Brain Tryptophan Availability Research Articles

A randomized clinical trial to test efficacy of chamomile and saffron for neuroprotective and anti-inflammatory responses in depressive patients

Depression is one of the common psychiatric problems in growing world population caused by long-term stressful events that may trigger the down regulation of neurogenesis. The pathogenesis of depression initially relies on serotonin deficiency which is associated with depressive feelings. Tryptophan (TRP) depletion participate crucial role in inducing depressive symptoms. Long-term reduction of 5-HT may disseminate to high sensitivity of MDD and alters the level of BDNF. Some studies have also revealed the strong association between excessive neuroinflammation and BDNF levels, due the release of pro-inflammatory cytokines. The treatment approach through FDA approved medicine has their own merits and drawbacks. Therefore, herbal alternatives have recently garnered attention for their effectiveness against depression. However, evidence-based synergic effects of antidepressant with different herbal agents are limited. The purpose of this study was to assess the synergistic effects of two well-known herbs, chamomile and saffron, as an adjuvant therapy in patients with mild to moderate depression. The present study was study randomized, open, blinded trial and comprised of 120 participants randomly allocated to control (n = 60) and test (n = 60). After consent, the patient health questionnaire- 9 (PHQ-9) was filled to obtain depression scores. The test participants were received herbal tea sachets twice a day for one month (20 mg Chamomile and 1 mg Saffron/sachet) along with routine medicines, while control participants were received only allopathic medications. Blood samples were taken before and after the treatment. The depressive symptoms improved significantly with both treatments. The effect of herbs enhanced the efficacy of medications and significantly improved PHQ-9 scale and BDNF while reduced the inflammatory markers (CRP) and TRP level in plasma thereby increased the availability of TRP in brain. It has been concluded that the herbal adjuvant therapy produced long term improvement against depression and enhanced the efficacy of allopathic treatment.

Acute Tryptophan Depletion Moja-De: A Method to Study Central Nervous Serotonin Function in Children and Adolescents.

Serotonin (5-HT) is widely implicated as a key neurotransmitter relevant to a range of psychiatric disorders and psychological processes. The role of central nervous 5-HT function underlying these processes can be examined through serotonergic challenge methodologies. Acute tryptophan depletion (ATD) is a key challenge method whereby a diminished dietary intake of tryptophan—the amino acid precursor to brain 5-HT synthesis—results in temporary diminished central nervous 5-HT synthesis. While this particular methodology has been used in adult populations, it was only recently that modifications were made to enable the use of ATD in child and adolescent populations. Additionally, the Moja-De modification of the ATD challenge methodology has demonstrated benefits over other ATD techniques used previously. The aim of this protocol paper is to describe the ATD Moja-De methodology in detail, its benefits, as well as studies that have been conducted to validate the procedure in child and adolescent samples. The ATD Moja-De protocol provides a potential methodology for investigating the role of central nervous 5-HT via manipulation of brain tryptophan availability in human psychopathology from a developmental viewpoint.

Mood, food, and cognition

Food is not only necessary as a metabolic fuel for the body, it becomes more and more evident that there exists an association between food and brain functions like mood and cognition. Tryptophan represents a key element for brain functioning, because of its role as a precursor for production of neurotransmitter serotonin (5-hydroxytryptamine). In clinical conditions, which involve chronic immune system activation or under cytokine therapy, lower tryptophan levels because of high catabolism of tryptophan as indicated by the kynurenine to tryptophan ratio are common and often associate with depressive mood. Studies in the in vitro model of mitogen-stimulated peripheral blood mononuclear cells revealed that several phytocompounds, mainly antioxidants like polyphenols and vitamins, can interfere with inflammatory signaling cascades including tryptophan breakdown. If extrapolated to the in vivo situation, such compounds could increase blood and brain tryptophan availability for serotonin production. Although there is some in vivo evidence for the effect of such compounds, outcomes are hardly predictable and most likely depend on the individual's immunological state. Not only a diet rich in tryptophan but also a diet rich in antioxidants can have a positive impact on mood and cognition. This could be of special relevance for individuals who present with low grade inflammation conditions.

Enhanced memory processes under the influence of herbal drug Somina and its effect on brain serotonin

A progressive decline in memory with advancing age is an established fact. The purpose of the present study was to investigate the effects of Somina (herbal drug) on memory processes of rat. Somina (285 mg/kg-body weight) was administered orally in rats for 29 consecutive days. It is observed in the present study that Somina is responsible for the enhanced memory related behavior significantly in both male and female rats (p < 0.025 and p < 0.0005 respectively) measured by elevated plus maze activity. It is also observed that Somina increased the availability of tryptophan in brain and hence increases 5-hydroxytryptamine (Serotonin: 5HT). Therefore it is suggested that administration of somina strengthens all processes involved in memory and learned behavior. Key words: Herbal medicine, tryptophan, serotonin, memory, elevated plus maze activity.

Effect of hydrolysed egg protein on brain tryptophan availability

Serotonin synthesis critically depends on plasma levels of tryptophan (TRP). Earlier studies have shown that for mood and cognitive benefits to occur, the ratio between TRP and other large neutral amino acids (LNAA) has to be increased by approximately 40%. The present study investigated the dose-dependent effects of a TRP-rich hydrolysed protein (egg-protein hydrolysate, EPH) on the plasma TRP:LNAA. Moreover, it was investigated whether EPH could increase TRP:LNAA in the presence of 2g of milk protein (MP). In a randomised double-blind crossover design, plasma amino acids were measured every 30min for 3·5h after ingestion of a drink containing either three different doses of 4, 8 and 12g EPH containing 270, 560 or 800mg of TRP, respectively, the combination of 4g EPH and 2g MP (74mg TRP), or 4g MP (148mg TRP) in twenty healthy subjects with a mean age of 52 years. All three EPH doses caused significant increases of TRP:LNAA above 40% at 30, 60 and 90min after consumption in a dose-dependent manner. Compared with the 4g EPH, the increase in TRP:LNAA in the 4g EPH with 2g MP condition was significantly lower at 60min (63 v. 44%, P<0·001) and did not differ significantly at 90min (58 v. 53%, P>0·05). The present study showed that a low dose of 4g EPH with even the addition of 2g MP was sufficient to increase the ratio of TRP:LNAA above 40%. Thus, EPH offers a viable ingredient to increase TRP availability.

Effect of tryptophan-rich egg protein hydrolysate on brain tryptophan availability, stress and performance

Reduced brain serotonin function is involved in stress-related disturbances and may particularly occur under chronic stress. Although serotonin production directly depends on the availability of its plasma dietary amino acid precursor tryptophan (TRP), previously described effects of tryptophan-rich food sources on stress-related behavior are rather modest. Recently, an egg protein hydrolysate (EPH) was developed that showed a much greater effect on brain TRP availability than pure TRP and other TRP-food sources and therefore may be more effective for performance under stress. The aim of the present study was to investigate the effects of EPH compared to placebo protein on plasma amino acids, stress coping and performance in subjects with high and low chronic stress vulnerabilities. In a placebo-controlled, double-blind, crossover study, 17 participants with high and 18 participants with low chronic stress vulnerabilities were monitored for mood and performance under acute stress exposure either following intake of EPH or placebo. EPH significantly increased plasma TRP availability for uptake into the brain, decreased depressive mood in all subjects and improved perceptual-motor and vigilance performance only in low chronic stress-vulnerable subjects. The acute use of a TRP-rich egg protein hydrolysate (EPH) is an adequate method to increase plasma TRP for uptake into the brain and may be beneficial for perceptual-motor and vigilance performance in healthy volunteers.

Acute tryptophan depletion in rats alters the relationship between cerebral blood flow and glucose metabolism independent of central serotonin

Acute tryptophan depletion (ATD) decreases the 5-HT precursor tryptophan (TRP) in blood and is used both clinically and preclinically to investigate the involvement of 5-HT in the development of depressive symptomatology. Depression is associated with both central 5-HT dysfunction and abnormalities in the normal relationship between regional cerebral blood flow (CBF) and glucose metabolism (CMRG). In this study, ATD was applied in Wistar rats to investigate the cerebrovascular effects of acute changes in peripheral TRP. Rats were orally fed with a protein–carbohydrate mixture, either containing or lacking TRP. Four hours later, CBF or CMRG was measured by quantitative autoradiographic imaging in 43 brain regions of interest (ROI). In plasma, ATD resulted in a 40% reduction in the ratio of TRP to the sum of other large neutral amino acids, but had no measurable effect upon TRP or 5-HT levels in hippocampus or prefrontal cortex. Nevertheless, ATD significantly reduced local CBF in 11 of the 43 brain ROIs, while local CMRG remained unchanged. Global analysis of all 43 ROIs revealed a close correlation between CBF and CMRG within both treatment groups. However, the overall ratio (=slope) after ATD (m=1.07) was significantly decreased compared to the control group (m=1.27), indicating a state of relative cerebral oligaemia. Since ATD induced a significant lowering of peripheral TRP, without affecting central TRP or 5-HT concentrations, the decrease in CBF and global change in the flow-metabolism relationship cannot be directly attributed to decreases in brain TRP availability. This could be explained if the raphe were selectively vulnerable to ATD, but the exact mechanism remains unknown. Nevertheless, these data suggest that cerebrovascular disturbances should be considered as a potential contributory factor in studies of serotonergic dysfunction, including depression, with important implications for imaging studies that use CBF alone as a measure of neuronal function.

Mood changes after delivery: role of the serotonin transporter gene

Polymorphic variations in the serotonin transporter gene (5-HTT) moderate the depressogenic effects of tryptophan depletion. After childbirth there is a sharp reduction in brain tryptophan availability, thus polymorphic variations in 5-HTT may play a similar role in the post-partum period. To study the role of 5-HTT polymorphic variations in mood changes after delivery. One thousand, eight hundred and four depression-free Spanish women were studied post-partum. We evaluated depressive symptoms at 2-3 days, 8 weeks and 32 weeks post-partum. We used diagnostic interview to confirm major depression for all probable cases. Based on two polymorphisms of 5-HTT (5-HTTLPR and STin2 VNTR), three genotype combinations were created to reflect different levels of 5-HTT expression. One hundred and seventy-three women (12.7%) experienced major depression during the 32-week post-partum period. Depressive symptoms were associated with the high-expression 5-HTT genotypes in a dose-response fashion at 8 weeks post-partum, but not at 32 weeks. High-expression 5-HTT genotypes may render women more vulnerable to depressive symptoms after childbirth.

Effects of carbohydrates on brain tryptophan availability and stress performance

Although glucose intake has been associated with enhanced mental performance, this does not follow a clear synchronized relationship and findings are inconsistent. Given the brain's need for glucose during demanding conditions, glucose intake may be beneficial for stress performance. Brain serotonin may be involved as a postprandial mechanism initiated by increases in plasma tryptophan to the sum of the other large neutral amino acids (Trp/LNAA ratio). We tested whether carbohydrate drinks compared to placebo drinks increase the plasma Trp/LNAA ratio and improve stress performance and mood. Thirty-seven healthy subjects were monitored in a double-blind placebo-controlled study for performance when continuously exposed to cold pressor stress; 2 h after carbohydrate- or placebo-intake. Cold pressor stress significantly increased cortisol and reduced mood and cognitive performance, whereas carbohydrates significantly increased plasma Trp/LNAA and positively influenced performance and mood under stress.

Decreased brain tryptophan availability as a partial determinant of post-partum blues

The post-partum blues is a transient mood alteration affecting most women a few days after delivery. Its stereotypic pattern of symptoms and time course, peaking on post-partum day 3-5, is suggestive of biological determinants superimposed on psycho-social factors. This study was designed to evaluate the possible role of the serotonin system during this period through assessment of brain tryptophan availability. Blood samples from 50 women were collected just before (D0) and 3 days after (D3) delivery. Based on plasma concentration of tryptophan, amino acids competing with tryptophan for transport across the blood-brain barrier and on their respective affinities for this transporter, a brain tryptophan availability index (BTAI) was calculated and its variation correlated with the intensity of post-partum blues evaluated through the Kennerley and Gath score at D3. The BTAI showed a -15% decrease between D0 and D3 (p < 0.01, paired t-test). This decrease was not supported by a drop in plasma tryptophan since its level rather increased (+19%). There was no evidence for change in placental indoleamine-2,3-dioxygenase activity since the variation in plasma l-kynurenine (+12%) paralleled the change in tryptophan level. The decreased BTAI appeared the consequence of a dramatic increase in plasma levels of most amino acids, particularly the competitor aminoacids leucine, isoleucine, valine and tyrosine, during the early post-partum. This decrease in brain tryptophan availability was concomitant to the post-partum blues, whose intensity significantly correlated with the amplitude of BTAI variation (Pearson's coefficient -0.283, p < 0.05). This study suggests that generalized, large amplitude metabolic and/or nutritional changes occurring in the early post-partum result in a transient decrease in brain tryptophan availability, partly accounting for the mood alteration referred to as the post-partum blues, a model for the triggering of puerperal mood disorder in vulnerable women.

Role of brain tryptophan and serotonin in secondary anorexia.

Anorexia and reduced energy intake contribute to worsen the prognosis of patients suffering from a number of chronic diseases, by promoting skeletal muscle wasting, leading to the development of malnutrition and eventually cachexia. The pathogenesis of cancer anorexia is still matter of debate. Many possible mediators, including hormones, peptides, and neurotransmitters, appear to be involved. However, consistent animal and clinical data suggest that brain tryptophan and serotonin may represent a common final pathway shared by many contributing factors. Supporting this hypothesis, recent data showed that the manipulation of brain tryptophan availability ameliorates anorexia and food intake in cancer patients.

Impaired regulation of brain serotonin function during dieting in women recovered from depression.

Amino acid mixtures that lower brain availability of the serotonin (5-HT) precursor tryptophan produce acute depressive relapse in women with a history of major depression. Dieting also lowers brain tryptophan availability, but its effects on brain 5-HT function in recovered depressed women have not been studied. To test the hypothesis that women with a history of major depression would show impaired regulation of brain 5-HT function during a period of dieting-induced tryptophan depletion. Women with and without a history of major depression were placed on a daily 1000 kcal (approximately 4200 kj) diet for three weeks. Before the diet and in the final week we measured fasting plasma tryptophan levels and the prolactin response to an intravenous tryptophan challenge. Dieting lowered plasma tryptophan levels equivalently in women with and without a history of depression. In women without a history of depression, dieting also increased the prolactin response to tryptophan. This increase did not occur in women with a history of depression. Women with a history of depression showed impaired regulation of brain 5-HT function in response to dieting.

Sex Differences in the Effect of Obesity on Human Plasma Tryptophan/Large Neutral Amino Acid Ratio

Backgrounds: The neurotransmitter serotonin (5-HT) contributes to the regulation of food intake and appetite behavior, and its rate of synthesis depends upon brain tryptophan (TRP) availability in relation to the large neutral amino acids (LNAAs). Thus, the ratio of TRP to the sum of LNAA (TRP/LNAA) will be representative of the 5-HT brain levels. Differences between men and women in the obesity-linked alterations in whole blood amino acid levels and compartmentation have been described. The aim of this work was to study the effect of obesity on brain TRP availability in men and women and to determine whether there are sex-linked differences. Methods: The plasma levels of TRP and LNAAs in 42 men and 46 women (classified according to their body mass index (BMI) into lean, overweight and obese) have been determined by HPLC. Results: The TRP/LNAA ratio shows a significant drop which is even more pronounced in men than in women as BMI increases. Moreover, the comparison of the values between the 3 BMI groups revealed that the drop in the TRP/LNAA ratio appears with overweight in men but only with obesity in women. Conclusion: These sex differences could affect hypothetical behavioral differences of feeling hunger when facing voluntary food restriction for weight loss in individuals of different genders and with varying degrees of obesity.

Plasma tryptophan levels and anorexia in liver cirrhosis.

Increased brain tryptophan (TRP) availability for serotonin synthesis may play a role in the pathogenesis of anorexia. Since in chronic liver failure, increased plasma and cerebrospinal fluid TRP concentrations are characteristically reported, we hypothesize that also in liver cirrhosis increased brain TRP availability may constitute the pathogenic mechanism of anorexia. To test this hypothesis, the association between anorexia and plasma TRP was investigated. Anorexia and plasma amino acid concentrations were evaluated in 16 patients with liver cirrhosis and compared with those obtained in 13 healthy volunteers. According to a questionnaire, 11 cirrhotic patients were considered as anorectic. In these patients, brain TRP availability was significantly higher than in nonanorectic patients and controls. Increased brain TRP availability is also associated with anorexia in liver cirrhosis, and supports the hypothesis that increased serotonergic activity may constitute the common pathogenic mechanism for anorexia associated with different diseases.

Effects of tryptophan and/or acute running on extracellular 5-HT and 5-HIAA levels in the hippocampus of food-deprived rats

The present microdialysis study has examined whether exercise-elicited increases in brain tryptophan availability (and in turn 5-HT synthesis alter 5-HT release in the hippocampus of food-deprived rats. To this end, we compared the respective effects of acute exercise, administration of tryptophan, and the combination of both treatments, upon extracellular 5-HT and 5-hydroxyindoleacetic acid (5-HLAA) levels. All rats were trained to run on a treadmill before implantation of the microdialysis probe and 24 h of food deprivation. Acute exercise (12 m/min for 1 h) increased in a time-dependent manner extracellular 5-HT levels (maximal increase: 47%). these levels returning to their baseline levels within the first hour of the recovery period. Besides, exercise-induced increases in extracellular 5-HIAA levels did not reach significance. Acute administration of a tryptophan dose (50 mg/kg i.p.) that increased extracellular 5-HIAA (but not 5-HT) levels in fed rats, increased within 60 min extracellular 5-HT levels (maximal increase: 55%) in food-deprived rats. Whereas 5-HT levels returned toward their baseline levels within the 160 min that followed tryptophan administration, extracellular 5-HIAA levels rose throughout the experiment (maximal increase: 75%). Lastly, treatment with tryptophan (60 min beforehand) before acute exercise led to marked increases in extracellular 5-HT and 5-HIAA levels (maximal increases: 100% and 83%, respectively) throughout the 240 min that followed tryptophan administration. This study indicates that exercise stimulates 5-HT release in the hippocampus of fasted rats, and that a pretreatment with tryptophan (at a dose increasing extracellular 5-HT levels) amplifies exercise-induced 5-HT release.

Cancer anorexia: new pathogenic and therapeutic insights.

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thus worsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Cancer anorexia: new pathogenic andtherapeutic insights

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thusworsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Low serum tryptophan to large neutral amino acids ratio in idiopathic infantile autism

The serum tryptophan to large neutral amino acids ratio (Try/LNAA) is considered a reliable marker of tryptophan availability for brain serotonin synthesis. A dysfunction of brain serotonergic activity has been postulated to exist in autistic disorder and supported by recent studies. On this basis, we determined the serum amino acids levels in 40 children with idiopathic infantile autism as well as in 46 control children. A significantly lower serum Try/LNAA ratio was observed in the autistic subjects compared to the normal controls. In 14 autistic children (35%) this ratio was 2 SD below the mean value obtained in the control group. These results suggest that a low brain tryptophan availability due to a low serum Try/LNAA ratio could be one of the possible mechanisms involved in the alteration of serotonergic function in autism.

The effect of zimelidine and amitriptyline on the brain concentration of some indolic and phenolic monoamines in the mouse

The increase in mouse brain tryptamine accumulation rate and 5-hydroxytryptamine (5-HT) concentration and the reduction in 5-hydroxyindole acetic acid concentration observed after zimelidine administration suggest that the treatment reduces the brain tryptophan availability. Amitriptyline produced no significant changes on tryptamine, 5-HT or 5-hydroxyindole acetic acid. Also, zimelidine reduced mouse brain p-tyramine, increased m-tyramine and increased homovanillic acid. Similar effects were observed after amitriptyline administration. The experiments show that both drugs affect dopamine turnover and tyramine concentration in a similar fashion to that observed for the antipsychotic group of drugs, thus suggesting that they may have some antipsychotic effects, especially if administered at the high dose levels. In addition, it may also possess some of the undesirable effects of this group of drugs.