanged ATP, ADP and AMP concentrations, are difficult to define. In all probability the results reflect an initial activation of glycolysis at the phosphofructokinase step and a further partial inhibition of primarily accelerated flux at the hexokinase level, with subsequent limitation of glucose influx. Such dynamic changes in regulatory mechanisms of glycolysis resulted in maintaining stable lactate/pyruvate ratios during 2 h of hypoxia, and suggest the acquirement of a new steady state of the glycolytic rate in conditions of long-lasting hypoxia.

COMPLICATIONS OF HYPERBILIRUBINEMIA IN THE NEWBOR—POSSIBLE RELATION TO THE METABOLISM OF AMMONIA

Concentrations of ammonia in blood from the umbilical vein have been determined during the course of 20 exchange transfusions on 16 infants. One of these infants subsequently died of kernicterus and another died with liver damage and intracranial hemorrhage. Only these two infants had concentrations of ammonia in blood from the umbilical vein greater than 2 µg/ml during exchange transfusion when half of the blood had been administered. The only other infants with significantly elevated concentrations of ammonia in blood from the umbilical vein had siblings who had died of kernicterus. A steady but gradual rise in the content of ammonia in stored blood has been shown to occur during storage. There is no relation between the content of ammonia in stored blood and the concentration of ammonia in the blood of the patient during exchange transfusion. It is postulated that the ammonemia of the patient with impairment of liver function due to hyperbilirubinemia causes a failure of energy metabolism of nerve cells, resulting in an increased permeability of the cells to bilirubin. Once the cells are stained, the lesion is irreversible.