The relevance of <i>both</i> plasma free tryptophan and insulin to rat brain tryptophan concentration

Fernando, J.C.R.; Knott, P. J.; Curzon, G.

doi:10.1111/j.1471-4159.1976.tb01598.x

Cited by 44 publications

(20 citation statements)

References 17 publications

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“…Also the absolute concentrations of tryptophan in the brain were decreased by streptozotocin (Table 1) and increased by aminophylline. The changes of brain concentration of tryptophan and of the other aromatic amino acids were less striking than the changes in the plasma-brain ratios (Table 1); in some circumstances they were absent Fernando et al, 1976).…”

Section: Discussionmentioning

confidence: 95%

“…One determinant of brain tryptophan concentration is insulin secretion as this can result in decreased plasma concentrations of large neutral amino acids which compete with tryptophan for uptake by brain (Femstrom & Wurtman, 1971;Madras, Cohen, Messing, Munro & Wurtman, 1974). Experiments with insulin and two drugs, aminophylline and streptozotocin, which alter its secretion suggest that the above mechanism and altered binding of plasma tryptophan to albumin can concurrently affect brain tryptophan concentration Fernando, Knott & Curzon, 1976). Also the increase of plasma insulin following imjection of the 5-HT receptor antagonist, methiothepin, has been suggested as a partial explanation of the increased brain 5-HT synthesis caused by this drug.…”

Section: Introductionmentioning

confidence: 99%

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Drugs Altering Insulin Secretion: Effects on Plasma and Brain Concentrations of Aromatic Amino Acids and on Brain 5‐hydroxytryptamine Turnover

Curzon

Fernando

1977

British J Pharmacology

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I An investigation was made into the effects of drugs which alter insulin secretion on the concentrations Of to hanWandacids in plasma and brain and on 5-hydroxv- streptozotocin, propranolol, tolbutamide and phentolamine. 2 Tolbutamide and phentolamine increased the plasma insulin concentrations by 100% and 300% respectively but with little effect on the brain/plasma ratios for the aromatic amino acids. Previously propranolol was found to decrease plasma insulin by 50% without altering the above ratios. The ratios were decreased by streptozotocin but only when plasma insulin fell by more than 50%. 3 Phentolamine and propranolol did not alter the brain/plasma ratios for the aromatic amino acids in streptozotocin-treated rats. 4 The results suggest that only large changes of insulin secretion e.g. those associated with food intake or aminophylline injection are likely to alter appreciably the brain/plasma ratios for the aromatic amino acids. STolbutamide displaced tryptophan from its binding to plasma albumin and increased brain 5-HIAA probably by inhibiting 5-HIAA efflux from brain. The other drugs did not alter brain 5-HT or 5-HIAA concentrations.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Drugs Altering Insulin Secretion: Effects on Plasma and Brain Concentrations of Aromatic Amino Acids and on Brain 5‐hydroxytryptamine Turnover

Curzon

Fernando

1977

British J Pharmacology

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“…The antilipolytic action of insulin may explain why plasma UFA did not rise until 3 h after aminophylline injection (Figure 1) and also why the increase of UFA was not directly proportional to drug dosage (Table 1) insulin was found to increase brain tryptophan in food-deprived rats (Fernstrom & Wurtman, 1971;Curzon & Knott, 1974) and also increased brain uptake of L-[G-3H1-tryptophan (Dickerson & Pao, 1975). Furthermore, the effects of insulin and streptozotocin on the disposition of tryptophan between plasma and brain in fed rats have been explained in terms of concurrent insulin and UFA changes (Fernando et al, 1976). The increases in the plasma concentrations of insulin and UFA following aminophylline treatment are both mediated by ,B-adrenoceptors and such receptors seem also to be required for the effects of the drug on the disposition of tryptophan and other amino acids between plasma and brain ( Figure 4) as these effects of aminophylline are prevented or decreased by propranolol.…”

Section: Discussionmentioning

confidence: 99%

Effect of Aminophylline on Tryptophan and Other Aromatic Amino Acids in Plasma, Brain and Other Tissues and on Brain 5‐hydroxytryptamine Metabolism

Curzon

Fernando

1976

British J Pharmacology

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1Aminophylline and other methylxanthines increase brain tryptophan and hence 5-hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated. 2 At lower doses (t> 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain. 3 Plasma unesterified fatty acid did not increase when aminophylline (100 mg/kg i.p.) was given to nicotinamide-treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred. 4 The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose. 5The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenylalanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose. 6 The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected. 7 The aminophylline-induced increases of the ratio of brain tryptophan to plasma free tryptophan no longer occurred when the drug was given to animals injected with the fl-adrenoceptor blocking agent propranolol or the diabetogenic agent streptozotocin. 8 The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.

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“…The role of albumin binding in relation to brain tryptophan (and other indole amine) levels is a controversial subject. European investigators suggest that brain tryptophan concentration is a function of free tryptophan levels in the plasma (34)(35)(36). In contrast, American workers indicate that brain tryptophan concentrations correlate with total (free plus bound) plasma tryptophan levels (37,38).…”

Section: Methodsmentioning

confidence: 97%

Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues.

Cornford¹,

Bocash²,

Braun³

et al. 1979

J. Clin. Invest.

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A B S T R A C T Tryptophol (3-indole ethanol) is a compound which induces sleep, and is formed: (a) in the liver after disulfiram treatment, and (b) by the parasite in trypanosomal sleeping sickness. We prepared, purified, and characterized radiolabeled tryptophol for the purpose of defining its tissue distribution in animals. Tryptophol was found to be highly lipophilic, with an octanol: water partition coefficient of 29.8. Brain extraction, determined after intracarotid injection, was high (brain uptake index = 117+3.5%), and nonsaturable, suggesting the absence of a carrier system. After intravenous administration, tryptophol distribution to tissues correlated with relative blood flow. More than 85% of the radioactivity remaining in brain 2-5 min after intravenous injection co-migrated with tryptophol standards when analyzed by thin-layer chromatography. Other evidence suggested that tryptophol binds to serum and in vivo may be stripped from serum albumin and taken up by brain in a single capillary transit. Our study suggests that in states such as trypanosomal sleeping sickness or disulfiram treatment, remotely formed tryptophol gains ready access to brain (it is 100% cleared in a single capillary passage), and could thus cause somnolence.

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The relevance of both plasma free tryptophan and insulin to rat brain tryptophan concentration

Cited by 44 publications

References 17 publications

Drugs Altering Insulin Secretion: Effects on Plasma and Brain Concentrations of Aromatic Amino Acids and on Brain 5‐hydroxytryptamine Turnover

Drugs Altering Insulin Secretion: Effects on Plasma and Brain Concentrations of Aromatic Amino Acids and on Brain 5‐hydroxytryptamine Turnover

Effect of Aminophylline on Tryptophan and Other Aromatic Amino Acids in Plasma, Brain and Other Tissues and on Brain 5‐hydroxytryptamine Metabolism

Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues.

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