Tryptophan reduces creatine kinase activity in the brain cortex of rats

Cornelio, Andrea Renata; Junior, Valnes Rodrigues; Wyse, Ângela T. S.; Dutra-Filho, Carlos Severo; Wajner, Moaçir; Wannmacher, Clóvis Milton Duval

doi:10.1016/j.ijdevneu.2003.12.004

Cited by 11 publications

(2 citation statements)

References 45 publications

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“…in the nervous tissue. It has been demonstrated that TRP inhibits CK activity in vivo and in vitro, and it is therefore conceivable that inhibition of this enzyme activity in the brain may be one of the mechanisms by which TRP might be neurotoxic (Cornelio et al, 2004).…”

Section: Hypertryptophanemiamentioning

confidence: 99%

Role of Kynurenines in the Central and Peripherial Nervous Systems

Németh¹,

Toldi²,

Vécsei

2005

CNR

150

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Kynurenine (KYN) is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier (BBB). In the brain, KYN can be converted to two other components of the pathway: the neurotoxic quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA). QUIN is probably the most widely studied metabolite of KYN, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate (NMDA) receptor complex, a type of glutamate receptor. KYNA is another metabolite of KYN; its synthesis is catalysed by KYN aminotransferases. This is the only known endogenous NMDA receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, KYNA non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid (EAA) receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the EAA receptor antagonist KYNA can exert a therapeutic effect in these neurological disorders. It has been established that KYNA has only a very limited ability to cross the BBB. Other KYNA derivatives have been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-chloro-KYNA), which are well transported across the BBB and act on the glutamate receptors. Moreover, it has been demonstrated that probenecid, a known inhibitor of the transport of organic acids (e.g. KYNA), increases the cerebral concentration of KYNA. There is another new perspective to the maintenance of a high level of KYNA in the brain: the use of enzyme inhibitors, which can block the synthesis of the neurotoxic QUIN. These are some of the most promising possibilities as novel therapeutic strategies for the treatment of neurodegenerative diseases, in which the hyperactivation of amino acid receptors could be involved. The presence and importance of KYN derivatives in the periphery are also discussed in the light of recent publications.

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Section: Hypertryptophanemiamentioning

confidence: 99%

Role of Kynurenines in the Central and Peripherial Nervous Systems

Németh¹,

Toldi²,

Vécsei

2005

CNR

150

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“…However, Trp inhibits creatine kinase in vitro and in vivo. In this case, inhibitory effect of Trp on creatine kinase activity is achieved by oxidation of essential thiol groups of the enzyme (Cornelio et al 2004 ). In human hypertryptophanemia, Trp accumulates in the brain and signifi cantly decreases the overall content of brain antioxidant defenses.…”

Section: Hypertryptophanemiamentioning

confidence: 99%

Tryptophan and Cell Death

Engin¹

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Cell death attributed to the tryptophan (Trp) metabolites is dependent on the exposure time and intracellular concentrations of cytotoxic Trp derivatives such as 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), 5-hydroxyanthranilic acid (5HAA), and quinolinic acid (QA). However, 3HAA, 3HK, and QA at low concentrations may also serve as a precursor for nicotinamide adenine dinucleotide [NAD + ] which has vital importance to maintain cell viability. Inhibition of indoleamine 2,3-dioxygenase (IDO) activity results in a dosedependent decrease in intracellular [NAD + ] levels. Mitochondrial permeability transition occurs in several forms of necrotic cell death. Disturbances in the normal function of the mitochondria are associated with the alterations in the balance of Trp metabolism. While kynurenic acid (KA) has proven to be neuroprotective with the potential endogenous antioxidant properties, QA is a specifi c agonist at the N-methyl-d -aspartate (NMDA) receptors and a potent neurotoxin with the marked free radical-producing property. QA-induced cytotoxic effects are mediated by overactivation of NMDA-like receptors and overexpression of inducible nitric oxide synthase (iNOS). l -Kynurenine-derived neurotoxin-induced apoptosis occurs through reactive oxygen species (ROS)-mediated pathways and is blocked by antioxidants. Unlike the kynurenine pathway, the methoxyindole metabolites of Trp metabolism protect cells against oxidative stress-induced apoptosis. Furthermore, deprivation of Trp triggers autophagy in a mammalian target of rapamycin (mTOR)-dependent manner. mTOR inhibition can suppress the activation of cyclin-dependent kinases and then inhibits the cell cycle progress, suppresses cell proliferation, and fi nally results in cell apoptosis.

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Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats

et al. 2011

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It is known that the accumulation of tryptophan and its metabolites is related to brain damage associated with both hypertryptophanemia and neurodegenerative diseases. In this study, we investigated the effect of tryptophan administration on various parameters of behavior in the open-field task and oxidative stress, and the effects of creatine and pyruvate, on the effect of tryptophan. Forty, 60-day-old male Wistar rats, were randomly divided into four groups: saline, tryptophan, pyruvate + creatine, tryptophan + pyruvate + creatine. Animals received three subcutaneous injections of tryptophan (2 μmol/g body weight each one at 3 h of intervals) and/or pyruvate (200 μg/g body weight 1 h before tryptophan), and/or creatine (400 μg/g body weight twice a day for 5 days before tryptophan twice a day for 5 days before training); controls received saline solution (NaCl 0.85%) at the same volumes (30 μl/g body weight) than the other substances. Results showed that tryptophan increased the activity of the animals, suggesting a reduction in the ability of habituation to the environment. Tryptophan induced increase of TBA-RS and total sulfhydryls. The effects of tryptophan in the open field, and in oxidative stress were fully prevented by the combination of creatine plus pyruvate. In case these findings also occur in humans affected by hypertryptophanemia or other neurodegenerative disease in which tryptophan accumulates, it is feasible that oxidative stress may be involved in the mechanisms leading to the brain injury, suggesting that creatine and pyruvate supplementation could benefit patients affected by these disorders.

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Tryptophan reduces creatine kinase activity in the brain cortex of rats

Cited by 11 publications

References 45 publications

Role of Kynurenines in the Central and Peripherial Nervous Systems

Role of Kynurenines in the Central and Peripherial Nervous Systems

Tryptophan and Cell Death

Creatine and pyruvate prevent behavioral and oxidative stress alterations caused by hypertryptophanemia in rats

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