Inhibition of tryptophan-degrading enzymes enhances central availability of tryptophan

The enzyme tryptophan dioxygenase (TDO), which is primarily found in the liver, breaks down tryptophan. Therefore, if tryptophan is administered in large quantities, the supply of free tryp to be taken up by the CNS does not rise in proportion to the dose ingested (Salter et al. 1995).

There is evidence to suggest that the administration of paracetamol inhibits TDO activity and increases the amount of tryp available for serotonin synthesis (Daya et al. 2000, Maharaj et al. 2004). Likewise, acetylsalicylic acid has been shown to have an inhibitory effect on TDO activity (Maharaj et al. 2004). Treatment with melatonin has also been associated with an inhibitory effect on TDO activity (Walsh et al. 1997). As melatonin, particularly in high doses, may affect the circadian rhythm, a combination with sleep-inducing tryp seems to be inappropriate for long-term treatment.

It should be noted that stress stimulates TDO activity through an increased release of cortisol which in turn contributes to the breakdown of tryp (Hirota T. et al 1985). This mechanism of action may partly explain the occurrence of depression under high-stress conditions as a result of relative serotonin deficiency (Miura et al. 2008). There is evidence suggesting that consumption of alcohol also raises TDO activity. Within two hours after consumption of alcohol a decline in the plasma levels of tryp and an increase in kynurenine metabolites were measured (Badawy et al. 2009). As previously discussed, physiological doses of vitamin B3 stimulate the enzyme TDO, thereby reducing the blood concentrations of tryp (Sainio et al. 1990).

Another important enzyme for the degradation of tryp is indoleamine-2,3-dioxygenase (IDO). A number of natural substances have been associated with the inhibition of IDO.

For example, rosmarinic acid inhibits IDO activity and thus the degradation of tryp (Lee et al 2007). Part of the beneficial effects of lemon balm extract (contains a high percentage of rosmarinic acid, e.g. Gastrovegetalin®) may be due to its influence on the serotonin system.

Likewise, curcumin (Curcuma) has been shown to have an inhibitory effect on IDO activity (Jeong et al. 2009). In the literature an antidepressant effect of curcumin has been described, with the effect being only partly mediated by serotonin receptors (Wang et al. 2008).

A recent study has provided the first evidence that cacao may also have an inhibitory effect on IDO activity (Jenny et al. 2009). Further investigations are required to show that cacao consumed in the usual quantities has a favourable effect on the availability of tryp.

Resveratrol, a substance that occurs naturally in grapes (particularly high concentrations have been found in red wine), also inhibits the enzyme IDO (Banerjee et al. 2008).

An in-vitro study demonstrates suppression of tryptophan degradation in stimulated human PBMC by acetylsalicylic acid. These data suggest that acetylic acid is able to counteract Interferon-γ production and consequently suppression of IDO activity in several cells in which IDO is inducible by Interferon-γ (Schroecksnadel et al. 2005).

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Other agents affecting the central availability of tryptophan

The following substances have an effect on the concentrations of FFA and may therefore indirectly affect the uptake of tryp by the CNS. The administration of chromium (chromium picolinate) leads to an acute and chronic increase in free tryp which is probably due to a rise in FFA (Franklin and Odontiadis 2004).

The administration of heparin as an anticoagulant (to inhibit coagulation) has also been shown to increase the concentration of free tryp due to a rise in FFA levels under heparin (Strüder et al. 1996).

Consumption of caffeine results in an elevation of FFA levels and thus raises the proportion of free (unbound) tryptophan, while showing an inhibitory effect on serotonin synthesis (inhibition of the enzyme tryptophan hydroxylase, Lim et al. 2001). Therefore, it cannot be recommended as adjuvant therapy for depressive symptoms and affective disorders.

There is evidence to suggest that the displacement of albumin-bound tryptophan in rat serum after administration of acetylic acid (aspirin) in vivo led to increased entry of tryptophan into the brain (Maharaj et al. 2004).

Niacin is known to lead to an acute decline in the FFA concentration (at a dose of 500 mg). It is, however, less known that approximately 3 hours after oral administration a rebound effect occurs with a pronounced increase in FFA (Peireira 1967, Kamanna 2007). If tryp is given about 3 hours after the administration of niacin, the concentration of free tryp is likely to rise, thus creating favourable conditions for an optimised bioavailability of tryp.

Treatment with physiological doses of niacin (vitamin B3) has a beneficial effect on serotonin synthesis in individuals with relative vitamin B3 deficiency. As a result of an inadequate supply of vitamin B3, the body uses a considerable proportion of the ingested tryp for the production of vitamin B3. The simultaneous administration of low-dose niacin (vitamin B3) and tryp in order to compensate for deficiencies is not appropriate, as niacin activates the enzyme (TDO) responsible for the breakdown of tryp in the liver (Sainio et al. 1990). Consequently, treatment for a deficient vitamin B3 status needs to be completed prior to the initiation of tryptophan therapy.

High doses of niacin (> 500 mg) have also been shown to have adverse effects on the availability of tryp for serotonin synthesis (Penberthy 2007). In high doses, niacin stimulates another important enzyme system (indoleamine-2,3-dioxygenase) responsible for the degradation of tryp.

It would seem that the higher the amount of tryp substituted, the higher the amount of tryp available for serotonin synthesis, but this is unfortunately not the case. Repeated administration of tryp does not produce high blood levels of tryp as expected. This is due to two enzymes that break down tryp. The activities of both enzymes are induced by a high intake of tryp. The enzyme tryptophan dioxygenase (TDO) is primarily found in the liver. As repeated high doses of tryp stimulate this enzyme it seems to be advisable to give tryp in several divided low doses and to schedule for regular tryp-free days. This treatment regimen is supported by pharmacokinetic studies of tryp which indicate that tryp plasma levels may return to normal 4-6 hours after administration at the latest (Green et al. 1980, Möller 1981). It should be noted that the single dose needs to be high enough that adequate levels of free tryp are produced (≥ 1.5 g of tryp) (Green et al. 1980). In summary, an intermittent dosage regimen with breaks in between to allow for periodic normalisation of TDO enzyme activity seems to be more beneficial than continuous therapy with tryp.

Another way to enhance the supply of tryp to the brain would be to administer substances that inhibit the TDO enzyme.

The second important enzyme for the degradation of tryp is indoleamine-2,3-dioxygenase (IDO). Unlike TDO, this enzyme can be found in numerous tissues and plays a special role in the development of tolerance to foreign antigens. IDO activity is also increased by a high supply of tryp, thus reducing the availability of tryp for serotonin synthesis.

Link: Tryptophan Literature

Increased central availability of tryptophan as a result of endurance exercise

Prolonged endurance training results in metabolic changes which have a favourable effect on the central availability of tryp (Chaouloff 1997). Moreover, animal experiments suggest that endurance exercise may stimulate endogenous serotonin synthesis. Administration of tryp prior to endurance exercise leads to a further increase in serotonin synthesis in the brain (Meeusen et al. 1996).

Numerous studies with beta2-sympathomimetic agents (e.g. salbutamol, clenbuterol) have shown that these drugs – probably by activating central beta2-receptors – promote the CNS uptake of tryp (Lenard et al. 2003). By increasing the release of noradrenaline/adrenaline, intense endurance training also leads to physiological activation of beta2-receptors; this mechanism of action is likely to result in the enhanced central availability of tryp.

As the uptake of tryp at the BBB depends, among other things, on the concentration of branched-chain amino acids (BCAA) using the same transport system, the increased uptake of BCAA (leucine, isoleucine, valine) into the working muscles as a result of physical exercise has a favourable effect on the tryp uptake in the brain (Blomstrand et al. 1991). Regardless of the presence or absence of insulin, BCAA are taken up into the muscle cells to provide energy during prolonged endurance exercise. In the course of endurance training, the blood tryp/BCAA ratio shifts increasingly in favour of tryptophan, thus heightening the likelihood of tryp uptake by the brain.
Moreover, tryp competes with free fatty acids (FFA) for binding to albumin in blood. Only the tryp that is not bound to albumin can pass the BBB. Any conditions that increase the FFA in the blood may also raise the concentration of free tryp (Strüder et al. 1996). These observations seem to suggest that low-impact exercise may be particularly suitable to enhance central tryptophan uptake or serotonin synthesis. Various studies, however, indicate that intense exercise is more likely to increase serotonin synthesis (Cuperuto et al. 2009). Therefore, a compromise would be high-intensity exercise, with the bulk of the body’s energy needs still being supplied by fat metabolism (70% - 75% VO2 max). Even under these circumstances the concentration of free fatty acids steadily rises in the course of exercise (Strüder et al. 1997). If exercise duration is 40-60 minutes or more, the fraction of free tryp increases parallel to the concentration of FFA. Moreover, if endurance exercise is initiated on an empty stomach (last meal > 4 hours earlier) FFA levels will be high right from the start. If tryp is administered in this setting at a dose of 1.5 mg 30 minutes prior to the start of exercise, high blood concentrations of free tryp will be achieved early on. Tryp should be taken with at least 100 ml of water (fruit juice is to be avoided, as subsequent release of insulin would reduce FFA levels). It takes approximately 30 minutes until tryp becomes systemically available. Throughout the duration of exercise there are optimal conditions for the uptake of tryptophan by the CNS. As the concentration of FFA is elevated for at least one hour after exercise (Henderson et al. 2007), the next meal should be postponed for some time, in order to maintain optimal conditions for tryp uptake in the brain for as long as possible. Prolonged endurance exercise results in increased uptake of tryp into the CNS, provided no carbohydrates are consumed during exercise (Blomstrand et al. 2005).

Link: Tryptophan Literature

Uptake of tryptophan in the brain

Requirements for a maximum uptake of tryptophan in the brain
 

Tryp competes with other amino acids such as phenylalanine, tyrosine, valine, leucine, and isoleucine for the same transporter in the blood-brain barrier (BBB). These amino acids belong to the group of large neutral amino acids (LNAA) or branched-chain amino acids (BCAA). A low ratio of tryp to the competing amino acids has repeatedly been observed in depressive patients (Möller 1985, Kaneko et al. 1992). Only free tryp that is not bound to protein can cross the BBB. Therefore, to ensure the maximum uptake of tryp in the brain, a high proportion of total tryp in the blood should be in the free state, and there should be a low concentration of competing amino acids (LNAA, BCAA). Pharmacokinetic studies suggest that adequate doses of tryp (at least 1 -1.5 g per single dose) have to be administered in order to achieve the high concentrations of free tryp required at the BBB (Green et al, 1980). In addition, these studies indicate that the concentration of free tryp is only high enough within the first 2 to 3 hours after oral administration to ensure effective tryp uptake by the brain. Furthermore, in order to stimulate central serotonin synthesis it seems to be necessary that a certain threshold in the ratio between tryp and the competing amino acids (tryp/LNAA ratio) in the blood should be exceeded. Accordingly, a 40 – 70% increase in the plasma tryp/LNAA ratio as compared to baseline may be required (Markus et al. 2008).

Link: Tryptophan Literature

  

Which Factors Affect the Availability of Tryptophan for Central Serotonin Synthesis?

Influence of tryptophan on the serotonin system in the brain


The conversion of tryptophan (tryp) to 5-hydroxytryptophan and eventually to 5-hydroxytryptamine (serotonin) in den CNS may be stimulated by the exogenous supply of tryp. A constant supply of free tryp at the blood-brain barrier seems to be required to ensure an adequate synthesis of serotonin in the brain.


After crossing the blood-brain barrier, tryp is hydroxylated by the enzyme tryptophan hydroxylase. This reaction is the rate-limiting step in the synthesis of serotonin. Tryptophan hydroxylase is only half-saturated under physiological conditions (Young and Gautier 1981) and its activity can be further stimulated by a high substrate supply (Fernstrom and Wurtman 1972, Heuther et al. 1992). In other terms, a high concentration of free tryptophan at the blood-brain barrier leads to the increased formation of 5-hydroxytryptophan (5-HTP), a precursor of serotonin (5-hydroxytryptamine). It should be noted that deficiencies of vitamin B6 (Hvas et al 2004) and magnesium (Durlach J. et al 2002, Korbitz BC. 1970) inhibit the activity of the enzyme and thus reduce serotonin synthesis. The same applies to caffeine which equally reduces the activity of tryptophan hydroxylase (Lim et al 2001). Regular consumption of coffee may therefore have an adverse effect on serotonin synthesis.

Link: Tryptphan Literature

 

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