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Results for “6-Aminonicotinamide”

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At least 19 recordsLinked to original sources
PubMed1975

Treatment of psoriasis with 6-aminonicotinamide.

Topical applications of a 1.5 percent aqueous solution of 6-aminonicotinamide for four weeks resulted in substantial improvement or complete clearing of plaques of psoriasis in 27 of 34 patients. These results were clearly superior to those that were obtained with the solvent alone. Dermatitis or marked itching occurred in five of 34 patients. Topically applied thionicotinamide also produced improvement or clearing of some psoriatic lesions in an initial screening trial. The toxic hazards of 6-aminonicotinamide to the central nervous system are discussed.

Acid-Base Equilibrium↗
PubMed1975

Inhibition of ATP synthesis associated with 6-aminonicotinamide (6-AN) teratogenesis in rat embryos.

Pregnant rats were injected ip with 6 mg/kg 6-aminonicotinamide (6-AN) at day 12 of gestation. Embryos removed between 1 and 48 h later had reduced adenosine triphosphate (ATP) concentrations, of about 50% of control values. All fetuses examined near term were malformed. Nicotinamide (NAM, 100 mg/kg) given ip 1 h after 6-AN afforded protection: malformations occurred in only 15% of the survivors; and there was minimal ATP reduction, 15% below control values. NAM given 2 and 4 h after 6-AN produced intermediate ATP concentrations and malformation frequencies. Thus, there was a relation between the embryotoxic and ATP-depressant actions of 6-AN in day 12 rat embryos.

6-Aminonicotinamide↗
PubMed1975

Decreased glycolytic flux rate in the isolated perfused rat brain after pretreatment with 6-aminonicotinamide.

Cerebral energy metabolism was studied in the isolated perfused rat brain after 6-aminonicotinamide (6-AN; 35 mg/kg i.p.) administered to the intact animals 7 hrs before perfusion was started. The metabolic alterations in the isolated rat brains were such as reported for rat and mouse brain in vivo: Inhibition of 6-phosphogluconate dehydrogenase was followed by an accumulation of 6-phosphogluconate, leading to a decreased activity of glucosephosphate isomerse. This was reflected by increased levels of glucose and glucose 6-phosphate and decreased levels of fructose 6-phosphate, pyruvate and lactate. Since the concentration of lactate in the perfusate of the isolated brain was also lowered, 6-AN must have reduced the glycolytic flux rate.

6-Aminonicotinamide↗
PubMed1975

Remyelination by Schwann cells of axons demyelinated by intraspinal injection of 6-aminonicotinamide in the rat.

Focal areas of primary demyelination were produced in the spinal cords of rats by means of local injections of 6-aminonicotinamide. Both astrocytes and oligodendrocytes underwent degeneration in the demyelinated area. Nearly all the demyelinated axons were remyelinated by Schwann cells; only a very small number of axons located adjacent to normally myelinated axons were remyelinated by oligodendrocytes. The glial limiting membrane was reconstituted around the ecge of the area remyelinated by Schwann cells. This experiment offers further evidence for an important role of astrocytes in controlling Schwann cell invasion of the central nervous system, and in addition suggests that astrocytes are also needed for oligodendrocyte remyelination to take place.

6-Aminonicotinamide↗
PubMed1975

[Ultrastructural reaction of the multipotential glia in the cerebellum of the rat after treatment with 6-aminonicotinamide].

6-Aminonicotinamide (6-AN), an antimetabolite of nicotinamide, damages the astrocytes and oligodendrocytes through a blockade of the pentose phosphate pathway. Both types of glia cells become hydropic. A third type of glia cell, described by VAUGHN and PETERS, the multipotential glia, is affected to a lesser extent. These cells phagocytize and form pseudopodia after treatment with 6-AN. Thus the multipotential glia cells are 'marked' by the action of 6-AN, since they are obviously less dependent on the pentose phosphate pathway in the carbohydrate metabolism.

6-Aminonicotinamide↗
PubMed1975

[Light- and electron microscopy studies on the cerebellum in 12-day-old rats after treatment with 6-aminonicotinamide (6-AN)].

Light- and electron-microscopie studies were performed in glia cells and neurons of the cerebellum of 12-day-old rats until 48 following intraperitoneal application of 8 mg/kg 6-aminonicotinamide (6-AN), an antimetabolite of nicotinamide that inhibits the oxidative pentose-phosphate pathway. Particularly sensitive were the neuroblasts of the external granular layer. The migration of the neuroblasts was clearly reduced. Parts of the internal granular layer were damaged, while the Purkinje cells and astrocytes remained unchanged. Oligodendrocytes and astrocytes showed vacuolar degeneration. Swelling of the myelin sheath occurred in the form of a status spongiosus. 48 h after 6-AN injection some mitoses and phagocytic cells were found in the internal granular layer.

Age Factors↗
PubMed1976

Spastic paresis after 6-aminonicotinamide: metabolic disorders in the spinal cord and electromyographically recorded changes in the hind limbs of rats.

In rats the application of 10 mg/kg 6-amino-nicotinamide (6-AN) leads to an accumulation of 6-phosphogluconate, by inhibition of 6-phosphogluconate dehydrogenase in the pentose phosphate pathway, in the cells of the spinal cord. The accumulation reaches its maximum after 18-24 h. It seems that there exists a relationship between the accumulation of 6-phosphogluconate and the lesion of the neuroglia, which is found in electron microscopic studies. Symptoms of a spastic paresis only develop later when the spinal interneurones are destroyed as a consequence of the lesion of the neuroglia. The accumulation of 6-phosphogluconate almost exceeds the 400 fold of the norm. No considerable differences are found between the effects of a dose of 35 mg 6-AN/kg and one of 10 mg 6-AN/kg. Free gluconate is identified enzymically in the cells of the spinal cords of the rats treated with 6-AN. The compound is very probably formed by dephosphorylation and diffuses into the blood. 6-Phosphogluconate is an inhibitor of the phosphoglucose isomerase. Its accumulation shifts the equilibrium towards glucose 6-phosphate. The lactate concentration decreases as compared with the untreated controls. Muscular action potentials are recorded extracellularly with a concentric needle electrode from the musculus gastrocnemius of rats treated with 6-AN. First activations of the electromyograms are found 48 h after the application of 10 mg 6-AN/kg. The electrical activities increase during the time in which a progressive destruction of the interneurones occurs. The electromyogram displays a permanent state of excitation with high amplitudes and an increased frequency. The continuity and intensity of the increased activity recorded by the electromyograph is the most important pathological finding. p-Chlorophenyl-GABA and, still more so, chlorpromazine cause temporary reduction of the excitation processes and an electromyogram nearly at rest. Under the same conditions, haloperidol is only slightly effective. The symptoms developed by the chemical destruction of the interneurones of the spinal cord, with rigidity and spasticity of the hind limbs, are suitable for testing antispastic drugs.

6-Aminonicotinamide↗
PubMed1977

Metabolism of 6-aminonicotinic acid in Escherichia coli.

A late-log-phase culture of an Escherichia coli nadB pncA double mutant took up 6-[7-14C]aminonicotinic acid and excreted 6-[14C]aminonicotinamide. This mutant also accumulated intracellularly several radioactive compounds which have been tentatively identified as 6-amino analogs of compounds in the pyridine nucleotide cycle. It is concluded that 6-aminonicotinamide and 6-aminonicotinic acid probably exert at least a portion of their bacteriostatic effects by being metabolized, by the enzymes of the pyridine nucleotide cycle, to 6-aminonicotinamide adenine dinucleotide and 6-aminonicotinamide adenine dinucleotide phosphate. These compounds are not electron acceptors and are known inhibitors of some pyridine nucleotide-linked dehydrogenases.

Escherichia coli↗
PubMed1979

Regulation of p-nitroanisole O-demethylation in perfused rat liver. Adenine nucleotide inhibition of NADP+-dependent dehydrogenases and NADPH-cytochrome c reductase.

Perfusion of rat livers with 10 mM-fructose or pretreatment of the rat with 6-aminonicotinamide (70 mg/kg) 6 h before perfusion decreased intracellular ATP concentrations and increased the rate of p-nitroanisole O-demethylation. This increase was accompanied by a decrease in the free [NADP+]/[NADPH] ratio calculated from concentrations of substrates assumed to be in near-equilibrium with isocitrate dehydrogenase. After pretreatment with 6-aminonicotinamide the [NADP+]/[NADPH] ratio also declined. Reduction of NADP+ during mixed-function oxidation may be explained by inhibition of of one or more NADPH-generating enzymes. Glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase and "malic" enzyme, partially purified from livers of phenobarbital-treated rats, were inhibited by ATP and ADP. Inhibitor constants of ATP for the four dehydrogenases varied considerably, ranging from 9 micrometer for "malic" enzyme to 1.85 mM for glucose 6-phosphate dehydrogenase. NADPH-cytochrome c reductase was also inhibited by ATP (Ki 2.8 mM) and by ADP (Ki 0.9 mM), but not by AMP. Concentrations of ATP and ADP that inhibited glucose 6-phosphate dehydrogenase and the reductase were comparable with concentrations in the intact liver. Thus agents that lower intracellular ATP may accelerate rates of mixed-function oxidation by a concerted mechanism involving deinhibition of NADPH-cytochrome c reductase and one or more NADPH-generating enzymes.

6-Aminonicotinamide↗
PubMedDate not supplied

Effect of experimental diabetes on drug metabolism in the rat.

The effect of experimental diabetes on hepatic drug metabolism was studied in male Holtzman rats. Treatment of animals with streptozotocin and 6-aminonicotinamide, both agents which produce an insulin-deficient animal, caused prolongation of hexobarbital sleeping times and inhibition of the rate of metabolism of both hexobarbital and, to a lesser extent, aniline in vitro. Treatment of animals with N-methylacetamide, a diabetogen which does not cause insulin deficiency in the animal but rather produces an insulin-resistant state, did not affect the metabolism in vitro of either hexobarbital or aniline. Neither insulin nor any of the diabetogenic agents had any direct effect on drug metabolism in vitro. Furthermore, hepatic microsomal protein and cytochrome P-450 contents were not significantly different in any of the diabetic animals from those of the control animals. Hyperglycemia produced by glucose infusion did not affect the metabolism of hexobarbital in vitro. The effects of streptozotocin and 6-aminonicotinamide appeared to be at least partially due to the presence of an inhibitor in the liver cytosol which correlated with elevated hepatic cyclic AMP concentrations.

6-Aminonicotinamide↗
PubMed2026

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context. MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms. KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription. SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Ferroptosis↗
PubMed1976

Inhibition of glucose phosphorylation in rat brain by thiopental.

The purpose of the present investigation was to shed some light on the suppression of the glycolytic pathway by anesthetics. The antimetabolite 6-aminonicotinamide (6-AN) was used to discriminate between the key enzymes hexokinase and phosphofructokinase which are suggested to be involved in the effect of anesthetics on glycolysis. The cerebral energy metabolism was studied in the isolated perfused rat brain after the addition of thiopental (0.15 mM) to the perfusion medium, after the administration of 6-AN (35mg/kg i.p.) to the intact animals 15 h before perfusion was started, as well as in brain preparations treated in the same manner with both 6-AN and thiopental. After a perfusion period of 30 min brain levels of the following substrates and metabolites were determined: phosphocreatine, ATP, ADP, AMP, glycogen, glucose, glucose 6-phosphate, fructose 6-phosphate, pyruvate, lactate, alpha-ketoglutarate, blutamate, ammonia, and 6-phosphogluconate. The metabolic alterations in the isolated rat brain caused by 6-AN or thiopental were such as reported in the literature. When the isolated brains of the 6-AN pretreated rats were perfused with thiopental we found as the most interesting result that the concentration of glucose 6-phosphate was reduced in comparison to that in brains only treated with 6-AN but still significantly higher than that in controls. The glucose concentration was significantly elevated and the lactate concentration decreased considerably. The effect of thiopental on cerebral glycolysis was interpreted as an inhibition of hexokinase activity.

6-Aminonicotinamide↗
PubMed1975

Electronmicroscopic study of the effect of 6-an on the sciatic nerve in newborn rats.

12 hrs, 1, 2, and 4 days after i.p. administration of 2, 3 or 5 mg/kg 6-AN (6-Aminonicotinamide) on postnatal day 5, the following findings were made in the sciatic nerve of the newborn rat. In the myelin-forming fibres a swelling between the axolemm and the first inner intraperiod-line of the Schwann cell develops with displacement of the otherwise intact axon. The myelin formation is not impeded. During the 4 days of control after administration of 6-AN there is continual growth of the myelin sheath with an orderly lamellar structure. Using any dose there is no demonstrable alteration in the Schwann cells--with the exception of the inner cytoplasmic tongue--either in the foetal promyelin and mature nonmyelinated fibres. These findings are discussed and compared with the known glia alterations of the spinal ganglia and dorsal radix after the application of 6-AN.

6-Aminonicotinamide↗