Possible involvement of indolamines in the glycogenic effect of the convulsant methionine sulfoximine in rat brain.

The aim of the present investigation was to look for the mechanisms causing disturbances in carbohydrate metabolism during the action of the epileptogenic agent methionine sulfoximine. The levels of glucose, glycogen, and indolamines were measured in seven different regions of rat brain. Methionine sulfoximine induced a decrease in serotonin level which was roughly dose-dependent. There were no obvious changes in tryptophan and 5-hydroxyindoleacetic levels in any area. Methionine sulfoximine induced the known increase in glucose and glycogen levels. The direct precursor of serotonin. 5-hydroxytryptophan, and benserazide (a decarboxylase inhibitor) were then injected into rats in association with methionine sulfoximine. In this case, methionine sulfoximine failed to induce seizures. Moreover, the serotonin level was unchanged and the carbohydrate content did not significantly increase. There was only a rise in 5-hydroxyindoleacetic acid level. This work shows a striking parallelism between serotonin decrease and glycogen increase.     

Suppression of the immune response by drugs interfering with the metabolism of serotonin

Summary The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.     

Suppression of the immune response by drugs interfering with the metabolism of serotonin

The work was based on the assumption that neurohumoral control of the immune response, particularly in stressed animals, involves central serotoninergic mechanisms. Rats immunized with sheep erythrocytes were stressed by repeated restraints and/or treated with a precursor of serotonin (5-hydroxytryptophan, 5-HTP) or with an inhibitor of serotonin synthesis (parachlorophenylalanine, PCPA). As expected, repeated stresses reduced the plaque-forming cell (PFC) response. Treatment with 5-HTP also reduced the PFC response, and potentiated the immunosuppressive effect of stress. This was accompanied by increased metabolism of serotonin in the brain, as indicated by increased concentration of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in cerebral tissue. Treatment with PCPA also suppressed the PFC response, but this suppression was accompanied by decreased levels of brain serotonin and of 5-HIAA. Plasma corticosterone levels were elevated in rats treated with PCPA. It seems that putative central effects of PCPA on serotoninergic regulation of the immune response were outweighed by its effects on corticosterone secretion and/or on lymphoid cells.     

Dial variations in the levels of blood glucose and hepatopancreatic glycogen in the slug,Laevicaulis alte (Ferussac 1821)

Summary InLaevicaulis alte maximal blood glucose level at 00.00 h alternates with minimal level at 12.00 h of the day, while hepatopancreatic glycogen showed an opposite trend. Variations in blood glucose levels are inversely proportional to the corresponding variations in hepatopancreatic glycogen content, while blood glucose level shoots up to a maximum, hepatopancreatic glycogen declines to a minimum and vice versa.Acknowledgment. The authors thank Prof. K.S. Swami for providing facilities. The financial assistance rendered by ICMR (DCR), UGC (VJ) and CSIR (KS), New Delhi, India is gratefully acknowledged.     

Effect of hypoxia on glycolysis in isolated fetal rat heart]

Glycolysis was assessed in the isolated foetal Rat in hypoxia. Measurements were made of glucose uptake, lactate output, C14 glucose incorporation into glycogen and tissular levels of ATP, PCr, glycogen and lactate. Glycolysis was stimulated by hypoxia to a greater extent in the young foetal heart of 16.5 days post coitum than in the foetal heart at term. Thus high energy phosphates were maintained at a higher level in the younger heart. The results are discussed in relation to the high resistance to hypoxia of the foetal heart.     

Glutathione and gamma-glutamyl cycle enzymes in rat mammary gland

The main enzymes of the gamma-glutamyl cycle during the lactogenic cycle in rat mammary gland were studied. A significant increase was found in all of them with the onset of lactogenesis. The effect of methionine sulfoximine on reduced glutathione concentration was studied in tissue slices of lactating mammary gland. The findings suggest that this compound effects glutathione synthesis by inhibiting gamma-glutamylcysteine synthetase.     

Demonstration of exocytosis in the sinus gland of Astacus Leptodactylus (Nordmann) under the influence of serotonin injections]

Following a serotonin injection, a rise of exocytosis in the sinus gland of the crayfish Astacus leptodactylus is observed together with an increase of the glucose level in the hemolymph. The phenomenon of exocytosis reaches a peak between 2 and 4 h after injection, wheras the highest glucose level in the hemolymph appears between 4 and 6 h after the same injection.     

Glutathione andγ -glutamyl cycle enzymes in rat mammary gland

Summary The main enzymes of theγ-glutamyl cycle during the lactogenic cycle in rat mammary gland were studied. A significant increase was found in all of them with the onset of lactogenesis. The effect of methionine sulfoximine on reduced glutathione concentration was studied in tissue slices of lactating mammary gland. The findings suggest that this compound affects glutathione synthesis by inhibitingγ-glutamylcysteine synthetase. This work was supported by grant B1138-8223 from the Servicio de Desarrollo Cientifico, Universidad de Chile.     

Tetanus intoxication causes an increment of serotonin in the central nervous system

Summary Mice injected with tetanus toxin (TTx) showed an increase of 5-hydroxytryptamine (serotonin, 5-HT) levels in the central nervous system. The increment was not uniform thoughout the central nervous system. Particularly significant were the 25% and 80% increases observed, respectively, in whole brain and spinal cord. The levels of dopamine and norepinephrine remained unchanged. The subsequent studies of 5-HT turnover revealed a synthesis rate in the tetanic animals that was almost double that of controls. The degradation rate of the amine as well as the levels of 5-hydroxyindolacetic acid were unaffected.     

Tetanus intoxication causes an increment of serotonin in the central nervous system

Mice injected with tetanus toxin (TTx) showed an increase of 5-hydroxytryptamine (serotonin, 5-HT) levels in the central nervous system. The increment was not uniform throughout the central nervous system. Particularly significant were the 25% and 80% increases observed, respectively, in whole brain and spinal cord. The levels of dopamine and norepinephrine remained unchanged. The subsequent studies of 5-HT turnover revealed a synthesis rate in the tetanic animals that was almost double that of controls. The degradation rate of the amine as well as the levels of 5-hydroxyindolacetic acid were unaffected.     

Effects of captivity on glucose tolerance in dogs

Captivity decreased tolerance to glucose and increased blood serotonin levels in 6 normal dogs investigated. Return to freedom brought normalization in the glucose tolerance test and reverted blood serotonin to control levels.     

The effect of epinephrine and the hyperglycemic factor of the scorpion's cephalothoracic ganglionic mass (CTGM) on the phosphorylase activity of hepatopancreas of the scorpion,Heterometrus fulvipes C. Koch

Summary Injection of epinephrine and CTGM extract showed different effects on hepatopancreatic phosphorylase activity and levels of total carbohydrate and glycogen in heterometrus fulvipes. The former hyperglycemic principle involves phosphorolysis of glycogen whereas the latter does not.The authors are grateful to Proff. K. S. Swami and S. Nagaiah. An award of Junior Research Fellowship by the Council of Scientific and Industrial Research, New Delhi is acknowledged by K. R.     

Glutamine deprivation initiates reversible assembly of mammalian rods and rings

Rods and rings (RR) are protein assemblies composed of cytidine triphosphate synthetase type 1 (CTPS1) and inosine monophosphate dehydrogenase type 2 (IMPDH2), key enzymes in CTP and GTP biosynthesis. Small-molecule inhibitors of CTPS1 or IMPDH2 induce RR assembly in various cancer cell lines within 15 min to hours. Since glutamine is an essential amide nitrogen donor in these nucleotide biosynthetic pathways, glutamine deprivation was examined to determine whether it leads to RR formation. HeLa cells cultured in normal conditions did not show RR, but after culturing in media lacking glutamine, short rods (<2 μm) assembled after 24 h, and longer rods (>5 μm) formed after 48 h. Upon supplementation with glutamine or guanosine, these RR underwent almost complete disassembly within 15 min. Inhibition of glutamine synthetase with methionine sulfoximine also increased RR assembly in cells deprived of glutamine. Taken together, our data support the hypothesis that CTP/GTP biosynthetic enzymes polymerize to form RR in response to a decreased intracellular level of glutamine. We speculate that rod and ring formation is an adaptive metabolic response linked to disruption of glutamine homeostasis.     

Post-transcriptional gene silencing of ribosomal protein S6 kinase 1 restores insulin action in leucine-treated skeletal muscle

Excessive nutrients, especially amino acids, impair insulin action on glucose metabolism in skeletal muscle. We tested the hypothesis that the branched-chain amino acid leucine reduces acute insulin action in primary myotubes via a negative feedback mechanism involving ribosomal protein S6 kinase 1 (S6K1). The effect of S6K1 on glucose metabolism was determined by applying RNA interference (siRNA). Leucine (5 mM) reduced glucose uptake and incorporation to glycogen by 13% and 22%, respectively, compared to the scramble siRNA-transfected control at the basal level. Leucine also reduced insulin-stimulated Akt phosphorylation, glucose uptake and glucose incorporation to glycogen (39%, 39% and 37%, respectively), and this reduction was restored after S6K1 silencing. Depletion of S6K1 enhanced basal glucose utilization and protected against the development of impaired insulin action, in response to excessive leucine. In conclusion, S6K1 plays an important role in the regulation of insulin action on glucose metabolism in skeletal muscle. Received 22 December 2008; received after revision 19 February 2009; accepted 23 February 2009     

Effect of L-carnitine and stimulated lipolysis on muscle substrates in the exercising rat

To test the effect of L-carnitine on glycogen sparing when fat oxidation is increased, 100 mg/kg/d were given to rats orally for 3 days, resulting in 1.8-fold higher muscle carnitine levels. Even when FFA were raised by heparin-stimulated lipolysis, the rate of glycogen degradation was not reduced during exercise.     

Effect of L-carnitine and stimulated lipolysis on muscle substrates in the exercising rat

Summary To test the effect of L-carnitine on glycogen sparing when fat oxidation is increased, 100 mg/kg/d were given to rats orally for 3 days, resulting in 1.8-fold higher muscle carnitine levels. Even when FFA were raised by heparin-stimulated lipolysis, the rate of glycogen degradation was not reduced during exercise.     

Metabolism of the snailCryptozona ligulata during regeneration of optic tentacles

Summary The biochemical changes in the hemolymph and tissues were followed during regeneration of the optic tentacles of the snailCryptozona ligulata (Pulmonata-Stylommatophora). There is a remarkable increase in total carbohydrates in hemolymph and tissues and glycogen in tissues at the expense of free amino acids and fatty acids. It is clear that ablation of the optic tentacles stimulates carbohydrate synthesis through glyconeogenic routes. The optic tentacles regenerate completely in 18–21 days.     

Effect of organophosphate pesticide Sumithion (Fenitrothion) on some aspects of carbohydrate metabolism in a freshwater fish, Sarotherodon (Tilapia) mossambicus (Peters)

A lethal (Lc50/48 h - 6 mg/l) concentration of the organophosphate (OP) pesticide Sumithion increased blood glucose levels and phosphorylase activity, but hepatic glycogen registered a fall which indicated that the observed hyperglycemia was due to breakdown of hepatic glycogen.     

Serotonin and 5-hydroxyindoleacetic acid concentrations in individual hypothalamic nuclei and other brain areas of rat

Summary Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) were measured in individual nuclei of rat hypothalamus and other brain areas using HPLC with electrochemical detection. 5-HIAA levels were first demonstrated in hypothalamic and some discrete brain areas. The 5-HIAA/5-HT ratio was highest in the n. caudatus putamen, high in the n. ventromedialis and lowest in the n. suprachiasmaticus.     

Evidence for a correlation between the latency of an early component of auditory evoked potentials and the brain levels of serotonin in albino rats

Summary Changes in brain serotonin levels are correlated with the latency of an early component of auditory evoked potentials (EAEP) in rats. In fact 5-hidroxytryptophan provokes an increase both in serotonin brain synthesis and in the latency of EAEP. On the other hand, PCPA provokes an opposite effect.