Mechanism of Decline in Rat Brain 5‐hydroxytryptamine After Induction of Liver Tryptophan Pyrrolase by Hydrocortisone: Roles of Tryptophan Catabolism and Kynurenine Synthesis

Young, Simon N.

doi:10.1111/j.1476-5381.1981.tb10480.x

Cited by 91 publications

(50 citation statements)

References 21 publications

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“…The exposure of emetogenic trigger sites to toxic stimuli may be reduced by modified capillary permeability of the CNS (Livera et al, 1985). Corticosteroids may reduce levels of 5-HT in neural tissue by depleting its precursor, tryptofan (Young, 1981). The anti-inflammatory properties of cortisol may act to prevent the release of serotonin in the gut or prevent activation of 5-HT receptors in the gastrointestinal system (Fredrikson et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids

Hursti

Fredrikson²,

Steineck³

et al. 1993

Br J Cancer

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Summary Lower pre-chemotherapy night time cortisol excretion predicted more severe cisplatin induced nausea and vomiting in 42 ovarian cancer patients receiving ondansetron as a single antiemetic agent. Dexamethasone administration added to the antiemetic effect of ondansetron principally in patients who had low excretion of cortisol.Corticosteroids as single antiemetic agents have a well documented effect on mild to moderate chemotherapy induced emesis (Cassileth et al., 1983). During highly emetogenic chemotherapy, there is a synergistic antiemetic effect of corticosteroids and metoclopramide or 5-hydroxytryptamine (5-HT3) receptor antagonists (Kris et al., 1989;Smith et al., 1991). Recently we reported that nausea during chemotherapy with low emetic potential was inversely related to urinary cortisol excretion (Fredikson et al., 1992 Patients rated their nausea during the past 24 h at the morning of the first and second day after the cisplatin infusion by choosing one of four alternatives ranging from none to severe nausea. At the first morning patients also used a 100 mm visual analog scale (VAS) to report the severity of nausea. A zero score is anchored at the left end with 'no nausea at all' and a maximum score of 100 'worst possible nausea'. Emetic episodes (vomiting or retching) were recorded by patients during both days.In the statistical analyses patients responding with 'no' or 'mild' nausea were treated as one group and those responding 'moderate' or 'severe' nausea formed the other group. Regarding the emetic episodes, patients with complete or major response ( <2 emetic episodes) formed one group whereas minor response and failure (> 3 emetic episodes) formed the other group. A median split approach was used to form groups with relatively high and low cortisol excretion. Relative risk was used to describe the association between urinary cortisol levels and nausea and vomiting. Relative risk was calculated as the ratio between the proportions of patients with moderate or severe nausea, or > 3 emetic episodes in respective groups of interest. Calculation of 95% confidence intervals was performed as described by Greenland & Robins (1985). Student's t-test with one-tailed P-values was used to analyse VAS-ratings of nausea and the total number of emetic episodes. ResultsThe median used to form groups high and low in cortisol excretion was 23.2pmolmin-'. The high and low excretion group had a mean (standard error of the mean) of 38.7 (2.5) and 16.5 (0.9) pmol min-', respectively. The groups did not differ concerning the percentage of 1-vs 2-day chemotherapy course (chi2 = 0.12, P = 0.73). The mean cortisol excretion in patients receiving dexamethasone was 28.8 pmol min-' and in those receiving placebo 25.8 pmol min-' (t (40) = 0.68, P = 0.50). Evaluating the importance of age for the studied variables, patients were categorised by their median age (50 years). No significant association was found between patient's age, cortisol excretion, nausea intensity or emetic episodes (t (40)<1.12, chi2 (1)<0.54, ...

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Section: Discussionmentioning

confidence: 99%

Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids

Hursti

Fredrikson²,

Steineck³

et al. 1993

Br J Cancer

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show abstract

“…We have shown (Badawy & Evans, 1981) that acute administration to rats of a 10 mg/kg dose of a large number of antidepressants, but not of many other drugs, inhibits the activity of liver tryptophan pyrrolase (tryptophan 2,3-dioxygenase, EC 1.13.11.11), which is quantitatively the most important tryptophan-degrading enzyme in man and rat (Badawy & Evans, 1976;Young, 1981), and elevates brain tryptophan concentration. Evidence was also presented by Badawy & Evans (1981) that this latter effect, which led to an enhancement of brain 5-hydroxytryptamine synthesis, was caused by an increase in the availability of circulating tryptophan to the brain secondarily to the above inhibition of liver pyrrolase activity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rat Liver Tryptophan Pyrrolase Activity and Elevation of Brain Tryptophan Concentration by Acute Administration of Small Doses of Antidepressants

Badawy

Evans

1982

British J Pharmacology

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1 Administration to rats of a 0.5 mg/kg dose of any of 19 antidepressants, but not that of many other drugs, causes a significant inhibition of the total enzyme and apoenzyme activities of liver tryptophan pyrrolase (of 24-48% and 37-65% respectively) and elevates brain tryptophan concentration by 13 -66 %. 2 When liver tryptophan pyrrolase activity is enhanced by pretreatment with cortisol or haematin, subsequent administration of a 0.5 mg/kg dose of some, but not other, antidepressants causes inhibition, which is weak (up to 38%). 3 This weak inhibition of the enhanced pyrrolase activity together with other pharmacological and physiological factors could explain the time lag between the start of antidepressant medication and the occurrence of a therapeutic response. 4 The cortisol-induced and haematin-activated pyrrolases respond differentially to inhibition by imipramine and amitriptyline, and this may explain the differential response to these two drugs of depressed patients in relation to urinary excretion of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol. 5 The results are discussed in relation to the mechanism of action of antidepressants and the possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.

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“…Second, it may affect the permeability of the blood-brain barrier and limit the influx of emetic agents to the brain (Davies et al, 1986). Third, cortisol possibly affects 5-hydroxytryptamine (5-HT) turnover in the central nervous system by shunting the metabolism of tryptophan away from 5-HT pathways (Young, 1981). We propose that the anti-inflammatory properties of cortisol may act to prevent the release of serotonin in the gut or prevent activation of 5-HT receptors in the gastrointestinal system.…”

mentioning

confidence: 99%

Nausea in cancer chemotherapy is inversely related to urinary cortisol excretion

Fredrikson

Hursti²,

Fürst³

et al. 1992

Br J Cancer

104

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Treatment with corticosteroids can control mild to moderate emesis during chemotherapy (Cassileth et al., 1983) and adds to the antiemetic effect of high-dose metoclopramide in severe emesis (Bruera et al., 1983). Moreover, pregnancy induced nausea is more common among women with low than high cortisol excretion (Jarnfelt-Samsioe et al., 1986). These findings warrant an investigation whether endogenous cortisol secretion is associated with nausea induced by chemotherapy.The aim of the present study was to relate endogenous cortisol secretion to individual differences in chemotherapy induced nausea and vomiting. Urinary cortisol excretion remain stable over time, particularly during resting conditions (Forsman & Lundberg, 1982). Therefore, night time urine was collected to assay cortisol excretion. Self-reports were used to assess nausea and vomiting. no nausea at all' and a maximum score of 100 denotes 'worst possible nausea'. Vomiting episodes were counted. Self-reports of nausea (VAS) and vomiting were given during (one report) and after (two reports) infusion on the treatment day. Patients also reported their nausea and vomiting every 6th hour for the 2 following days. The daily averages of these values are reported. Vomiting was excluded from further analyses because of its low occurrence.The median used to form groups high and low in cortisol excretion was 60.5 pmol min-'. The high and low excretion group had an average (s.e.m.) of 107.3 (10.8) and 31.4 (5.7) pmol min-' respectively. Figure 1 shows that the group with high compared to low night-time cortisol excretion experienced significantly less nausea.Nausea was higher in patients with relatively lower cortisol levels during (t(18) = 2.55; P<.02) and after (t(18) = 3.01; P <.01) the chemotherapy infusion as well as on the first (t(18) = 2.47; <,.02) and second (t(18) = 2.77; <.01) day after treatment. The group with low excretion rates was younger (45.2; s.e.m. = 2.5) than the group with high excretion (56.1; s.e.m. = 3.3) (t(18) = 2.66; <.02). Using a median split defined by age, the average level (s.e.m.) of nausea during the treatment day was 12.1 (5.4) in young patients and 4.9 (2.8) in older ones (t(18) = 1.18; n.s.). Averaged over post-treatment days 1 and 2 nausea was 22.1 (8.0) and 12.0

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Mechanism of Decline in Rat Brain 5‐hydroxytryptamine After Induction of Liver Tryptophan Pyrrolase by Hydrocortisone: Roles of Tryptophan Catabolism and Kynurenine Synthesis

Cited by 91 publications

References 21 publications

Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids

Endogenous cortisol exerts antiemetic effect similar to that of exogenous corticosteroids

Inhibition of Rat Liver Tryptophan Pyrrolase Activity and Elevation of Brain Tryptophan Concentration by Acute Administration of Small Doses of Antidepressants

Nausea in cancer chemotherapy is inversely related to urinary cortisol excretion

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