Myoinositol and phosphatidylinositol metabolism in synaptosomes from galactose-fed rats.

Abstract

The effects of experimental galactose toxicity on inositol and phosphatidylinositol (PtdIns) metabolism in synaptosomes from 0-to 30day-old rats were investigated. Galactose toxicity was induced by feeding mothers a 40% galactose diet from the 12th day of pregnancy until 19 days postpartum when the offspring were weaned onto the maternal diet. There was no decrease in myoinositol concentrations and only a small decrease in PtdIns in synaptosomes from galactose-fed rats relative to glucose-fed controls. Synaptosomes from rats on the two diets converted equivalent amounts of [ U-14Clglucose to inositol and PtdIns. Acetylcholine stimulated [2-MlHinositol incorporation into PtdIns while producing a net decrease in Ptdlns concentration in synaptosomes from 22-to 30-day-old rats. However, the phospholipid response to acetylcholine in synaptosomes from galactose-fed rats was impaired. Thus, the acetylcholine-stimulated labeling of PtdIns was 40-50% lower in these synaptosomes while the effect on Ptdlns concentration was reduced by a maximum of 55%. The data suggest that galactose-fed rats may have either a deficiency in the number of acetylcholine receptors or a defect in some step between receptor-neurotransmitter interaction and PtdIns breakdown.Since mental retardation appears to be the only incompletely reversible outcome of galactosemia caused by deficiency of the enzyme, galactose-1-phosphate uridylyltransferase, much interest has centered around the cause of the neurotoxicity. Wells and coworkers (1, 2) have reported increased concentrations of galactose and galactitol and a decrease in the concentration of free and lipid-bound myoinositol (Ins) in brain and nerve tissue of several galactosemic infants, and Schwarz (3) has demonstrated an increased concentration of galactose-1-phosphate in the nervous system of such patients. However, the mechanism by which galactose or its metabolites exert their toxic effects on the developing nervous system remains to be elucidated.In rats and chickens, experimental galactose toxicity results in decreased brain development, decreased nerve conduction, and decreased concentrations of glucose and of free amino acids in brain and nerve tissues (4). Wells and Wells (5) reported elevation of galactitol concentration and depression of free and lipid-bound Ins concentrations in brains of developing rats whose mothers were maintained on high galactose diets throughout pregnancy and lactation. In addition, these investigators demonstrated a decrease in the ability of brain slices from young galactose-toxic rats to convert [14C]glucose to Ins or phosphatidylinositol (PtdIns). Kozak and Wells (6) demonstrated decreased labeling of phosphatidic acid (PtdA) and PtdIns in brains of galactose-toxic chickens after intracranial injection of 32P1, although no change in total amount of phospholipid phosphorus was observed.These observations suggesting an impairment in Ins and Ins phospholipid synthesis or metabolism in galactose-toxic animals are of special significance in view of the e...

On the involvement of serotonin in galactose brain toxicity

“…Galactose added to synaptosomal incubations did not inhibit serotonin uptake even with a galactose-serotonin ratio of 25,OOO:l. We have not monitored a biochemical or physiological response of serotonin uptake. We have, however, previously studied the phosphatidylinositol turnover of synaptosomes in uitro in response to acetylcholine and found an alteration during galactose toxicity (WARFIELD & SEGAL, 1978). This is in contrast to the findings of WOOLLEY & GOMMI (1964) that the contraction response of stomach strips from galactose toxic rats to acetylcholine is normal.…”

Specificity of Muscarinic Acetylcholine Receptor Regulation by Receptor Activity

“…Our data suggest that reduced PI turnover could result from a muscarinic receptor deficit. Interestingly, cholinergic-stimulated PI turnover is reduced in an animal model for galactosemia (Warfield and Segal, 1978), a disease characterized by mental retardation. PI turnover has been implicated in mechanisms for calcium gating (Michell, 1975) and for prostaglandin synthesis (Banschbach and Hokin-Neaverson, 1980).…”

Treatment with Dehydroepiandrosterone Increases Peripheral Benzodiazepine Receptors of Mitochondria from Cerebral Cortex in d‐Galactose‐Induced Aged Rats

“…Early in 1978, d‐ galactose‐fed rats were used in the studies of d‐ galactose toxicity to receptors and receptor‐neurotransmitter interaction in brain [28]. In 1985, it was first reported in China that injection of a low dose of d ‐galactose into mice caused brain ageing.…”