Jean Holowach Thurston

Taurine: A role in osmotic regulation of mammalian brain and possible clinical significance

Abstract Chronic hypernatremic dehydration induced in developing mice by water deprivation and salt loading for 4 days increased 16 of the 19 amino acids measured in brain. Taurine accounted for over one-half of the total increase. It is well known that during adaptation to increased environmental salinity, levels of amino acids in invertebrate and amphibian tissues increase to maintain osmotic equilibrium and to limit the loss of cell water. The findings in young mice support a similar function for amino acids, taurine in particular, in mammalian brain and suggest that the phenomenon may be causally related to the cerebral edema that develops during overly rapid rehydration of infants and children with chronic hypernatremic dehydration.

Prognosis in childhood epilepsy: additional follow-up of 148 children 15 to 23 years after withdrawal of anticonvulsant therapy.

To evaluate the risk of relapse in children with epilepsy whose anticonvulsant therapy has been withdrawn after prolonged control, we studied 148 such children for 15 to 23 years or until relapse. Forty-one of the 148 patients (28 per cent) had recurrence of seizures; of these, 35 (85 per cent) had relapses within five years of drug withdrawal. Factors associated with an increased risk of relapse were a long duration of epilepsy before control, neurologic dysfunction, and jacksonian seizures or combinations of seizure types. We found no association between risk of recurrence and age at onset of epilepsy, total number of seizures before control, age at discontinuation of therapy, electroencephalographic abnormalities, or family history of epilepsy. We conclude that children who do not have the additional risk factors noted above have an excellent chance of remaining seizure free after the withdrawal of anticonvulsant drugs.

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

ABSTRACT: 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.

Reduced brain glucose with normal plasma glucose in salicylate poisoning

After the intraperitoneal injection into young mice of 700-800 mg/kg of salicylate, brain glucose fell to one-third or less of control values despite normal plasma glucose levels; brain lactate was nearly doubled and there were small decreases in phosphocreatine (18%) and in glycogen (17%). ATP, pyruvate, alpha-ketoglutarate, and glutamate were unchanged. In liver, glycogen was reduced 79% and lactate was five times higher than in control animals; glucose, glucose-6-phosphate, and ATP were unchanged. Since salicylate uncouples oxidative phosphorylation, it is postulated that high energy phosphate in the brain is maintained near normal levels by a compensatory increase in cerebral glycolysis. Apparently the brain glucose level falls because the rate of utilization exceeds the rate at which glucose can be supplied from the blood. Concurrent administration of glucose with salicylate elevated brain glucose concentration and was associated with striking improvement in the condition and the increased survival of the animals. These findings stress the fact that in salicylate poisoning the supply of glucose to the brain may be inadequate even when blood glucose levels are normal.

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 cycle 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.

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.

EFFECTS OF SALT AND WATER LOADING ON CARBOHYDRATE AND ENERGY METABOLISM AND LEVELS OF SELECTED AMINO ACIDS IN THE BRAINS OF YOUNG MICE

—This is a report of the effect of extreme changes in plasma sodium concentration induced by chronic (5 d) water deprivation and hypertonic saline injections and acute (4 h) overhydration with hypotonic glucose or fructose on the water and electrolyte content and levels of selected metabolites in the brains of young mice. In the dehydrated hypernatremic mice (plasma Na+, 186 × 3 mequiv./1) significant increases were found in brain glucose (82%), alanine (16%), aspartate (45%), glutamate (19%), gamma‐amino butyrate (34%) and glutamine (42%) concentrations. In striking contrast, water‐intoxicated mice (plasma Na+, 110 × 4 mequiv./1) had significantly decreased levels of alanine (17%), aspartate (38%) and glutamate (33%). Significant reductions in brain lactate (30–40%) and malate concentrations (23%) in both groups of experimental mice are suggestive of reduced cerebral metabolic rate.

Lactate Reverses Insulin-Induced Hypoglycemic Stupor in Suckling-Weanling Mice: Biochemical Correlates in Blood, Liver, and Brain

The recovery of weanling mice from insulin-induced hypoglycemic stupor–coma after injection of sodium -l(+)-lactate (18 mmol/kg) was as rapid (10 min) as in litter-mates treated with glucose (9 mmol/kg). Stimulated by this dramatic action, we studied the effects of lactate injection on brain carbohydrate and energy metabolism in normal and hypoglycemic mice; blood and liver tissue were also studied. Ten minutes after lactate injection in normal mice, plasma lactate levels increased by 15 mmol/L; plasma glucose levels were unchanged, but the β-hydroxybutyrate concentration fell 59%. In the brains of these animals, glucose levels increased 2.3-fold, and there were significant increases in brain glycogen (10%), glucose-6-phosphate (27%), lactate (68%), pyruvate (37%), citrate (12%), and malate (19%); the increase in α-ketoglutarate (32%) was not significant. Lactate injection reduced the cerebral glucose-use rate 40%. These changes were not due to lactate-induced increases in blood [HCO−3] and pH (examined by injection of 15 mmol/kg sodium bicarbonate). Although lactate injection of hypoglycemic mice doubled levels of glucose in plasma and brain (not significant) and most of the cerebral glycolytic intermediates, values were far below normal (still in the range seen in hypoglycemic animals). By contrast, citrate and α-ketoglutarate levels returned to normal; the large increase in malate was not significant. Reduced glutamate levels increased to normal, and elevated aspartate levels fell below normal. Thus, recovery from hypoglycemic stupor does not necessarily depend on normal levels of plasma and/or brain glucose (or glycolytic intermediates). Near normal levels of the Krebs citric acid cycle intermediates suggest that changes in these metabolites, amino acids, or derived substrates relate to the dramatic recovery of hypoglycemic mice after lactate injection.

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

ABSTRACT: 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 β-oxidation. The present study shows for the first time that in developing mice, when pantothenic acid and carntine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the β-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 β-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.

Chronic valproate administration reduces fasting ketonemia in children

We previously found that chronic administration of sodium valproate to suckling infant mice reduced plasma β-hydroxybutyrate levels but had no effect on plasma free fatty acid or glycerol concentrations. We now report that valproate has a similar effect in children taking the drug for epilepsy. In larger doses, valproate also depleted the infant mouse liver glycogen content. These findings may relate to the hepatic toxicity of valproate. We advise caution if the drug is being considered for use in chronically malnourished childrea or when the caloric intake of normal children is likely to be reduced during periods of acute illness.