Plasma Anthranilic Acid and Leptin Levels Predict HAM-D Scores in Depressed Women.

Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin and tryptophan-kynurenine (Trp-Kyn) (TKP) pathways. Leptin, a pro-inflammatory cytokine, activates Trp conversion into Kyn. However, leptin association with down-stream Kyn metabolites in MDD is unknown.

Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes.

About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10 % of pre-diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D.

Kynurenic Acid in the digestive system-new facts, new challenges.

This review provides information on the most recent findings concerning presence, origin, and role of kynurenic acid (KYNA), a tryptophan metabolite, in the digestive system. KYNA is an antagonist of both the ionotropic glutamate receptors and the alpha7 nicotinic acetylcholine receptor, as well as an agonist of G-protein coupled GPR35 receptor. Since the GPR35 receptor is mainly present in the gastrointestinal tract, researchers have concentrated on the digestive system in recent years.

Neopterin as a marker of response to antiviral therapy in hepatitis C virus patients.

Predicting the efficacy of antiviral treatment of hepatitis C virus (HCV) is of importance for both patient well-being and health care expense. The expression of interferon-stimulated genes (IFN-SGs) in the liver was suggested as a marker of response to anti-viral therapy. IFN-SGs encode the guanosine triphosphate cyclohydrolase 1 (GTPCH), a rate-limiting enzyme of pteridines biosynthesis.

Extension of life span of Drosophila melanogaster by the inhibitors of tryptophan-kynurenine metabolism.

Upregulation of kynurenine (KYN) formation from tryptophan (TRY) was associated with aging in animal and human studies. TRY - KYN metabolism is affected by the activities of TRY 2,3-dioxygenase 2 (TDO) and ATP-binding cassette (ABC) transporter regulating TRY access to intracellular TDO. We studied the effects of TDO inhibitor, alpha-methyl tryptophan (aMT), and ABC transported inhibitor, 5-methyl tryptophan (5MT), on the life span of wild strain female Drosophila flies (Oregon-R).

Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.

This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)-kynurenine (KYN) and guanine-tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD.

Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later.

The original 1969 Lancet paper proposed in depression the activity of liver tryptophan-pyrrolase is stimulated by raised blood corticosteroids levels, and metabolism of tryptophan is shunted away from serotonin production, and towards kynurenine production. Discovery of neurotropic activity of kynurenines suggested that up-regulation of the tryptophan-kynurenine pathway not only augmented serotonin deficiency but also underlined depression-associated anxiety, psychosis and cognitive decline. The present review of genetic and hormonal factors regulating kynurenine pathway of tryptophan metabolism suggests that this pathway mediates both genetic and environmental mechanisms of depression.

Quinone reductase 2 and antidepressant effect of melatonin derivatives.

Melatonin and its immediate precursor, N-acetylserotonin (NAS), exert antidepressant effects in experimental models and clinical studies. We reported that melatonin and NAS decreased immobility time (an indicator of antidepressant activity) in the mouse tail suspension test. Melatonin type 3 receptor (MT3) was identified as the same protein as quinone reductase 2 (QR2) detoxifying and antioxidant enzyme.

Ramelteon attenuates age-associated hypertension and weight gain in spontaneously hypertensive rats.

The neuroendocrine theory of aging suggests the common mechanisms of developmental (prereproductive) and aging (postreproductive) processes and identified a cluster of conditions (hypertension, obesity, dyslipidemia, type 2 diabetes, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndrome (MetS). Because melatonin attenuated development of MetS is age-dependent, that is, in young and old, but not in middle-aged rats, we studied the effect of the selective melatonin agonist, Ramelteon, on the two core symptoms of MetS/AAND: hypertension and body weight gain in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto male rats (WKY).

Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism.

The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age-associated neuroendocrine disorders (AAND).

The extended life span of Drosophila melanogaster eye-color (white and vermilion) mutants with impaired formation of kynurenine.

Animal and human studies suggest that aging is associated with increased formation of kynurenine (KYN) from tryptophan (TRY). The rate-limiting factors of TRY-KYN metabolism are transmembrane transport of TRY, and activity of enzyme, TRY 2,3-dioxygenase (TDO2). Eye-color mutants, white (w1118) (impaired TRY transport) and vermilion (v48a and v2) (deficient TDO activity), were compared with wild-type Oregon-R (Ore-R) strain of Drosophila melanogaster.

Effect of luzindole and other melatonin receptor antagonists on iron- and lipopolysaccharide-induced lipid peroxidation in vitro.

Melatonin and its precursor, N-acetylserotonin (NAS), have been shown in in vivo and in vitro studies to inhibit iron- and lipopolysaccharide (LPS)-induced lipid peroxidation in rats and mice. Using in vitro studies, we examined whether these effects will be affected by the melatonin receptor antagonists luzindole (a competitive MT(1)/MT(2) antagonist), DH 97 (MT(2)), prazosin (MT(3)), and 4-P-PDOT (MT(2)). Lipid peroxidation in the form of malondialdehyde (MDA) was assayed by measuring thiobarbituric acid-reactive substances.

Effect of methyl derivatives of dopamine on tumor necrosis factor alpha and lipid peroxidation.

We recently demonstrated that melatonin, N-acetylserotonin (NAS), and N-acetyldopamine (NAD) attenuate the synthesis of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) and the generation of oxidant radicals. In this study, we examined whether acetyl and methyl derivatives of dopamine modulate LPS-stimulated TNF-alpha synthesis and LPS- and iron-induced lipid peroxidation. Differentiated THP-1-derived human monocytes were coincubated with Escherichia coli and rising concentrations of NAS, NAD, N-methyldopamine (NMD), or 4-O-methyldopamine (4-O-MD).

Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging.

Impairment of cognition that is caused by (or associated with) vascular factors has been termed vascular cognitive impairment (VCI). The hallmark of VCI is an impairment of brain executive, or planning, functions caused by inflammatory changes of brain microvessels. VCI is characterized by impairment of the executive function and is distinct from Alzheimer's-type and multi-infarct dementias, although VCI might overlap with Alzheimer's disease.

The in vitro effect of estradiol and testosterone on iron-induced lipid peroxidation in rat brain and kidney tissues.

The effects of estradiol and testosterone on iron-induced lipid peroxidation were compared in rat brain and kidney homogenates in vitro. Lipid peroxidation in the form of malondialdehyde (MDA) was evaluated by the measurement of thiobarbituric acid (TBA) reactive substances. Estradiol inhibited lipid peroxidation in both tissues studied in a dose-dependent manner.

N-acetyldopamine inhibits rat brain lipid peroxidation induced by lipopolysaccharide.

The effects of N-acetyldopamine, a sepiapterin reductase inhibitor, on lipopolysaccharide-induced lipid peroxidation were examined in rat brain homogenates in vitro. Lipid peroxidation in the form of malondialdehyde (MDA) was evaluated by the measurement of thiobarbituric acid (TBA) reactive substances. N-Acetyldopamine inhibited the formation of MDA in a concentration-dependent manner.

Immune-modulating effects of melatonin, N-acetylserotonin, and N-acetyldopamine.

Melatonin and N-acetylserotonin (NAS) have antioxidant properties. In the present study, we examined whether melatonin, NAS, and N-acetyldopamine (NAD) have a modulatory effect on tumor necrosis factor-alpha (TNF-alpha) synthesis and superoxide production. Differentiated THP-1-derived human monocytes were coincubated with Escherichia coli lipopolysaccharide (LPS) and rising concentrations of melatonin, NAS, or NAD.

Mitochondria as a target for neurotoxins and neuroprotective agents.

Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca(2+) homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores.

Differential effects of lipopolysaccharide on lipid peroxidation in F344N, SHR rats and BALB/c mice, and protection of melatonin and NAS against its toxicity.

The effect of bacterial lipopolysaccharide (LPS) injection on the lipid peroxidation process in Fischer (F344N) rats, spontaneously hypertensive (SHR) rats, and BALB/c mice was studied. Lipid peroxidation, as measured by malondialdehyde + 4-hydroxyalkenals (MDA + HAE) levels, was decreased in brain, kidney, and liver homogenates of F344N rats injected with lower LPS doses of 0.5, 1.

Mating attenuates aging-associated increase of lipid peroxidation activity in C57BL/6J mice.

In the frame of the free-radical hypothesis of aging and literature data on increased life span of mated animals, we evaluated brain, kidney, and liver lipid peroxidation in C57Bl/6J mice of various ages and compared lipid peroxidation activity in mated and non-mated mice of both genders. An aging-associated increase (from 3 to 12 months of age) of lipid peroxidation, as measured by malonaldehyde and 4-hydroxyalkenals (MDA + HAE) levels, was observed in the liver and kidney, but not in the brain. Tissue MDA + HAE levels were lower in 12-month old mated mice (housed with animals of opposite gender from three to five months of age) than in 12-month old non-mated animals.

Melatonin and jet lag syndrome: experimental model and clinical implications.

What is the effect of melatonin on jet lag syndrome? Jet lag desynchronizes the internal sleep-wakefulness cycle with the environmental light/dark cycle. Advance (but not delay) of light onset is known to abolish pineal N-acetyltransferase activity and urine excretion of 6-sulphatoxymelatonin. Measurements of pineal serotonin, the substrate of melatonin biosynthesis; N-acetylserotonin (NAS), the immediate melatonin precursor; and melatonin (high-performance liquid chromatography-fluorimetric method) in the animal (rat) model of jet lag revealed that prolonged delay of dark-phase onset disrupted the rhytms in comparable ways as the advance of light-phase onset.

Ontogenetic effects of MAO-A inhibition on rat pineal n-acetylserotonin and melatonin during the first month of neonatal life.

Inhibitors of monoamine oxidase A (MAO-A) but not MAO-B stimulate the activity of pineal serotonin N-acetyltransferase (AANAT) in the adult rat pineal leading to increased formation of N-acetyl serotonin (NAS) and melatonin (MEL). The pineal gland of the neonatal rat has AANAT activity, but the second enzyme in melatonin biosynthesis, HIOMT (hydroxyindole-O-methyltransferase) converting NAS to MEL, is absent during the first week of neonatal life. In this study we examined the effects of acute clorgyline treatment in vitro and in vivo, on pineal indoles over the first month of neonatal life.

The effect of nifedipine, Ca(2+) antagonist, on activity of MAO inhibitors, N-acetylserotonin and melatonin in the mouse tail suspension test.

An antidepressive effect is associated with the A type monoamine oxidase (MAO) inhibitors which selectively stimulate serotonin conversion into N-acetylserotonin and melatonin. The current study compared the effect of these compounds with the non-selective MAO inhibitors and selective MAO-B inhibitors on the duration of immobility in the mouse tail suspension test, a variant of the 'behavioural despair' test. Since the Ca(2+) antagonist, nifedipine, potentiated the effect of tricyclic and atypical antidepressants in the tail suspension test, the additional aim of the current study was to evaluate the effect of nifedipine in combination with ineffective doses of MAO inhibitors.