Cerebral transmitter precursors and metabolites in advanced renal disease.

Patients with chronic renal disease had low plasma total tryptophan but an abnormally high proportion of this was in the free state. The subjects with encephalopathy had raised plasma free tryptophan, CSF tryptophan, and CSF 5-hydroxyindoleacetic acid. CSF tryptophan correlated better with plasma free than with plasma total tryptophan. Plasma and CSF tyrosine concentrations were normal but CSF homovanillic acid was raised especially in subjects with encephalopathy. The possible significance of these changes in advanced renal disease is discussed.     

Free tryptophan response to intravenous insulin in depressed patients

Levels of free plasma tryptophan, total plasma tryptophan, and total amino acids were determined at various times after insulin administration in patients with either major depressive disorder or dysthymic disorder and normal control subjects. Prior to insulin administration, there were no significant differences among the three groups in any of the parameters. However, following insulin, free plasma tryptophan levels fell significantly among the patients with major depressive disorder for the first 30 min, but not among normal controls. The rate of decline among the patients with dysthymic disorder was intermediate between those of the patients with major depressive disorder and normal controls. The levels of total tryptophan and amino acids following insulin did not differ significantly among the three groups.     

A study of relationships of serum glucose, insulin, free fatty acids, and free and total tryptophan to mental illness

To explore possible disturbances of cerebral monoamines linked to glucose metabolism, 18 schizophrenics, 21 neurotics, and 21 controls were given a 5-hr glucose tolerance test, and the effect of the glucose load on total and free tryptophan, insulin, and free fatty acids in serum was studied in medication-free patients. The data indicated intragroup differences (fasting to subsequent hours) in serum glucose, insulin, free fatty acids, and free and total tryptophan values. Intergroup differences were noted in insulin values at the first hour, in free fatty acids at fasting with neurotics exhibiting the highest values, and in free tryptophan at fasting with schizophrenics having the lowest values. Schizophrenics with perceptual disturbances (e.g., hallucinations) exhibited lower free tryptophan values when compared with other schizophrenics. The results indicated a glucose-tryptophan interaction in schizophrenics.     

Brain transmitter precursors and metabolites in diabetic ketoacidosis.

Patients studied during recovery from an episode of ketoacidotic diabetes had raised blood glucose, plasma free fatty acid and plasma free tryptophan concentrations. Plasma total tryptophan was decreased. Well controlled diabetics showed normal values. The ketoacidotic patients had increased lumbar CSF tryptophan and 5-hydroxyindoleacetic acid concentrations. Plasma tyrosine and CSF tyrosine and homovanillic acid concentrations were normal in both diabetic groups. The results are discussed in relation to somewhat similar findings in uraemic and hepatic encephalopathy and to changes in rats with streptozotocin diabetes.     

Parallel variation of ventricular CSF tryptophan and free serum tryptophan in man.

Tryptophan was measured in the ventricular CSE and serum and the neutral amino acids leucine, isoleucine, valine, phenylalanine, and tyrosine were measured in the serum of two cases with ventricular drains. Samples were taken every two hours for 24 hours in one case and for 16 hours in the other. The CSF tryptophan was correlated significantly with the free--that is, non-albumin-bound--serum tryptophan but not with the total serum tryptophan. CSF tryptophan was not correlated significantly with the ratio of free serum tryptophan to the sum of the neutral amino acids. These data suggest that, in man, brain tryptophan concentrations are influenced by the free and not the total serum tryptophan and that physiological variations of the neutral amino acids do not appreciably influence the concentration of brain trytophan.     

Pulsatile growth hormone,prolactin, and thyrotropin secretion in rats with hypothalamic deafferentation

Rats submitted to regular 12 h cycles of light and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in serm were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. The peaks of 5-HT and 5-HIAA levels were detected during the light and dark periods respectively, the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in previous studies^16,17 carried out in similar experimental conditions, it was concluded that the parallel increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time¹⁶.     

Effect of various oral protein doses on plasma neutral amino acid levels

Summary Six healthy fasting females each received, on different days, 0, 6, 12.5 or 25 g of albumin dissolved in 200 ml water. Blood was collected before and at intervals after the albumin ingestion and assayed for plasma levels of large, neutral amino acids (LNAA), insulin and glucose. Insulin increased significantly after ingestion of 12.5 and 25 g of albumin, whereas changes in serum glucose were small and inconsistent. Increases of plasma LNAA concentrations were dose-related and correlated significantly with the molar percentage in the albumin of the respective amino acids at 1 and 2 hours but not at 3 and 4 hours after consumption. Ratio in plasma of tyrosine to other LNAA increased by 20 to 60%, and still at 4 hours the plasma tyrosine ratio was significantly elevated above control level after all 3 albumin doses. The plasma ratio of tryptophan to other LNAA decreased by 30 to 50%, and at 4 hours the plasma tryptophan ratio was still significantly below control level after the 2 larger albumin doses. The marked changes in the plasma tryptophan and tyrosine ratio suggests that the central serotonin and catecholamine synthesis could possibly be affected following ingestion of pure protein.     

Evaluation of the relative potency of individual competing amino acids to tryptophan transport in endogenously depressed patients

There is evidence that the plasma ratio of tryptophan to five competing amino acids may predict the response of depressed patients to treatment with L-tryptophan. The relative potency of the individual competitors has been evaluated retrospectively. Phenylalanine consistently reduced, and isoleucine slightly reduced the predictive value of the plasma tryptophan ratio. The ratio of tryptophan to the sum of valine, leucine, and tyrosine was identified as most predictive for the therapeutic response. The L-tryptophan responders showed a normal plasma total tryptophan concentration as did the nonresponders, whereas the concentration of the three competitors was significantly elevated. It is concluded that while the plasma ratio of tryptophan to the sum of valine, leucine, and tyrosine is a useful predictor of the course of depressive on L-tryptophan, it does not definitely separate out the L-tryptophan responders from the control subjects.     

Levels of low molecular weight scavengers in the rat brain during focal ischemia.

Ascorbic acid, cysteine, glutathione, uric acid, tyrosine and tryptophan were quantified in samples of frontoparietal cortex, striatum, hippocampus and cerebellum from both sides of rat brain 0.5 h, 4 h and 24 h after focal ischemia. Cysteine, tyrosine and tryptophan were increased in cortex and striatum at 0.5 h, returning afterwards to normal. Uric acid was increased, whereas ascorbic acid and glutathione were correspondingly decreased. Although changes can be explained primarily by energy failure they are also consistent with free radical activity during early stages of ischemia.     

Plasma free tryptophan concentration in children with attention deficit disorder

In order to examine the serotonin metabolism in children with attention deficit disorder (ADD), plasma tryptophan, which is the precursor of serotonin, was measured in 10 children with ADD and 12 normal children. The mean plasma total tryptophan level in the children with ADD was not significantly different from that of the normal children. The mean plasma free tryptophan level in the children with ADD was significantly higher than that in the normal children. There tended to be a positive correlation between the plasma free tryptophan level and the Werry-Weiss-Peters Activity Scale in children with ADD. In other words, the more severe the hyperactivity of ADD, the higher the plasma free tryptophan level. The mean ratio of plasma free to total tryptophan levels in the children with ADD was significantly higher than that in the normal children, which means that the children with ADD showed a high amount of free tryptophan in the total tryptophan level. These results suggest that there might be some disturbance in the tryptophan-serotonin metabolism in the brain of a child with ADD.     

Short-term effects of CHO, fat and protein loads on total tryptophan/tyrosine levels in plasma as related to %REM sleep.

The effect on plasma amino acid levels and sleep parameters of three experimental diet conditions was investigated in 12 healthy young men. A total of 71 sleep records and 715 plasma samples were analysed for %REM (TDT) and total plasma tryptophan and tyrosine respectively. The ratio of tryptophan to tyrosine was virtually the same under the fat supplement as under the nosupplement conditions. The ratio associated with the CHO load was found to be 14 per cent higher, however. A 29 per cent higher value found with the Protein load may be misleading due to the nature of the supplement used. %REM (TDT) was not found to be significantly related to any of the above conditions.     

Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis.

The levels of the antioxidants ascorbic acid, cysteine, reduced glutathione and alpha-tocopherol, of the free-radical marker uric acid and of the amino acids tyrosine and tryptophan were measured by means of high-pressure liquid chromatography in plaques, adjacent white matter and distant white matter from patients with multiple sclerosis, and in central nervous system tissue from patients without neurological diseases. Cholesterol and DNA were also determined, to check demyelination and cellularity. Uric acid was increased and glutathione correspondingly decreased in plaques; alpha-tocopherol was lowest in plaques and highest in distant white matter in all cases. Ascorbic acid, cysteine, tyrosine and tryptophan were not significantly changed in any tissue. The results provide evidence supporting the involvement of free radicals in multiple sclerosis.     

Relationships between tryptophan in serum and CSF, and 5-hydroxyindoleacetic acid in CSF of man: effect of cirrhosis of liver and probenecid administration.

Tryptophan was measured in the lumbar CSF and serum of patients undergoing neurological investigation (controls) and in patients with hepatic cirrhosis. Samples were taken from the fasting patients at 8:00 a.m. Under these conditions, in the controls the mean CSF, free )mpm-albumin-bound) and total serum tryptophan were in the approximate ratio 1:4:24. In this cross-sectional study, for the controls, CSF tryptophan was correlated significantly and positively with the total serum but not with the free serum tryptophan. In patients with advanced hepatic cirrhosis the mean CSF tryptophan concentration was greatly elevated. However, the mean total serum tryptophan was unchanged and the free serum tryptophan only slightly elevated. Administration of probenecid, which displaces tryptophan from binding sites on serum albumin, and thereby increases the proportion of serum tryptophan in the free form, did not affect CSF tryptophan.     

Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders

Catabolism of tryptophan and tyrosine in relation to the isoprenoid pathway was studied in neurological and psychiatric disorders. The concentration of trytophan, quinolinic acid, kynurenic acid, serotonin and 5-hydroxyindoleacetic acid was found to be higher in the plasma of patients with all these disorders; while that of tyrosine, dopamine, epinephrine and norepinephrine was lower. There was increase in free fatty acids and decrease in albumin (factors modulating tryptophan transport) in the plasma of these patients. Concentration of digoxin, a modulator of amino acid transport, and the activity of HMG CoA reductase, which synthesizes digoxin, were higher in these patients; while RBC membrane Na+-K+ ATPase activity showed a decrease. Concentration of plasma ubiquinone (part of which is synthesised from tyrosine) and magnesium was also lower in these patients. No morphine could be detected in the plasma of these patients except in MS. On the other hand, strychnine and nicotine were detectable. These results indicate hypercatabolism of tryptophan and hypocatabolism of tyrosine in these disorders, which could be a consequence of the modulating effect of hypothalamic digoxin on amino acid transport.     

Efficacy of antidepressants selected as a function of erythrocyte membrane transport and plasma levels of L-tyrosine and L-tryptophan

The present study concerned 69 depressed patients (26 men, 43 women). The antidepressant drug was prescribed in accordance with perturbations of tyrosine and tryptophan membrane transports (MT) across the red cell, measured in vitro after a wash-out period of ten days. After two to four months of treatment, the clinical results were divided into two groups: normal mood (AMDP - Depression Scale less than 6) and no recovery (AMDP - Depression Scale greater than 6). The initial criteria (e.g. MT) was completed by using plasma tyrosine, tryptophan and the product MT by plasma level. Indeed, the success of this treatment was corresponding to precise abnormalities of variable: (i) tyrosine and tryptophan values for imipramine, (ii) tyrosine values, plasma tryptophan and tryptophan product for desipramine, (iii) tryptophan variables and plasma tyrosine for fluvoxamine (and indalpine). The analysis of clinical failures permitted to complete our previous choice of antidepressant drug.     

Erythrocyte membrane transport and plasma levels of tyrosine and tryptophan in depression

L-Tyrosine and L-Tryptophan were studied in 80 depressed patients, hospitalised in Genova and Marseille. After a washout period of ten days, the erythrocyte membrane transports (MT) of L-Tyrosine and L-Tryptophan were measured, as well as their plasma levels; plasma phenylalanine was moreover measured. 33 normal subjects served as control group. In the whole population of patients, the mean of MT's was different compared to controls (MT tyrosine low and MT tryptophan high) and the plasma tyrosine was low. The perturbations of these variables were different according to diagnostic groups (DSM III): MT tyrosine, plasma tyrosine and tryptophan low in bipolar disorders depressed; MT tyrosine low, MT tryptophan high, plasma tryptophan low in major depressions; MT tryptophan high in dysthymic disorders. Phenylalanine was in the normal range compared to controls. The perturbations of MT's involved the part incubated at 37 degrees C for tyrosine, e.g. the facilitated diffusion, and the part incubated at 0 degrees C for tryptophan, e.g. probably the passive and facilitated diffusion. These results were in agreement with the monoaminergic hypothesis of affective disorders and might provide a useful peripheral model.     

Changes in the Albumin Binding of Tryptophan During Postoperative Recovery: A Possible Link With Central Fatigue?

Tryptophan is the precursor of the neurotransmitter 5-hydroxytryptamine (5-HT), known to be involved in sleep and fatigue. In the blood, tryptophan binds to albumin, and that which does not, free tryptophan, competes with branched chain amino acids (BCAA) for entry into the brain. The plasma concentrations of albumin, free tryptophan, total tryptophan, and BCAA were measured before and after major surgery in nine elderly and nine coronary artery bypass graft (CABG) patients. In both the elderly and the CABG patients plasma free tryptophan concentrations were increased after surgery, compared with baseline levels; the plasma free tryptophan/BCAA concentration ratio was also increased significantly after surgery. Plasma albumin concentrations were decreased significantly after surgery in both the elderly and the CABG patients. Plasma BCAA concentrations were not affected by surgery in either group. The effect of exercising to exhaustion on 5-HT and tryptophan were investigated in Nagase analbuminemic rats (NAR). The intrasynaptosomal concentration of tryptophan, 5-hydroxytryptophan, and 5-HT was increased by fatigue after exercise. In addition, running time to exhaustion was shortened in NAR. These data suggest that free tryptophan uptake and 5-HT synthesis were enhanced in the nerve terminal. A decrease in plasma albumin may account for the increase in plasma-free tryptophan levels. An increase in plasma free tryptophan, resulting in an enhanced plasma concentration ratio of free tryptophan/BCAA, may lead to a higher 5-HT concentration in some parts of the brain and, consequently, to central fatigue. It is suggested that provision of BCAA as a dietary supplement may counteract the increase in plasma free tryptophan and thus improve the status of some patients after major surgery.     

Uptake of tryptophan and tyrosine in some cases of manic depressive psychosis and schizophrenia (author's transl)

The uptake of tryptophan and tyrosine by the brain has been studied in 6 manic-depressive patients and in 8 schizophrenics. In an attempt to saturate the blood-brain transport mechanisms, this uptake has been evaluated by measuring the arteriovenous differences (arterial plasma-internal jugular plasma) of these two amino acids before and after perfusion with L-dopa and L-5-HTP. Considering a positive difference as an uptake and a negative one as an outflow, results show (1) in melancholia an uptake of tryptophan and an outflow of tyrosine; (2) in mania an uptake of tyrosine and an outflow of tryptophan, and (3) in schizophrenia an outflow of tryptophan accompanied with either an uptake or an outflow of tyrosine. In addition, the kinetics of tryptophan binding to plasma proteins and the ratio of tryptophan/tyrosine uptake are different in manic-depressive illness and in schizophrenia. These results support the view that a disturbance in the blood-brain transport mechanisms of tryptophan and tyrosine could be involved in the physiopathology of manic-depressive illness and schizophrenia.     

Hypothalamic digoxin and isoprenoid pathway dysfunction relation to alcoholic addiction,alcoholic cirrhosis,and acquired hepatocerebral degeneration--relation to hemispheric chemical dominance

The isoprenoid pathway produces three key metabolites--endogenous digoxin (modulate tryptophan/tyrosine transport), dolichol (important in N-glycosylation of proteins), and ubiquinone (free radical scavenger). It was considered pertinent to assess the pathway in alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration. Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. In the patient group there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites, as well as reduced endogenous morphine synthesis from tyrosine. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Alcoholic cirrhosis, alcoholic addiction, and acquired hepatocerebral degeneration are associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to NMDA excitotoxicity and altered connective tissue/lipid metabolism important in its pathogenesis. Endogenous morphine deficiency plays a role in alcoholic addiction. The same biochemical patterns were obtained in those with right hemispheric chemical dominance. Alcoholic addiction, alcoholic cirrhosis, and acquired hepatocerebral degeneration occur in right hemispheric, chemically dominant individuals.     

Effect of dialysis on plasma and CSF tryptophan and CSF 5-hydroxyindoleacetic acid in advanced renal disease.

Patients with uraemic encephalopathy were previously found to have low total tryptophan (bound plus free), but high free tryptophan concentrations in the plasma and high CSF tryptophan concentrations. The 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid was also raised in the CSF. A study of the effect of dialysis treatment on these substances in chronic uraemic patients with and without dialysis dementia is described. After an episode of dialysis the patients without dialysis dementia showed increased plasma total tryptophan and decreased free tryptophan. These changes were associated with a decrease of plasma free fatty acid. The patients with dialysis dementia did not show changes in tryptophan, but plasma free fatty acid rose. CSF concentrations of 5-hydroxyindoleacetic acid fell moderately in both groups of patients on dialysis.