Brain Adenosine Triphosphate Research Articles

Physiologic and metabolic alterations associated with seizures in normoxic and asphyxiated neonatal dogs.

The effect of asphyxia on seizures was determined in neonatal dogs. In normoxic (paralyzed and ventilated) neonatal dogs, bicuculline-induced seizures produced significant elevations of arterial blood pressure, PO2, glucose, lactate, and epinephrine. Cerebral blood flow increased severalfold; brain glucose, adenosine triphosphate (ATP), and phosphocreatine (PCr) did not decrease significantly. In contrast, seizures during asphyxia were associated with hypoxia, hypotension, hypercarbia, and acidosis. Significant cerebral ischemia developed. Brain glucose, ATP, and PCr were significantly depleted. Complete oxygen deprivation during neonatal seizures exhausts brain energy stores, which leads to cessation of seizure activity.

Microwave effects on energy metabolism of rat brain.

Rat brain was exposed to 591-MHz, continuous-wave (CW) microwaves at 13.8 or 5.0 mW/cm2 to determine the effect on nicotinamide adenine dinucleotide, reduced (NADH), adenosine triphosphate (ATP) and creatine phosphate (CP) levels. On initiation of the in vivo microwave exposures, fluorimetrically determined NADH rapidly increased to a maximum of 4.0%-12.5% above pre-exposure control levels at one-half minute, than decreased slowly to 2% above control at three minutes, finally increasing slowly to 5% above control level at five minutes. ATP and CP assays were performed on sham- and microwave-exposed brain at each exposure time. At 13.8 mW/cm2, brain CP level was decreased an average of 39.4%, 41.1%, 18.2%, 13.1%, and 36.4% of control at exposure points one-half, one, two three, and five minutes, respectively, and brain ATP concentration was decreased an average of 25.2%, 15.2%, 17.8%, 7.4%, and 11.2% of control at the corresponding exposure periods. ATP and CP levels of rat brain exposed to 591-MHz cw microwaves at 5mW/cm2 for one-half and one minute were decreased significantly below control levels at these exposure times, but were not significantly different from the 13.8 mW/cm2 exposures. For all exposures, rectal temperature remained constant. Heat loss through the skull aperture caused brain temperature to decrease during the five-minute exposures. This decrease was the same in magnitude for experimental and control subjects. Changes in NADH, ATP, and CP levels during microwave exposure cannot be attributed to general tissue hyperthermia. The data support the hypothesis that microwave exposure inhibits mitochondrial electron transport chain function, which results in decreased ATP and CP levels in brain.

Status epilepticus in immature rats. Protective effects of glucose on survival and brain development.

The role of glucose metabolism in alleviating the complications of status epilepticus (SE) was investigated in developing rats. Pretreatment with glucose reduced mortality from SE by 90% in rats under 1 week of age, 80% in 10-day-old rats, 50% in 15- to 20-day-olds, and not at all in adults. In 4-day-old animals, brain DNA synthesis during seizures, and in survivors, brain weight, DNA, RNA, protein, and cholesterol contents at 7 days of age were reduced less in glucose-treated than in saline-treated littermates. In the saline group, seizures caused a progressive fall in brain glucose level but no fall in blood glucose level, suggesting that glucose transport from blood to brain could not keep pace with glycolytic demands. In glucose-treated rats, blood and brain glucose concentrations remained elevated throughout the convulsive period. There was no reduction of brain adenosine triphosphate levels in either group. Thus, the protection by glucose appears to be related to its roles as a carbon source rather than an energy source. It is concluded that in immature animals, depletion of brain glucose can occur in the absence of hypoglycemia, and may be an important and potentially treatable complication of status epilepticus.

Brain tryptophan hydroxylation: dependence on arterial oxygen tension.

The accumulation of cerebral 5-hydroxytryptophan after decarboxylase inhibition was decreased in rats maintained at arterial O(2) tensions below 60 mm-Hg. In contrast, brain lactate was stable above 40 mm-Hg and brain adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were unchanged above 30 mm-Hg. There was a linear correlation of brain 5-hydroxytryptophan accumulation to cerebral venous O(2) tension. Cerebral tryptophan hydroxylase appears to have a poor affinity for oxygen and to be affected by slight hypoxia. The resultant decreases in monoamine neurotransmitter metabolism may explain the behavioral changes of mild oxygen deprivation.

ENZYMIC AND CEREBRAL METABOLIC EFFECTS OF 2‐DEOXY‐d‐GLUCOSE

Abstract—The time course of effects of 2‐deoxy‐d‐glucose on cerebral glucose metabolism has been studied in vivo and the inhibitory actions of 2‐deoxy‐d‐glucose and 2‐deoxy‐d‐glucose‐6‐phosphate on cerebral glycolytic enzymes in vitro. Mice were given 2‐deoxy‐d‐glucose 3 g/kg intraperitoneally. Blood 2‐deoxy‐d‐glucose/glucose ratio was 2–3 from 5 to 30 min after injection, the hyperglycaemic response to 2‐deoxy‐d‐glucose having been suppressed with propranolol. Maximal cerebral 2‐deoxy‐d‐glucose uptake observed was 1μ11 μmol/g/min between 5 and 10 min after injection. At 10 min brain concentrations of 2‐deoxy‐d‐glucose and 2‐deoxy‐d‐glucose‐6‐phosphate were 5·82 and 3·12 μmol/g. Analysis of the fate of d‐[U‐14C] glucose given subcutaneously 5 min before death showed that glucose uptake was reduced to 40–60 per cent of control from 5 to 30 min after 2‐deoxy‐d‐glucose. However brain glucose concentration rose three to five‐fold 20–30 min after 2‐deoxy‐d‐glucose. The majority of glucose entering the brain after 10 min of 2‐deoxy‐d‐glucose treatment was recovered as glucose. Conversion of brain glucose to other acid soluble components was reduced to 1/3 at 10 min and 1/5 at 20–30 min. Glucose‐6‐phosphate concentration rose from 5 min onwards and was maintained at twice control concentration from 10–30 min. However, because of the rapid entry of 2‐deoxy‐d‐glucose and its conversion to 2‐deoxy‐d‐glucose‐6‐phosphate, the 2‐deoxy‐d‐glucose 6‐P/glucose 6‐P ratio was between 19 and 32. Brain adenosine triphosphate concentration did not change, creatine phosphate concentration fell after 25 min.Measurement of enzyme activities in cerebral homogenates (using 1 mivs substrate concentration) showed that hexokinase (EC 2.7.1.1) was 40 per cent inhibited by 5 mm‐deoxy‐d‐glucose (but not by 2‐deoxy‐d‐glucose 6‐P). Glucose 6‐P dehydrogenase (EC 1.1.1.49), 6‐phosphogluconate dehydrogenase (EC 1.1.1.43) and phosphoglucomutase (EC 2.7.5.1) were not affected by either 2‐deoxy‐d‐glucose (5 mm) or 2‐deoxy‐d‐glucose 6‐P (5 or 20 mm). Hexose‐phosphate isomerase (EC 5.3.1.9) was 70 per cent inhibited by 20 mm‐d‐deoxy‐d‐glucose 6‐P. Phosphofructokinase (EC 2.7.1.11) was inhibited by 17 per cent by 2‐deoxy‐d‐glucose 6‐P (20 mm). During the initial impairment of cerebral function by 2‐deoxy‐d‐glucose there is competitive inhibition of glucose transport into the brain; later, glycolysis is more powerfully depressed by the inhibition of isomerase produced by the high intracerebral concentration of 2‐deoxyglucose‐6‐phosphate.

Ethanol oxidation: effect on the redox state of brain in mouse.

Administration of a single large dose of ethanol to mice results in increases, for concentrations in the brain, of ratios of lactate to pyruvate, of aglycerophosphate to dihydroxyacetone phosphate, of malate to oxaloacetate, and of glutamate to the product of alpha-ketoglutarate and ammonium ion. These changes are noticed as early as 5 minutes after the single dose is given. Ethanol administration for 30 days also produces these changes in metabolite concentrations in the brain. However, in contrast to the single alcohol dose, long-term alcohol administration results in a marked decrease in the concentration of adenosine triphosphate in brain and increases in those of adenosine diphosphate and adenosine monophosphate. Pyrazole, an inhibitor of alcohol dehydrogenase, prevents the effects of ethanol on the concentration of brain metabolites. These results may provide new insight into the biochemical and pharmacological effects of alcohol on brain metabolism and the importance of alcohol dehydrogenase activity in the brain.

Brain adenosine triphosphate: decreased concentration precedes convulsions.

The concentration of adenosine triphosphate in the brain decreased before the onset of generalized convulsions in unanesthetized rats subjected to acute hypoxia or treated with hydroxylamine or pentylenetetrazole (Metrazol). As the convulsive episode continued, adenosine triphosphate decreased further. Stimulation of adenosine triphosphate production forestalled its disappearance from the brain and delayed the development of seizure activity.

The effects of phenobarbitone, leptazol, dexamphetamine, iproniazid, imipramine, LSD, chlorpromazine, reserpine and hydroxyzine on the in vivo levels of adenine nucleotides and phosphocreatine in the rat brain.

1. Enzymic and ion-exchange chromatographic analyses were used to measure adenosine triphosphate (ATP), diphosphate (ADP) and monophosphate (AMP) in brain extracts from rats treated with a wide range of centrally acting drugs. Phosphocreatine (PC) was assayed by the acid molybdate method.2. An anaesthetic dose of phenobarbitone caused an increase in brain levels of ATP and PC, and a reduction in ADP and AMP. A convulsant dose of leptazol gave rise to precisely opposite effects. Subanaesthetic (hypnotic) and subconvulsive doses of the two drugs, respectively, produced no alterations in brain nucleotide levels.3. Among the psychotropic drugs, dexamphetamine, LSD and hydroxyzine, at the doses used, caused no changes in brain levels of the adenine nucleotides. Iproniazid and imipramine caused slight increases in the ATP level and ATP / ADP ratio, respectively. Chlorpromazine failed to give rise to any effect in the nucleotides 3 hr after administration, but produced a rise in brain ATP after 6 hr. Reserpine, on the other hand, caused a fall in the ATP/ADP ratio 6 hr after injection.4. These results indicate that some psychotropic drugs can cause small changes in the rat brain ATP/ADP ratio but do not support claims by certain workers that such changes correlate closely with the behavioural effects of these drugs.

The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest

Summary Development of an improved method for instantaneous freezing (-196° C.) of sequential cerebral biopsies permits the accurate determination of ATP (adenosine triphosphate) disappearance during complete circulatory arrest and recovery. Control cerebral ATP concentrations in biopsies from 30 normothermic dogs equalled 2.42 ± 0.16 micromoles per gram (S.D.). Simultaneous aortic and vena caval occlusion, for periods of 4, 6, or 8 minutes, resulted in a 50 per cent decrease of cerebral ATP within 3.8 minutes. Electroen-cephalographic silence occurred at 20.9 ± 3.1 seconds, coincident with the loss of less than 10 per cent of control ATP content. Reappearance of brain ATP after resumption of flow correlated inversely with the duration of circulatory arrest. Eleven dogs were cooled to 5° to 11° C. (esophageal) with the use of high-flow extracorporeal perfusion for 50 minutes with attendant reduction of cerebral ATP to 88.6 ± 7.4 per cent of normothermic control levels. EEG silence occurred at 16.8° ± 3.5° C. (esophageal), coincident with the loss of less than 10 per cent of control ATP concentrations. Circulatory arrest resulted in a 50 per cent reduction in cerebral ATP after 13.3 minutes. Recovery of ATP with rewarming was observed after 30 and 60, but not 90, minutes of hypothermic arrest. EEG recovery was associated with return of ATP concentrations to 89 per cent of normothermic control levels. Profound hypothermia results in a three- to fourfold increase in survival of cerebral ATP during circulatory arrest. We wish to thank Robert Gelein and Marvin Nunn for valuable technical assistance.

Influence of subcellular structures on the activity of Na +, K +-activated adenosine triphosphate in brain

Influence of subcellular structures on the activity of Na +, K +-activated adenosine triphosphate in brain