Glycyrrhiza uralensis

Glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice inhibits of the activity of 11β-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone (Mackenzie et al, 1999). The pathways of cortisol inactivation is through a conversion to cortisone. GA inhibited cortisone and enhanced cortisol synthesis consistent with 11β-hydroxysteroid dehydrogenase type 2 inhibition and increases circulating and thereby, salivary levels of unconjugated deoxycorticosterone and dehydroepiandrosterone by inhibiting their conjugation at source within the adrenal cortex (Al-Dujaili et al 2010). GA may delay the clearance of cortisol and prednisolone and prolong their biological half-life (Ojima et al, 1990).

The Influence of Glycyrrhetinic Acid on Plasma Cortisol and Cortisone in Healthy Young Volunteers

Mackenzie MA, Hoefnagels WHL, Jansen RWMM, Benraad TJ & Kloppenborg PWC. (1990) Journal of Clinical Endocrinology & Metabolism Vol. 70, No. 6 Pp.1637-43.

doi:10.1210/jcem-70-6-1637

Based on studies in laboratory animals and on measurements of the urinary metabolites (allo)tetrahydrocortisol and tetrahydrocortisone in human volunteers it has been claimed that liquorice-induced mineralocorticoid excess is caused by a unique defect in the conversion of cortisol to cortisone. To further evaluate this hypothesis we have investigated the influence of glycyrrhetinic acid (GA), the mineralocorticoid-active constituent of liquorice, on plasma cortisol and cortisone in 10 healthy young normotensive volunteers. Pure GA (500 mg/day), administered orally from days 3-10 of the study, exerted pronounced mineralocorticoid activity. Ingestion of GA resulted in an elevated urinary excretion of free cortisol and virtually unchanged plasma cortisol levels in the presence of markedly decreased levels of both plasma cortisone and urinary free cortisone. These results provide direct clinical support for the hypothesis that GA induces an inhibition of the activity of 11β-dehydrogenase, resulting in a blockade in the conversion of cortisol to cortisone.

Liquorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vivo and in vitro by inhibiting adrenal SULT2A1 activity.

Al-Dujaili EA, Kenyon CJ, Nicol MR, Mason JI. Mol Cell Endocrinol. 2010 Dec 22.

The mineralocorticoid effects of liquorice are mediated by the inhibitory effects of one of its active components glycyrrhetinic acid on 11β-hydroxysteroid dehydrogenase type 2. However, liquorice is reputed to have many medicinal properties and also contains a number of other potentially biologically active compounds. Here we have investigated the wider effects of oral liquorice on steroidogenesis focussing particularly on possible inhibitory effects of glycyrrhetinic acid on adrenal sulfotransferase activity. Salivary steroids were profiled by ELISA in groups of normal male and female volunteers after consuming either liquorice-containing or non-liquorice-containing confectionary for one week. Cortisol and cortisone levels reflected expected inhibition of 11β-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid. Salivary aldosterone was decreased but deoxycorticosterone, dehydroepiandrosterone and testosterone were increased. To assess whether glycyrrhetinic acid directly affected steroidogenesis, free and conjugated steroids were measured in incubates of adrenocortical H295 cells, firstly, in the presence or absence of forskolin and secondly, with radiolabeled deoxycorticosterone or dehydroepiandrosterone. Glycyrrhetinic acid inhibited cortisone and enhanced cortisol synthesis consistent with 11β-hydroxysteroid dehydrogenase type 2 inhibition. Basal and forskolin-stimulated syntheses of deoxycorticosterone and dehydroepiandrosterone conjugates were also inhibited in a dose-dependent manner; glycyrrhetinic acid inhibited the conjugation of deoxycorticosterone and dehydroepiandrosterone with IC50 values of 7μM. Inhibition of deoxycorticosterone and dehydroepiandrosterone conjugation was apparent within 4h of starting glycyrrhetinic acid treatment and was not associated with changes in the expression of SULT mRNA. SULT2A1 encodes the enzyme sulfotransferase 2A1 which is responsible for the sulfonation of deoxycorticosterone and dehydroepiandrosterone as well as pregnenolone and 17-hydroxypregnenolone in human adrenal glands. We suggest that the glycyrrhetinic acid constituent of liquorice increases circulating and thereby, salivary levels of unconjugated deoxycorticosterone and dehydroepiandrosterone by inhibiting their conjugation at source within the adrenal cortex. This effect may contribute to the mineralocorticoid actions of glycyrrhetinic acid and gives substance to claims that liquorice also has androgenic properties.

The inhibitory effects of glycyrrhizin and glycyrrhetinic acid on the metabolism of cortisol and prednisolone--in vivo and in vitro studies

Ojima M, Satoh K, Gomibuchi T, Itoh N, Kin S, Fukuchi S, Miyachi Y. Nippon Naibunpi Gakkai Zasshi. 1990 May 20;66(5):584-96.

This experiment was carried out to investigate the inhibitory effects of glycyrrhizin and its aglycon, glycyrrhetinic acid, on the metabolism of cortisol and prednisolone in vivo and in vitro. The effects of glycyrrhetinic acid on the metabolism of cortisol were examined in vitro using rat and bovine liver homogenate. Glycyrrhetinic acid inhibits both hepatic delta 4-5-reductase and 11 beta-hydroxysteroid dehydrogenase in a dose-dependent manner, resulting in the decrease of conversion of cortisol to cortisone, dihydrocortisol and tetrahydrocortisol in rats. The concentrations of glycyrrhetinic acid inducing 50% inhibition of rat liver delta 4-5-reductase and 11 beta-hydroxysteroid dehydrogenase were 2.5 x 10(-6) M and 8.5 x 10(-6) M, respectively. Glycyrrhetinic acid also inhibits bovine liver 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase in a dose-dependent manner, resulting in the decrease of conversion of cortisol to dihydrocortisol and prednisolone to 20-dihydroprednisolone. The concentrations of this drug inducing 50% inhibition of 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase were 8.2 x 10(-6) M and 6.5 x 10(-6) M, respectively. This is the first report which demonstrates the marked inhibitory effects of glycyrrhetinic acid on 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase in vitro. The effects of glycyrrhizin on the rate of metabolism of cortisol as well as prednisolone were studied in 23 patients with or without adrenal insufficiency. Glycyrrhizin had no effect on diurnal rhythm of plasma cortisol in 7 control subjects with normal pituitary adrenal axis, whereas glycyrrhizin significantly increased the half-time (T 1/2) and area under the curve (AUC) for plasma cortisol in 4 patients with adrenocortical insufficiency taking oral cortisol. Glycyrrhizin also increased T 1/2 and AUC for plasma prednisolone in 12 patients taking an oral prednisolone for at least 3 months. These results indicate that the suppression of hepatic delta 4-5-reductase, 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase by glycyrrhizin and glycyrrhetinic acid may delay the clearance of cortisol and prednisolone and prolong the biological half-life of cortisol or prednisolone.

Withania somnifera

Withanolide plus Withanoside and Reconstruction of Neuronal Networks.

"The reconstruction of neuronal networks in the damaged brain is necessary for the therapeutic treatment of neurodegenerative diseases. We have screened the neurite outgrowth activity of herbal drugs, and identified several active constituents. In each compound, neurite outgrowth activity was investigated under amyloid-beta-induced neuritic atrophy. Most of the compounds with neurite regenerative activity also demonstrated memory improvement activity in Alzheimer's disease-model mice. ... Withanolide derivatives (withanolide A, withanoside IV, and withanoside VI) isolated from the Indian herbal drug Ashwagandha, also showed neurite extension in normal and damaged cortical neurons. ..."1 Withanolide A (WL-A) isolated from the Indian herbal drug Withania somnifera showed neurite extension in normal and damaged cortical neurons.2

Results indicate that the WL-A drug treated animals show better stress tolerance (Archana & Namasivayam, 1998). WL-A supports predominantly Th1 immunity with increase in macrophage functions.

Withanolide and Neuritic Regeneration and Synaptic Reconstruction.

"We investigated whether withanolide A (WL-A), isolated from the Indian herbal drug Ashwagandha (root of Withania somnifera), could regenerate neurites and reconstruct synapses in severely damaged neurons. We also investigated the effect of WL-A on memory-deficient mice showing neuronal atrophy and synaptic loss in the brain. ... Subsequent treatment with WL-A ... induced significant regeneration of both axons and dendrites, in addition to the reconstruction of pre- and postsynapses in the neurons. WL-A ... recovered A beta(25-35)-induced memory deficit in mice. At that time, the decline of axons, dendrites, and synapses in the cerebral cortex and hippocampus was almost recovered. WL-A is therefore an important candidate for the therapeutic treatment of neurodegenerative diseases, as it is able to reconstruct neuronal networks."2

Antistressor effect of Withania somnifera

Withania somnifera is an Indian medicinal plant used widely in the treatment of many clinical conditions in India. Its antistressor properties have been investigated in this study using adult Wistar strain albino rats and cold water swimming stress test. The results indicate that the drug treated animals show better stress tolerance.3

Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice

Perfumi M & Mattioli L. Phytotherapy Research. Volume 21, Issue 1, Pp 37–43, January 2007. DOI: 10.1002/ptr.2013

depression, enhancing work performance, eliminating fatigue and treating symptoms of asthenia subsequent to intense physical and psychological stress. Due to these therapeutic properties, R. rosea is considered to be one of the most active adaptogenic drugs. To confirm and extend results obtained in the few preclinical and clinical studies available in English language journals, the purpose of the present study was to re-investigate the effects produced by a single oral administration of an R. rosea hydroalcohol extract (containing 3% rosavin and 1% salidroside) on the central nervous system in mice. The extract was tested on antidepressant, adaptogenic, anxiolytic, nociceptive and locomotor activities at doses of 10, 15 and 20 mg/kg, using predictive behavioural tests and animal models. The results show that this R. rosea extract significantly, but not dose-dependently, induced antidepressant-like, adaptogenic, anxiolytic-like and stimulating effects in mice. This study thus provides evidence of the efficacy of R. rosea extracts after a single administration, and confirms many preclinical and clinical studies indicating the adaptogenic and stimulating effects of such R. rosea extracts. Moreover, antidepressant-like and anxiolytic-like activities of R. rosea were shown in mice for the first time.

Rhodiola rosea L. extract reduces stress- and CRF-induced anorexia in rats

Mattioli L & Perfumi M. J Psychopharmacol September 2007 vol. 21 no. 7 Pp. 742-50. DOI: 10.1177/0269881106074064

Rhodiola rosea l. is one of the most popular adaptogen and anti-stress plants in European and Asiatic traditional medicine. Its pharmacological properties appear to depend on its ability to modulate the activation of several components of the complex stress-response system. Exposure to both physical and psychological stress reduces feeding in rodents. The aim of this work was thus to determine whether in rats an hydroalcoholic R. rosea extract standardized in 3% rosavin and 1% salidroside (RHO) reverses hypophagia induced by (1) physical stress due to 60 min immobilization; (2) intracerebroventricular injection of corticotrophin-releasing factor (CRF, 0.2 μg/rat), the major mediator of stress responses in mammals; (3) intraperitoneal injection of Escherichia coli Lipopolysaccharide (LPS, 100 μg/kg); (4) intraperitoneal administration of fluoxetine (FLU, 8 mg/kg). The effect of the same doses of the plant extract was also tested in freely-feeding and in 20 h food-deprived rats. RHO was administered acutely by gavage to male Wistar rats 1 h before the experiments. The results show that at 15 and 20 mg/kg, RHO reversed the anorectic effects induced both by immobilization and by intracerebroventricular CRF injection. Moreover, at the same doses, RHO failed to reduce the anorectic effect induced both by LPS and FLU, and did not modify food intake in both freely-feeding and food-deprived rats. These findings strongly demonstrated that RHO is able selectively to attenuate stress-induced anorexia, providing functional evidence of claimed adaptogen and anti-stress properties of Rhodiola rosea L.

Eleutherococcus senticosus

New Substances of Plant Origin which Increase Nonspecific Resistance. Eleutherosides B+E showed marked resistance to stress.4

Plant adaptogens III.* Earlier and more recent aspects and concepts on their mode of action

Panossian A, Wikman G & Wagner H. (1999) Phytomedicine, Vol. 6(4), Pp. 287–300

DNA-dependent RNA polymerase was inhibited in cell nuclei from skeletal muscles and liver of rats after swimming for 15 min. The inhibition of enzymatic activity was partly prevented by an i.p. administration of eleutherosides 45 minutes before swimming. The eleutherosides did not influence the RNA-polymerase activity in vitro. It was demonstrated in a human study in blood donors that an extract containing eleutherosides stimulated the hematopoiesis.

Effect of Eleutherococcus senticosus on submaximal and maximal exercise performance

Dowling EA, Redondo DR. Branch DJ, Jones, S, Mcnab G & Williams MH. Medicine & Science in Sports & Exercise. April 1996 Volume 28 Issue 4 Pp 482-9.

We investigated the effect of Eleutherococcus senticosus Maxim L(ESML) on performance during submaximal and maximal aerobic exercise. Twenty highly trained distance runners randomly assigned in matched pairs to either an experimental (ESML) or placebo (PL) group, participated in an 8-wk double-blind study during which they completed five trials of a 10-min treadmill run at their 10 km (10K) race pace and a maximal treadmill test(Tmax). Following a baseline trial, ESML and PL consumed, respectively, 3.4 ml of ESML extract or placebo daily for 6 wk. Subjects were tested every 2 wk during supplementation and 2 wk following withdrawal. Heart rate (HR), oxygen consumption (˙VO2), expired minute volume (˙VE), ventilatory equivalent for oxygen (˙VE/˙VO2), respiratory exchange ratio (RER), and rating of perceived exertion (RPE) were measured during the 10K and Tmax tests. Resting, post-10K and post-Tmax blood samples were analyzed for serum lactate. No significant differences were observed between ESML and PL for: HR, ˙VO2, ˙VE,˙VE/˙VO2, RER, or RPE; Tmax time to exhaustion; or serum lactate. The data do not support an ergogenic effect of ESML supplementation on selected metabolic, performance, or psychologic parameters associated with submaximal and maximal aerobic exercise tasks.

References

1. Tohda C, Kuboyama T, Komatsu K. Search for natural products related to regeneration of the neuronal network. Neurosignals. 2005;14(1-2):34-45;

2. Kuboyama T, Tohda C, Komatsu K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol. 2005 Apr;144(7):961-71.

3. Archana R & Namasivayam A. Journal of Ethnopharmacology. Volume 64, Issue 1, 1 January 1998, Pp 91-3. doi:10.1016/S0378-8741(98)00107-X

4. Brekhman II, & Dardymov IV. Annual Review of Pharmacology. Vol. 9: 419-430 (1969)