Hematological changes in rats chronically exposed to oral aluminum.

This study was aimed to investigate the effects of the long-term oral exposure to aluminum sulfate on hematological parameters in rats. For this purpose, 24 adult female Wistar rats were divided in three groups with 8 animals each (control, citrate, and citrate plus aluminum groups). Rats from control and citrate groups had free access to tap water and to a sodium citrate solution (35 mM), respectively. Rats from citrate plus aluminum group received, as unique source of liquid, an aluminum sulfate solution (30 mM) diluted in the above-mentioned sodium citrate solution, ad libitum. After the treatment period (18 months), aluminum-exposed rats showed a significant decrease in the number of red blood cells, blood hemoglobin concentration and hematocrit when compared to rats from the control group. Serum iron levels were also significantly lower in citrate plus aluminum group, whereas total iron binding capacity did not change after citrate plus aluminum exposure. Erythrocyte thiobarbituric acid-reactive substances (TBARS) and nonprotein thiols (NPSH) levels, erythrocyte osmotic fragility and hepatic delta-aminolevulinic acid dehydratase (delta-ALA-D) activity did not change after treatment with citrate plus aluminum. Conversely, aluminum exposure increased delta-ALA-D activity in bone marrow. The present results indicate that long-term oral exposure to low doses of aluminum sulfate promotes alterations on erythrocyte parameters in rats, probably as a consequence of alterations in the iron status. In addition, although the details of the underlying mechanism remain unclear, our study reports, for the first time, a stimulatory effect of chronic aluminum exposure on bone marrow delta-ALA-D activity.

Effects of methylmalonic and propionic acids on glutamate uptake by synaptosomes and synaptic vesicles and on glutamate release by synaptosomes from cerebral cortex of rats.

Neurological dysfunction is common in patients with methylmalonic and propionic acidemias. However, the mechanisms underlying the neuropathology of these disorders are far from understood. In the present study we investigated the in vitro effects of methylmalonic (MMA) and propionic (PA) acids at various concentrations (1 microM-5 mM) on three parameters of the glutamatergic system, namely the basal and potassium-induced release of L-[3H]glutamate by synaptosomes, Na+-dependent L-[3H]glutamate uptake by synaptosomes and Na+-independent L-[3H]glutamate uptake by synaptic vesicles from cerebral cortex of male adult Wistar rats. The results showed that MMA significantly increased potassium-induced but not basal L-[3H]glutamate release from synaptosomes with no alteration in synaptosomal L-[3H]glutamate uptake. A significant reduction of L-[3H]glutamate incorporation into vesicles caused by MMA was also detected. In contrast, PA had no effect on these parameters. These findings indicate that MMA alters the glutamatergic system. Although additional studies are necessary to evaluate the importance of these observations for the neuropathology of methylmalonic acidemia, it is possible that the effects elicited by MMA may lead to excessive glutamate concentrations at the synaptic cleft, a fact that may explain previous in vivo and in vitro findings associating MMA with excitotoxicity.

Glycine, serine, and leucine metabolism in different regions of rat central nervous system.

We have investigated the glycine, serine and leucine metabolism in slices of various rat brain regions of 14-day-old or adult rats, using [1-14C]glycine, [2-14C]glycine, L-[3-14C]serine and L-[U-14C]leucine. We showed that the [1-14C]glycine oxidation to CO2 in all regions studied occurs almost exclusively through its cleavage system (GCS) in brains of both 14-day-old and adults rats. In 14-day-old rats, the highest oxidation of [1-14C]glycine was in cerebellum and the lowest in medulla oblongata. In these animals, the L-[U-14C]leucine oxidation was lower than the [1-14C]glycine oxidation, except in medulla oblongata where both oxidations were the same. Serine was the amino acid that showed lowest oxidation to CO2 in all structure studied. In adult rats brains, the highest oxidation of [1-14C]glycine was in cerebral cortex and the lowest in medulla oblongata. We have not seen difference in the lipid synthesis from both glycine labeled, neither in 14-day-old rats nor in adult ones, indicating that the lipids formed from glycine were not neutral. Lipid synthesis from serine was significantly high than lipid synthesis and from all other amino acids studied in all studied structures. Protein synthesis from L-[U-14C]leucine was significantly higher than that from glycine in all regions and ages studied.

Study of developmental changes on hexoses metabolism in rat cerebral cortex.

We have studied the developmental changes of glucose, mannose, fructose and galactose metabolism in rat cerebral cortex. As the animals aged, glucose, mannose and fructose oxidation to CO2 increased, whereas galactose oxidation decreased. Lipid synthesis from glucose and fructose also increased with age, that from mannose decreased and galactose did not change. Cytochalasin B, a potent non-competitive inhibitor of sodium-independent glucose transport, significantly impaired glucose, mannose and galactose metabolism, but had no effect on fructose metabolism. Both galactose or fructose did not change, whereas mannose declined the glucose metabolism. Glucose decreased fructose, galactose and mannose metabolism. Our results show that besides glucose, the metabolism of mannose, galactose and fructose present developmental changes from fetal to adult age, and reinforce the literature data indicating that mannose and galactose are transported by glucose carriers, while fructose is not.

Diphenyl diselenide and diphenyl ditelluride affect the rat glutamatergic system in vitro and in vivo.

The aim of this study was to investigate the possible involvement of the glutamatergic system in the toxicity of organochalcogens, since this is an important neurotransmitter system for signal transduction and neural function. The results indicated that 100 microM diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) inhibit by 50 and 70% (P<0.05), respectively, [(3)H]glutamate binding in vitro. Acute administration of 25 micromol/kg (PhSe)(2) or 3 micromol/kg (PhTe)(2) caused a significant reduction in [(3)H]glutamate (30%, P<0.05) or [(3)H]MK-801 binding (30%, P<0.05) to rat synaptic membranes. These results suggest that (PhSe)(2) and (PhTe)(2) affect, in a rather complex way, the glutamatergic system after acute in vivo exposure in rats. In vitro, total [(3)H]GMP-PNP binding was inhibited about 40% at 100 microM (PhSe)(2) and (PhTe)(2). Acute exposure in vivo to (PhSe)(2) decreased the stable [(3)H]GMP-PNP binding to 25% and (PhTe)(2) to 68% of the control value (P<0.05, for both compounds). Simultaneously, the unstable binding of [(3)H]GMP-PNP was decreased about 30 and 50% (P<0.05, for both compounds) after exposure to (PhSe)(2) and (PhTe)(2), respectively. GMP-PNP stimulated adenylate cyclase (AC) activity significantly in control animals. (PhSe)(2)- and (PhTe)(2)-treated animals increased the basal activity of this enzyme, but GMP-PNP stimulation was totally abolished. These results suggest that the toxic effects of organochalcogens could result from action at different levels of neural signal transduction pathways, possibly involving other neurotransmitters besides the glutamatergic system.

Undernutrition decreases serine palmitoyltransferase activity in developing rat hypothalamus.

BACKGROUND/AIMS: Undernutrition reduces the hypothalamic ganglioside concentration. This may be attributed to some modifications in the contents of precursors of sphingolipid biosynthesis in undernourished rats. The present study evaluated the serine palmitoyl transferase activity (SPT; EC 2.3.1.50) during the development of the rat hypothalamus. This work also shows the L-[3-(14)C]serine metabolic labeling of hypothalamic sphingolipids in normal and undernourished rats at weaning. METHODS: The SPT activity was determined in microsomal fractions obtained from the hypothalamus of normal rats (diet: 25% protein) and pre- and postnatally undernourished rats (diet: 8% protein since pregnancy) at 21 days of gestational age and at 7, 14, and 21 days of postnatal life. RESULTS: The enzymatic activity was lower in the hypothalamus of undernourished than in the hypothalamus of control rats since the 7th postnatal day. Incorporation of the precursor L-[3-(14)C]serine into sphingolipid fraction was lower in the hypothalamus of undernourished rats than in the hypothalamus of control rats on the 21st postnatal day which coincided with the age of the highest difference in SPT activity between normal and undernourished rats. CONCLUSION: These results indicate that undernutrition reduces the biosynthesis of the main sphingolipids during the period of brain growth spurt.