STUDIES ON CEREBRAL ENERGY METABOLISM DURING THE COURSE OF GALACTOSE NEUROTOXICITY IN CHICKS¹

Abstract

—At various times during a 2‐day study, the levels of adenine nucleotides and selected glycolytic intermediates were determined in brains of chicks fed a diet containing d‐galactose (40%, w/w). The levels of ATP and glucose 6‐phosphate had decreased by 9 h after initiation of the diet, whereas those of fructose 1,6‐diphosphate, 3‐phosphoglycerate, l‐α‐glycerophosphate, and lactate were not reduced until after 18 h had elasped. Although glucose 1‐phosphate was not appreciably affected, glucose and glycogen were depleted during the latter stages of the toxicity. The cerebral levels of 3′,5′‐cyclic AMP and citrate did not differ significantly between the two dietary groups at 48 h. The changes in the levels of cerebral glycolytic intermediates and high‐energy phosphates during ischemia indicated that the glycolytic rate was diminished in the chicks fed galactose and that high‐energy phosphate compounds were depleted sooner than in controls. After intraperitoneal injection of [14C]glucose, the specific radioactivity and levels of glucose in the plasma from chicks fed either diet were similar, whereas they were significantly reduced in the brains from galactosefed animals. We suggest that galactose interferes with the uptake of glucose into the brain and that this mechanism may be an important factor in d‐galactose‐induced neurotoxicity in the chick.

Partial Enzyme Deficiencies: Residual Activities and the Development of Neurological Disorders

“…in the brain [We//.vet al. 1965] or may be related to the inhibition of glucose uptake across the blood-brain barrier by high blood galactose levels [Granett et al, 1972], A number of patients have been identified with a moderate galactose tolerance; some have even remained asymptomatic while in gesting milk. In liver and intestine of the lat ter patients, galactose-l-phosphate uridyl transferase activities around 10% of normal have been found [Segrt/, 1983], Phenylketonuria and galactosemia, as well as many other disorders, such as Refsum syndrome (inability to metabolize the branched chain carboxylic acid phytanic acid, due to a defect in «-oxidation of fatty acids [Herndon et al, 1969]), share in common that the substance the metabolism of which is impaired is mainly of dietary origin and hence they are accessible to dietary treatment.…”

Utilization of Galactose in Cultured Brain Cells of Neonatal Mice

“…Haworth et al (1 1) demonstrated a 5-15% decrease in brain DNA content which was associated with reduced body weight in preterm and term fetuses of rats made galactosemic in pregnancy. In the galactose-toxic chick, reduced levels of glycolytic intermediates and brain lactate have been observed repeatedly (10,14,17). Brain glucose (10,14,16) was reduced in this model probably because of the competition between glucose uptake and the excessive plasma galactose levels amounting to 28-56 mM (14,16), and possibly also due to inhibition of several glycolytic enzymes by elevated galactose-lphosphate concentrations (1 7).…”

“…Animal models, such as the galactose-toxic rat and the chicken, have permitted some insight into the mechanism of galactose brain toxicity, but, admittedly, these models differ markedly from the human disease states and some studies yielded contradictory findings (25). The toxic effects of galactose on the CNS include decreased brain development and decreased DNA content (1 l), Schwann cell changes and demyelination (2 I), reduced cerebral entry and content of glucose (lo, 14,16), inhibition of glycolysis (10,17), and energy metabolism (10).…”

Impaired hexose uptake by diploid skin fibroblasts from galactosaemic patients. Connection with cell growth and amino acid metabolism, and possible bearing on late‐onset clinical symptoms

“…Contrary to the reduced galactose consumption, the persistent reduction of glucose uptake by [GalT-] and [GalK-] SF cultured in the presence of glucose as the only hexose was unexpected and never published. Extensive research has been done on the neurotoxicity of galactose in galactose-fed chicken (Granett et al 1972;Malone et al 1972): competition between glucose and galactose for the same transporter was proved to be responsible (Granett et al 1972), because this competition leads to a decrease in brain glucose. In the present work, even if trace amounts of galactose contaminated the G1 medium, although highly purified glucose and normal human serum were used for the medium preparation, this would not explain the marked and persistent decrease in glucose utilization by galactosaemic cells cultured in G1, compared to glucose utilization by normal cells in this medium.…”