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

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

 

Web Directory

High PR Directories

Diroo

Triple W Directory

Promotion Business Directory