The effect of 6-Methoxy-2-Benzoxazolinone (6-MBOA) on indoleamine regulation and its possible role in depression
- Authors: Tanda, Sindiswa Eunice
- Date: 2000
- Subjects: Tryptophan -- Physiological effect , Tryptophan -- Therapeutic use , Antidepressants
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3912 , http://hdl.handle.net/10962/d1003971 , Tryptophan -- Physiological effect , Tryptophan -- Therapeutic use , Antidepressants
- Description: Tryptophan is an essential amino acid that is obtained from the diet. Approximately 98 % of ingested tryptophan is metabolized by the enzyme tryptophan 2,3-dioxygenase (TDO). The metabolism of tryptophan by TDO is an important determinant of tryptophan bioavailability to the brain for serotonin (5-HT) biosynthesis, an essential amine in affective disorders such as depression. Studies done on circadian rhythmicity of the enzyme activity have shown that, TDO activity is high during the scoto-phase (dark-phase), which is attributable to the de novo enzyme synthesis that occurs during this phase. 6-Methoxy-2-benzoxazolinontr-(6-MBOA), a structural analogue of melatonin (aMT) was shown to inhibit TDO activity in both the photo-phase (light-phase) and the scoto-phase with greater potency during the light-phase. Further studies were directed at demonstrating the effects of 6-MBOA on the brain tryptophan hydroxylase (TH) activity, which is a rate limiting enzyme in 5-HT biosynthesis and subsequently on 5-HT levels. The findings showed that, 6-MBOA induces TH activity with a concomitant rise in brain 5-HT levels. The blockade of 5-HT re-uptake into the presynaptic neuron leads to an increase in 5-HT available for the stimulatory action of 5-HT receptors. An attempt to establish whether the administration of 6-MBOA would block the binding of 5-HT to receptors on the synaptosomal membrane showed that 6-MBO A only inhibits the binding of 5 -HT at specific concentrations. In view of the positive effects imposed by 6-MBOA on brain 5-HT levels, urinary 5-hydroxyindole acetic acid (5-HIAA) excretion was measured before and after treatment with 6-MBOA. 5-HIAA excretion was found to be significantly increased after 6-MBOA treatment. Extensive research on the biosynthesis of pineal metabolites has been conducted in the past two decades. The pineal metabolites are synthesized from the precursor tryptophan. In order to obtain an overall picture of the effect of6-MBOA on pineal indole metabolism, an organ culture technique was employed. The results obtained showed that although 6-MBOA administration to rats caused a significant increase in aMT production, there was an insignificant increase in NAS production. This is an immediate precursor of aMT. Other pineal indoles were not affected at all by 6-MBOA administration. Furthermore, the production of pineal NAS and aMT showed an inter-individual variation with some animals producing very high, some very low and some produced average levels of these two metabolites in both photo and scoto-phase experiments. A study undertaken to investigate the circadian rhythm in endogenous aMT production using the competitive ELISA technique showed a clear pattern with high levels of aMT produced during the dark-phase and low levels ofaMT produced during the light-phase. Furthermore, the administration of6-MBOA to rats lead to a significant rise in endogenous aMT production.
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- Date Issued: 2000
An investigation into the antioxidative potential and regulatory aspects of liver tryptophan 2,3-dioxygenase by tryptophan and related analogues
- Authors: Antunes, Ana Paula Martins
- Date: 1998
- Subjects: Tryptophan -- Physiological effect , Antioxidants , Liver
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4010 , http://hdl.handle.net/10962/d1004070 , Tryptophan -- Physiological effect , Antioxidants , Liver
- Description: The amino acid, tryptophan, obtained through dietary means, is metabolised by the enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase. All the enzymes have an effect on circulating tryptophan levels, especially TDO, since it is the major site of tryptophan catabolism in the liver and results in the production of kynurenine metabolites, viz. kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and quinolinic acid. Extrahepatically, IDO is responsible for the synthesis of the kynurenine metabolites. Tryptophan 2,3-dioxygenase and IDO activity is increased by hormones or substrates such as tryptophan, and inflammation, in the case of IDO. Tryptophan availability for serotonin (5-HT) synthesis by the enzyme tryptophan hydroxylase is primarily dependent on TDO activity. A study was attempted in order to ascertain whether any of the endogenous metabolites of the kynurenine and serotonergic pathways would be able to inhibit TDO activity. Results showed that although the kynurenines had no effect, the indoleamines, except for the indoleacetic acids, were able to reduce TDO activity. 6-Methoxy-2-benzoxazolinone (6-MBOA), a structural analogue to melatonin, was the most potent inhibitor with a reduction in activity of 55 % compared with the control. The pineal gland in the rat brain has been shown to have the highest IDO activity. With induction, the kynurenine metabolite concentrations of kynurenic acid and quinolinic acid are increased. The effects of both compounds were determined on the serotonergic pathway. Although kynurenic acid produced no significant effect, quinolinic acid significantly reduced N-acetylserotonin and melatonin synthesis at concentrations of lOJLM and 100 JLM respectively. Many authors have implicated oxygen derived species as causative agents in the important neurodegenerative disorders such as Parkinson's and Huntington's disease. Increased radical generation and lipid peroxidation have been suggested to be responsible for the toxic destruction of neurons, especially in the brain because of its high lipid content and oxygen demand. The brain is therefore vulnerable to oxidative attack. During inflammatory diseases, IDO is induced with a resultant increase in kynurenines. This study was also an attempt at determining the effect of kynurenines on lipid peroxidation. All metabolites of the kynurenine pathway were able to induce lipid peroxidation significantly. The antioxidative potential of various tryptophan analogues, viz. serotonin, melatonin and 6-methoxy-2-benzoxazolinone, was determined using quinolinic acid-induced lipid peroxidation. Serotonin, melatonin and 6-MBOA were able to significantly reduce quinolinic acid-induced lipid peroxidation.
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- Date Issued: 1998