Influence of experimental diabetes on brain levels of monoamine neurotransmitters and their precursor amino acids during tryptophan loading

Masiello, Pellegrino; Balestreri, Ettore; Bacciola, Domenico; Bergamini, Ettore

doi:10.1007/bf02732052

Cited by 19 publications

(7 citation statements)

References 16 publications

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“…Therefore, the infusion of L-Trp profoundly reduces brain influx of tyrosine (as shown in animal studies to about 40%, see Masiello et al 1987) and its availability for catechotamine synthesis. Indeed, decreased cerebrospinal fluid levels of dopamine and noradrenaline metabolites have been reported after the infusion of L-Trp in man and the same authors suggested that the neuroendocrine responses to L-Trp may more likely be mediated by decreased catecholaminergic activity instead of increased output of hypothalamic 5-HT terminals (van Praag et al 1987).…”

Section: Discussionmentioning

confidence: 96%

The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites

et al. 1992

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L-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated. This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time). The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed after L-Trp infusions. The administration of L-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported after L-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.

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Section: Discussionmentioning

confidence: 96%

The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites

et al. 1992

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“…Secondly, we assessed whether the cerebral concentration of aromatic amino acids including tryptophan which may serve as precursors of neurotransmitter synthesis-in agreement with observations from experimental diabetes in rat [7,16,[18][19][20]-were also decreased in postmortem human brain tissue of deceased individuals with diabetes mellitus. An increased tryptophan-2,3-dioxygenase activity is known to occur in the liver of streptozotocin-diabetic rats resulting in an accelerated catabolism and clearance of tryptophan from the bloodstream [19,20].…”

Section: Discussionmentioning

confidence: 85%

“…An increased tryptophan-2,3-dioxygenase activity is known to occur in the liver of streptozotocin-diabetic rats resulting in an accelerated catabolism and clearance of tryptophan from the bloodstream [19,20]. The reduced level of tryptophan is considered as major factor leading to a decreased carrier-mediated uptake of tryptophan into the brain [7,16,20].…”

Section: Discussionmentioning

confidence: 99%

Brain amino acid abnormalities in kidney disease and diabetes mellitus

Schmidt¹,

Mußhoff²,

Hilgers³

et al. 2004

Forensic Science International

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“…Impaired accumulation of TRP in the brain concomitantly with a much faster disappearance of the administered TRP from the bloodstream was observed in streptozotocin-diabetic rats after TRP load (Masiello et al 1987 ). Surplus of dietary TRP, the initial substrate for the formation of KYN, KYNA, 3-HK, and 3H-KYNA, induces insulin resistance (IR), a precursor of T2D, in pigs (Koopmans et al 2009 ).…”

Section: Dysregulation Of Trp-kyn Metabolism In T2dmentioning

confidence: 98%

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

Oxenkrug

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Aging, obesity, depression, Parkinson's and other neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs are highly associated with insulin resistance (IR) and type 2 diabetes mellitus (T2D). Molecular mechanisms of increased associations remain uncertain. Current review of literature and our data suggest that one such mechanism is the overproduction of diabetogenic factors resulting from dysregulation of upstream and downstream pathways of tryptophan (TRP)-kynurenine (KYN) metabolism. Proinfl ammatory factors and stress hormones activate two upstream steps of TRP-KYN pathway: TRP conversion into KYN, a substrate for formation of kynurenic acid (KYNA), and KYN conversion into 3-hydroxyKYN (3-HK). The fi rst step of downstream pathway of 3-HK metabolism, formation of 3-hydroxyanthranilic acid (3-HAA), is catalyzed by pyridoxal-5-phosphate (P5P)-dependent kynureninase (KYNase). P5P defi ciency, associated with infl ammation, stress, and treatment with antipsychotic drugs, diverts metabolism of overproduced 3-HK from formation of 3-HAA to the excessive formation of 3-hydroxykynurenic acid (3H-KYNA). Human and experimental studies suggested diabetogenic (e.g., impairment of production, release, and biological activity of insulin) effect of KYN, 3H-KYNA, KYNA, and their metabolites. We propose that one of the mechanisms of increased association of IR (and T2D) with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs is overproduction of 3H-KYNA resulting from upregulated formation of 3-HK augmented by P5P defi ciency. Pharmacological regulation of upand downstream TRP-KYN metabolic pathways might be a new approach for prevention and treatment of IR (and IR progression to T2D) associated with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs.

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Influence of experimental diabetes on brain levels of monoamine neurotransmitters and their precursor amino acids during tryptophan loading

Cited by 19 publications

References 16 publications

The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites

The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites

Brain amino acid abnormalities in kidney disease and diabetes mellitus

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

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