Biomedical subjects

J H Thurston

Publications and source records attributed to J H Thurston.

At least 19 recordsLinked to original sources

PubMed1992

Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance.

Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of beta-oxidation. The present study shows for the first time that in developing mice, when panthothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the beta-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of beta-oxidation and other CoA- and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase.

Animals↗

PubMed1989

Effect of momentary stress on brain energy metabolism in weanling mice: apparent use of lactate as cerebral metabolic fuel concomitant with a decrease in brain glucose utilization.

The hypothesis that the anxiety induced by repeated injections affects brain energy metabolism was tested. Normal 19- to 21-day-old mice were stressed by two sham intraperitoneal injections within 4 min, at which time they were decapitated. Noninjected, control littermates were quickly decapitated. Momentary stress increased plasma glucose (12%), glycerol (85%), beta-hydroxybutyrate (108%), and lactate (153%)--a reflection of elevated plasma cortisol (25%) and glucagon (45%). In brain, stress increased levels of glucose-6-P (15%) and fructose-6-P (17%). The brain pyruvate concentration increased 74%; lactate 76%. Citrate, alpha-ketoglutarate, and malate increased 15, 95, and 37%, respectively. Levels of glycogen, glucose, phosphocreatine, ATP, ADP, and AMP were unchanged. The brain lactate/pyruvate ratio was normal but the brain/plasma lactate ratio fell 32%. Metabolite changes in the stressed animals were compatible with a decrease in the glycolytic flux at the phosphofructokinase step and a paradoxical increased flux in the Krebs citric acid cycle. The decreased brain/plasma lactate ratio supported increased uptake of lactate from plasma and increased brain lactate oxidation. Metabolite changes similar to those described above occurred in unstressed mice injected with lactate. Findings confirm a positive effect of stress on brain metabolism, support a role for lactate as an oxidative fuel for brain, and caution that the rate of cerebral glucose utilization may not always reflect brain energy (oxidative) metabolism accurately.

Animals↗

PubMed1989

Valproate doubles the anoxic survival time of normal developing mice: possible relevance to valproate-induced decreases in cerebral levels of glutamate and aspartate, and increases in taurine.

We have previously reported that chronic administration of valproate in developing mice decreased brain aspartic and glutamic acid levels and increased the brain taurine content. The direction of the valproate-induced changes in the cerebral levels of these neurotransmitter amino acids - excitatory in the case of aspartate and glutamate, inhibitory in the case of taurine - appeared relevant to the mechanism of its anticonvulsant action. Since the neuropathology of hypoxia-ischemia also appears to be mediated by release of glutamate/aspartate at the synapse, the valproate-induced reduction of the levels of these neuroexcitatory/neurotoxic amino acids suggested that valproate might increase the tolerance of young mice to anoxia. A doubling of the length of survival of the intact animal in an atmosphere of pure nitrogen gas and a three-fold increase in the duration of respiratory activity (gasping) of the isolated head after chronic administration of valproate support the speculation.

Animals↗

PubMed1989

myo-inositol: a newly identified nonnitrogenous osmoregulatory molecule in mammalian brain.

Sugar alcohols have been found to play an important osmoregulatory role both in unicellular organisms and, more recently, in multicellular organisms, including mammals. This study shows that myo-inositol accumulates in the brains of chronically hypernatremic mice, as had been earlier found in rats, and demonstrates for the first time a profound decrease of myo-inositol in the brains of chronically hyponatremic mice. Together with decreases in better known cerebral osmoles (amino acids and related nitrogenous compounds), the decrease in myo-inositol apparently allows the brain to balance its intracellular osmolality with that of the plasma, permitting a normal brain water content (no edema) despite profound hyponatremia.

Adaptation, Physiological↗

PubMed1987

Brain amino acids decrease in chronic hyponatremia and rapid correction causes brain dehydration: possible clinical significance.

In animals, rapid correction of chronic hyponatremia produces brain lesions similar to those seen in central pontine myelinolysis. This is the first study of the effects of rapid correction (9 h) of chronic hyponatremia (3 d) on brain electrolyte, water, and amino acid contents in young mice. Despite profound hyponatremia, decreases in brain electrolytes and amino acids permitted an apparent osmotic balance between blood and brain with a normal brain water content. Rapid elevation of the depressed plasma sodium concentration to normonatremic levels caused dehydration of the brain. Although brain Na+ and K+ levels were returned to normal, the relatively brief interval of treatment was insufficient to allow complete recovery of brain amino acid levels. Findings support an osmotic disequilibrium--plasma osmolality higher than brain--in the pathogenesis of the brain lesions following rapid correction of chronic hyponatremia and suggest caution in the rate of elevation of the depressed plasma Na+ levels.

Amino Acids↗

PubMed1987

Adaptive decreases in amino acids (taurine in particular), creatine, and electrolytes prevent cerebral edema in chronically hyponatremic mice: rapid correction (experimental model of central pontine myelinolysis) causes dehydration and shrinkage of brain.

The experimental model of central pontine myelinolysis--chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline--was used in young fasted and thirsted mice. In normal controls chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cyclic metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium--blood osmolality higher than brain--in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.

Acclimatization↗

PubMed1987

Ketamine protects hippocampal neurons from anoxia in vitro.

Ketamine, a dissociative, general anesthetic, blocks the excitation produced by activating one class of excitatory amino acid receptors, the N-methyl-D-aspartate receptor in the rat. We have found that ketamine can protect hippocampal neurons in culture and slice from anoxia. When added to cultures immediately prior to anoxic exposure, ketamine prevented the neuronal destruction seen after a day of anoxia. Neurons appeared undamaged and had normal resting and action potentials. Adenosine triphosphate levels in ketamine-protected anoxic cultures were approximately two-thirds of normal controls. Ketamine also prevented the irreversible loss of the population spike seen in hippocampal slices after prolonged perfusion with anoxic buffer. These results suggest that ketamine may have therapeutic potential in preventing anoxic damage from stroke in man.

Anesthesia, General↗

PubMed1987

Delayed neurotoxicity of excitatory amino acids in vitro.

The acute neurotoxicity produced by glutamate and related excitatory amino acids is probably caused by depolarization leading to excessive anionic and cationic fluxes and osmotic lysis. Recently, a more delayed form of glutamate neurotoxicity, which is critically dependent upon calcium influx, has been described in cultured neocortex. We investigated this phenomenon in cultures of dispersed rat hippocampal neurons. When these cultures were briefly incubated with various excitatory amino acids in low extracellular chloride, there was no acute toxicity, but a gradual drop-out of neurons occurred over the next day. When calcium was removed from the extracellular medium during amino acid incubation, this late neuronal loss was not seen. Interestingly, blocking excitatory amino acid receptors in cultures after the amino acid exposure also prevented this delayed neuronal death. In addition, these treated cultures contained neurons with normal physiological properties, and had concentrations of adenosine triphosphate that were close to control values. The findings suggest an amino acid-induced calcium influx may elevate the release of endogenous excitatory transmitter, likely glutamate, and/or increase the sensitivity of these neurons to glutamate. These in vitro observations may partially explain the delayed neuronal loss seen in some pathological conditions affecting man.

Amino Acids↗

PubMed1986

Beta-hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels.

In normal suckling-weanling mice, DL-beta-hydroxybutyrate (30 mmol/kg ip) stimulated insulin secretion and reduced plasma glucose levels. In the brains of these animals, glucose levels were tripled due to a reduced rate of glucose utilization (determined by deoxyglucose phosphorylation). Other metabolite changes were compatible with inhibition of hexokinase, phosphofructokinase, glyceraldehyde-P-dehydrogenase, and pyruvate dehydrogenase activities. In contrast to the decrease in cerebral glycolysis, metabolite changes were compatible with an increase in the Krebs citric acid metabolic flux. The brain energy charge was also elevated. While it is generally believed that ketone bodies cannot sustain normal brain metabolism and function in the absence of glucose, DL-beta-hydroxybutyrate (20 or 30 mmol/kg ip) reversed insulin (100 U/kg sc)-induced hypoglycemia despite the persistence of a critically reduced plasma glucose concentration and near-zero brain glucose levels. Metabolic correlates of possible significance in the behavioral recovery from coma were reductions of the elevated levels of brain aspartate to below normal and ammonia levels to normal. Levels of acetyl CoA were unchanged both before and after treatment with beta-hydroxybutyrate.

3-Hydroxybutyric Acid↗

PubMed1986

Effects of acute hyperosmolar NaCl or urea on brain H2O, Na+, K+, carbohydrate, and amino acid metabolism in weanling mice: NaCl induces insulin secretion and hypoglycemia.

This study compares early and late effects of the injection of hyperosmolar NaCl and urea of equal osmolarity on selected aspects of brain water, electrolyte, carbohydrate, amino acid, urea, and energy metabolism in normal suckling-weanling mice. One hour after treatment, salt-treated mice were critically ill, while the behavior of urea-treated animals could not be distinguished from that of controls. This clinical difference could not be explained on the basis of differences in plasma osmolality, the brain water content, or the degree of hemorrhagic encephalopathy. The injection of NaCl induced a 14-fold increase in plasma insulin and a progressive fall in the plasma glucose concentration (a reduction of 66% at 1 hr). In contrast, plasma glucose levels in urea-injected mice were unchanged. Prior to the fall in plasma glucose levels, metabolite changes in the brains of NaCl-injected mice were compatible with facilitation of transfer of glucose from the blood to the brain, increased metabolic flux in the Embden-Meyerhof and Krebs citric acid cycle pathways, and increased energy production. With the exception of the glucose content (unchanged), similar metabolite changes were seen in brain soon after urea injection. In the brains of the hypoglycemic NaCl-treated mice, glucose levels were reduced 80%, and glycogen 41%. Other metabolite changes were compatible with decreased glycolysis and metabolic flux through the Krebs citric acid cycle. In contrast, with few exceptions, at a similar time after injection, metabolite levels had returned to normal in the urea-treated mice. Permeability of the brain to urea was also examined. Brain urea reached high levels at 2 hr but returned to near baseline at 6 hr. Both hyperosmolar solutions increased the brain content of aspartic and glutamic acids 1 hr after injection. The failure of hypoglycemic mice with hypernatremia and elevated plasma osmolality (range, 416-434 mOsm/kg H2O) to respond to 1 M glucose (30 ml/kg) may have been due to the ill effects of the additional hyperosmolar load. The possibility remains that the encephalopathy induced by hyperosmolar NaCl, but not by hyperosmolar urea, is in some way related to the sudden elevation of brain Na+ and/or Cl- ions.

Amino Acids↗

PubMed1985

A single therapeutic dose of valproate affects liver carbohydrate, fat, adenylate, amino acid, coenzyme A, and carnitine metabolism in infant mice: possible clinical significance.

We have previously reported that chronic valproate administration reduced ketonemia in suckling mice and fasting epileptic children. The present study demonstrates that even a single dose of valproate in the therapeutic range for man caused a prolonged reduction of plasma beta-hydroxybutyrate levels in normal infant mice; the plasma glucose concentration was also significantly lowered. In the livers of these animals, there were extraordinary decreases in levels of free coenzyme A, acetyl CoA and free carnitine. Concomitantly concentrations of acid-soluble fatty acid (short-chain, non-acetyl) coenzyme A esters and of acid-insoluble (long-chain) fatty acid carnitine esters increased. There was evidence for inhibition of the metabolic flux through the Krebs citric acid cycle at those enzyme reactions which require coenzyme A. While valproate doubled liver alanine levels, concentrations of liver aspartate, glutamate and glutamine were reduced. All of the valproate-induced metabolite changes can be explained by the decrease of coenzyme A due to the accumulation of acid-soluble (non-acetyl) coenzyme A esters (presumably valproyl CoA and further metabolites). Decreased coenzyme A would limit the activities of one or more enzymes in the pathway of fatty acid oxidation and the Krebs citric acid cycle. Secondary decreases in acetyl CoA would limit both ketogenesis and gluconeogenesis. Decreased levels of selected hepatic amino acids could reflect their use as alternative fuels. The effect of clinical doses of valproate in infant mice may relate to the valproate-associated syndrome of hepatic failure and Reye-like encephalopathy in some infants and children and suggest a simple screen for those who may be at particular risk.

3-Hydroxybutyric Acid↗

PubMed1978

Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice.

In weanling mice treated with pharmacologic doses of aminophylline, the concentrations of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in the brain increased 44 and 36 percent, respectively, and the cerebral metabolic rate was three times that in controls. In neonatal mice, therapeutic doses of aminophylline greatly decreased the rate of anoxic survival in vivo and the duration of gasping of the isolated head. The findings suggest caution in the use of this drug and other methylxanthines in hypoxic human newborns.

Adenine Nucleotides↗

PubMed1978

Hyperglycemia, hypoinsulinemia, and hyperglucagonemia in acute water intoxication.

When acute (four-hour) hyponatremia with clinical signs of water intoxication was produced in normal weanling mice by the use of hypotonic glucose or deionized water, there was a two-to-fourfold increase in plasma glucose concentration. Concomitantly, concentrations of plasma insulin fell 63 to 68 per cent, whereas plasma glucagon increased to 262 per cent of control. The findings are compatible with stress-induced catecholamine release.

Acute Disease↗

PubMed1977

Insulin and brain metabolism. Absence of direct action of insulin on K+ and Na+ transport in normal rabbit brain.

In fed, unanesthetized rabbits, regular zinc insulin, 50 U./kg. intravenously, decreased plasma glucose levels 52 per cent, p = 0.002, 35 minutes after injection. In 15-hour-fasted, unanesthetized animals, the same dose of insulin decreased plasma glucose levels 68 per cent, p less than 0.001. Plasma K+ concentration was not affected by insulin injection in the fed animals; in fasted rabbits, plasma K+ levels fell 26 per cent, p = 0.006. Despite this unequivocal evidence of insulin action in both sets of animals, there was no change in the K+, Na+, or H2O content in the brains of the same animals 35 minutes after insulin injection. These results, which give no evidence of a direct effect of insulin on electrolyte transport in brain, are in sharp contrast with those found in anesthetized rabbits, which suggested that insulin affects brain potassium and water content before any change in plasma glucose occurs.

Animals↗

PubMed1976

Fluorometric determination of pyruvate and alpha-ketoglutarate in cerebrospinal fluid and plasma of infants and children. A simple test that screen for metabolic disorders.

Levels of pyruvate and alpha-ketoglutarate in the cerebrospinal fluid (CSF) of 26 children, aged 4 months to 5 1/2 years, with febrile seizures and of 19 children, aged 4 months to 14 years, with the diagnosis of epilepsy were not different from values seen in 119 "normal" children 8 days to 14 years of age. The CSF samples from 24 adults, 24 to 81 years of age, suspected of having a herniated disk were also examined. In the pediatric age group, the data showed a highly significant downward trend of CSF and plasma alpha-ketoglutarate values with age; pyruvate values did not change. A correlation of the values of the two keto acids in the blood and CSF of 42 other children without apparent neurologic disease was also made. Findings in a child with thiamine deficiency suggest that CSF alpha-ketoglutarate may be a more sensitive indicator of deficiency than plasma alpha-ketoglutarate or pyruvate. Measurements of these keto acids in plasma and CSF may be diagnostically useful in a variety of metabolic disorders. Findings in 155 children from birth (20 minutes) to 17 years of age without neurologic disease are submitted as a standard of reference.

Adolescent↗

PubMed1976

Insulin and brain metabolism. Absence of direct action of insulin on K+ and Na+ transport in mouse brain.

This is a study of the effect of insulin on the transport of K+ and Na+ from the blood into the brains of normal mice. Despite profound reductions in plasma and brain glucose levels, reduction of plasma K+ concentration and progressive deterioration of neurologic function 30-120 minutes after insulin injection, in 20-22-day-old animals there was no increase in brain K+ and Na+ concentrations. In fact, at 120 minutes, when the brain water content increased 0.7 per cent, brain K+ concentration was significantly reduced, not elevated. The effect of insulin on brain electrolyte and water content in adult mice was also studied. Although brain water increased 0.5 per cent at 120 minutes, there was no changes in brain Na+ or K+ concentrations at any time after insulin injection. The data from mice do not support a role of insulin in electrolyte transport in brain.

Age Factors↗

PubMed1975

Effects of alloxan diabetes, anti-insulin serum diabetes, and non-diabetic dehydration on brain carbohydrate and energy metabolism in young mice.

Alloxan-induced diabetes of 4 days duration produced metabolite changes in brain compatible with severe reduction in cerebral metabolism (phosphocreatine increased 70%), and reduced phosphofructokinase activity (fructose diphosphate levels fell 38%). There was a 56% reduction in brain lactate concentration, but pyruvate levels were unchanged. In 5 of 23 animals, brain glycogen levels increased; in the remainder blycogen levels decreased. Brain fructose concentration, 0.4 mmol/kg, was only 1/30 of the glucose concentration. The alloxan-treated animals were also severely dehydrated. Therefore, to determine the casual relation of insulin deficiency to these findings, the effects of chronic dehydration and acute insulin deficiency were investigated. Findings in the brains of severely dehydrated animals (water deprivation and mannitol injections for 4 days) were almost identical with those seen after alloxan treatment. The exceptions were that, in the dehydrated mice, reductions in lactate and pyruvate were proportional, and glycogen levels were consistently reduced. In acute diabetes (6 to 24 hours after repeated anti-insulin serum injections) P-creatine, fructose diphosphate, and lactate levels were normal. Pyruvate levels were normal at 6 hours, but increased 39% by 12 to 24 hours; glycogen was 36% higher at 6 hours and 63% at 12 to 24 hours. Insulin (and glucose) appeared to be specific in correcting the metabolic abnormalities found in the brains of animals with alloxan-induced diabetes. At 4 and one half hours after treatment with insulin and glucose, glucose 6-phosphate levels fell 25%, fructose diphosphate increased 28%, and lactate and the lactate to pyruvate ratio returned to normal; glycogen increased 50%. However, the treatment also had a dramatic clinical effect. Since animals gained 8 to 27% of body weight during therapy, at least some of the improvements in metabolite levels could be related to rehydration.

Animals↗

PubMed1975

Failure of adrenaline to induce hyperglycaemia after fructose injection in young mice.

In control animals a 2-fold increase in liver phosphorylase activity 10min after adrenaline treatment was associated with a 55% increase in plasma glucose (P less than 0.001); at 20 min plasma glucose was 247% of the control value (P less than 0.001). Liver phosphorylase activity was decreased by 74%, 20 min after fructose injection (P less than 0.001), and, although phosphorylase activity increased 5-fold within 5 min of adrenaline injection, no increases in plasma glucose concentration over that found in fructose-injected animals which did not receive adrenaline occurred at either 5, 10 or 20 min. The data confirm inactivation of liver phosphorylase after fructose injection and suggest inhibition of the adrenaline-activated enzyme by the decrease in Pi and elevation of fructose 1-phosphate concentrations produced by the injection of fructose. These findings may be causally related to the hypoglycaemia and the lack of response to glucagon seen in patients with hereditary fructose intolerance after fructose ingestion.

Animals↗