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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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