This is really long, but if you are interested enough to wade through it I think you might find it interesting. Take it for what it is.
This would pertain to products such as Scivation's
Anagen, Thermolife's ECDY and
E-Bol, and a few others as well (and NP is working on their own private label product too).
The pharmacological actions of ecdysteroids on vertebrates have been reviewed in several previous articles (Burdette, 1962, 1972; Ogawa et al., 1974; Syrov, 1984, 1994; Sláma and Lafont, 1995; Xu et al., 1997; Syrov, 2000; Kholodova, 2001; Báthori, 2002). We will therefore focus on some aspects only, especially on those where recent developments have occurred. The most important data are summarised in Table 1.
Ecdysteroids and growth (Table 2)
The anabolic effects of several phytoecdysteroids (20E, cyasterone, turkesterone, viticosterone E – see structures on Ecdybase) on mice or rats were reported long ago (see e.g. Okui et al., 1968; Syrov and Kurmukov, 1975a&b; 1976a–c, Syrov et al., 1978, 1981a; Stopka et al., 1999). Growth-promoting effects have also been more recently reported for pigs (Kratky et al., 1997) and Japanese quails (Koudela et al., 1995; Sláma et al., 1996). In many instances however, these effects are not spectacular when considering the growth (weight) curves as they are observed during certain phases of growth or for one sex only and, in many cases, adequate statistical analyses are lacking. Nevertheless, even small effects (i.e. <5 % increase) on growth could be of economical interest for nutritionists, but their firm establishment requires the use of large numbers of animals, which is hardly feasible with large mammals.
The addition of E to sheep food increases body growth rate and also wool growth (Purser and Baker, 1994). Surprisingly, these effects were obtained with minute amounts of ecdysone (0.02 µg/kg per day!), and were more evident when animals were fed on a poor quality diet, which indicates that E improves food utilization. In this case, it has been suggested that the effect results from the toxicity of E towards rumen protozoa, but this has not been fully established.
In fact, through a stimulation of protein synthesis (and/or a reduction of protein catabolism), ecdysteroids would increase the lean body mass. In pigs, doses of 0.2–0.4 mg/kg/day resulted in better nitrogen retention and a body weight increase of 112–116% relative to controls, while food consumption was lowered by 11–17% (Kratky et al., 1997). Other experiments used diets supplemented with ecdysteroid-containing plants (e.g. Rhaponticum carthamoides) and reported similar growth-promoting effects on pigs over a 30-day period (Selepcova et al., 1993b). In quails, 20E in the diet promoted increased growth (115% of controls), but this was associated with a decreased index of food conversion (Sláma et al., 1996). From these data, it appears difficult to draw general conclusions.
Ecdysteroids and physical performance
20E is claimed to have tonic properties (Abubakirov et al., 1988).
Indeed it stimulates muscle growth, provided that protein supply is adequate. Such anabolic effects result in increased physical performance without training (Chermnykh et al., 1988). This was for instance demonstrated using the forced swimming test with rats: animals given ecdysteroids for one week were able to swim for significantly longer times (Azizov and Seifulla, 1998). . These effects are similar to those of anabolic steroids. 20E is also able to increase muscle ATP content in vitamin D-deprived rats (Kholodova et al., 1997).
Ecdysteroids: effects on cellular proliferation and differentiation
Wound-healing effects of ecdysteroids have been described (Syrov and Khushbatkova, 1996; Darmograi et al., 1998). 20E (applied at 0.1% w/w in liposomes) shortens the duration of skin repair after superficial wounding and 20E (2 × 10−4M) stimulates keratinocyte differentiation in vitro (Detmar et al., 1994), an effect measured by the increase of the activity of transglutaminase (an enzyme involved in protein connection through isopeptidic bond formation). Accordingly, ecdysteroids show psoriasis-inhibiting effects (Inaoka et al. 1997). These results have led to many patents concerning the use of ecdysteroids in cosmetics (Lin and Lin, 1989; Meybeck and Bonté, 1990, 1993; Meybeck et al., 1994; Tsuji et al., 1995a&b; Darmograi et al. 1998; Meybeck 1999a&b). In this context, the incorporation of 20E or its acyl ester (2,3,22-tripalmitate) into liposomes has been tested as a slow-release form (Politova et al., 2001).
20E administered orally to rats (5 mg/kg) accelerates the healing process after an experimental bone fracture (Syrov et al., 1986a), and the same molecule (10–100 ng/ml) can stimulate the in vitro proliferation of rat osteosarcoma UMR106 cells (osteoblasts) by 41% (Gao and Wang, 2000). Similarly, 20E stimulates proliferation of human umbilical vein endothelial cells (Lin et al., 1997; Wu et al., 1998b), and several phytoecdysteroids can stimulate erythropoiesis in rats (Syrov et al., 1997b).
The effects of ecdysteroids on tumorous cell proliferation are somewhat conflicting: Lagova and Valueva (1981) reported that 20E (0.1–300 mg/kg, subcutaneous injections for 5 days) was mainly ineffective on tumour growth in mice, but it stimulated the growth of mammary gland carcinomas in mice and rats. El-Mofti (1987, 1994) reported that E was able to induce neoplastic lesions in toads and mice; other authors reported inhibitory effects on tumor cell proliferation (Hirono et al., 1969; Burdette, 1974; Shibatani et al., 1996). More recently, Konovalova et al. (2002) showed that injected 20E had a synergistic effect with low doses of an antitumour drug (cis-platin). Most probably, the results may differ according with the cell types, the nature and concentration of ecdysteroids used, and this clearly requires more extensive studies. In addition, genoprotective effects of ecdysteroids have been reported (Gubskii et al., 1993; Levitskii et al., 1993a&b, 1996; Chabanny et al., 1994); ecdysteroids can prevent chromatin damages induced by various chemicals.
Ecdysteroids and protein synthesis
Stimulatory effects of ecdysone on protein synthesis were reported as early as 1963 (Burdette and Coda, 1963), and the discovery of phytoecdysteroids made these molecules available in large amounts for pharmacological assays. It was rapidly shown that ecdysteroids were able to stimulate protein synthesis in mouse liver (Okui et al., 1968; Otaka et al., 1968, 1969a&b). In fact, it was shown that 20E stimulates the incorporation of [14C]leucine in a cell-free translation system (rat liver polysomes), i.e. it increases the efficiency of the translational machinery (Syrov et al., 1978). Such conclusions have been confirmed and extended to other tissues, especially heart and muscles (Syrov et al., 1975a; Aizikov et al., 1978; Khimiko et al., 2000). Recent structure-activity studies (Syrov et al., 2001) as measured by a stimulation of [14C] aminoacid incorporation into proteins showed that among the compounds tested turkesterone was the most active, followed by cyasterone and 20E.
Ecdysteroids and glucose metabolism
It was shown early on (Table 3) that 20E given per os to rats reduces hyperglycaemia induced either by glucagon or by alloxan treatment (Matsuda et al., 1970; Uchiyama and Ogawa, 1970; Yoshida et al., 1971, Uchiyama and Yoshida, 1974). In fact, 20E stimulates the incorporation of glucose into glycogen and protein in mouse liver (Yoshida et al., 1971) and more generally it enhances glucose utilization by tissues (Syrov et al., 1997a).
The mechanism involved seems to be an increase of tissue sensitivity to insulin (Kosovsky et al., 1989) and preparations containing phytoecdysteroids have been proposed as oral antidiabetics (Takahashi and Nishimoto, 1992; Yang et al., 2001). Depending on the extent of hyperglycaemia, phytoecdysteroid effects may be more or less pronounced that those of manilil, a widely used pharmacological molecule (Kutepova et al., 2001).
Ecdysteroids and lipid metabolism
Ecdysteroids display hypocholesterolaemic effects (Lupien et al., 1969; Mironova et al., 1982; Syrov et al., 1983), through a reduction of cholesterol biosynthesis and an increase of its catabolism (Uchiyama and Yoshida, 1974). 20E (5 mg/kg per os) stimulates the conversion of cholesterol into bile acids in rats (Syrov et al., 1986b), and such an effect is reminiscent of some oxysterols (Schroepfer, 2000). In connection with these effects, ecdysteroids may also have antiatherosclerotic actions (Matsuda et al., 1974; Syrov et al., 1983). Intraperitoneally injected 20E (0.5 mg/kg in rats) also enhances [14C]acetate incorporation into liver triglycerides and reduces triglyceride lipase activity (Catalán et al., 1985).
Ecdysteroids: a “universal medicine“?
An impressive number of papers dealing with ecdysteroid effects are available in the literature. They concern almost every physiological function, and we will give below a brief insight of the published data. It must be noted, however, that in many instances that, in addition to the difficulties caused by language barriers, the experiments are not always described with all the desirable details.
Ecdysteroids improve nervous function: in early studies, it was shown that 20E induced glutamic decarboxylase (an enzyme involved in GABA biosynthesis) in rat brain (Chaudhary et al., 1969), and that E was able to induce acetylcholinesterase in rat brain too (Catalán et al., 1984). More recently, ecdysteroids were shown to represent neuron-protective agents; they reduce glutamate-induced cell death in cortex neurons of rat foetuses and they are proposed as a therapy against mental and behavioural disorders (Aikake et al., 1996). In addition, they may protect against amnesia induced by diazepam or alcohol (Xu et al., 1999). Similar neuroprotective effects have been described for progesterone and oestradiol mixtures in animal models of neurodegeneration (Vongher and Frye, 1999).
Ecdysteroids stimulate hepatic functions: 20E accelerates recovery after hepatitis induced by heliotrine treatment (Syrov et al., 1981b). 20E and other ecdysteroids (turkesterone, cyasterone) administered (10 mg/kg) to rats with hepatitis induced by subcutaneous injection of carbon tetrachloride prevent its hepatotoxic action (Syrov et al., 1992). Moreover, a pretreatment with 20E (5 mg/kg) for one week will reduce the effects of a subsequent heliotrine treatment (Badal'yants et al., 1996).
Ecdysteroids improve heart and lung function: 20E has been recommended for the prevention of myocardial ischaemia, arrhythmia and is described as enhancing VEGF expression (Wu, 2001). An antiarrhythmic effect of 20E was also reported by Kurmukov and Yermishina (1991) and Yang et al. (1996), and an extract of Leuzea carthamoides containing high amounts of 20E also showed a similar effect (Maimeskulova and Malslov, 2000). In rabbits experimentally rendered atherosclerotic (by a high cholesterol diet), 20E (10 mg/kg/day per os) given for 28 days was able to increase Na+/K+ ATPase in myocardium (Khushbaktova et al., 1987). Intravenous injection of 20E showed also a therapeutic effect after lung contusion (Wu et al., 1997, 1998a).
Ecdysteroids improve renal function: when rats are given a nephrotoxic mixture (uranyl acetate + glycerol), 20E (5 mg/kg) seems thereafter able to
restore a normal glomerular filtration rate and to suppress albuminuria (Saatov et al., 1999; Syrov and Khushbaktova, 2001).
Ecdysteroids and the immune system: various immunomodulatory effects of ecdysteroids have been described. Single intraperitoneal injections of various ecdysteroids (20E, 2dE, 2d20E, polB, turkesterone, 1–5 mg/kg) increase the concentration of antibody-forming cells in the spleen of mice immunised with sheep red blood cells (Sakhibov et al., 1989). Low (7.5×10−12–7.5×10−8 M) concentrations of 20E induce the activation (E-rosette formation test) of human lymphocytes (Trenin et al., 1996; Trenin and Volodin, 1999). Low to moderate (10−12–10−5 M) concentrations of 20E or other ecdysteroids stimulate, whereas higher (10−4M) concentrations eventually inhibit, DNA synthesis in concanavalin A – activated lymphocytes (Kuzmitsky et al., 1990; Fomovska et al., 1992; Chiang et al., 1992).
20E (10–20 mg/kg/day per os) has antiinflammatory properties similar to cortisone acetate in rats and mice (Kurmukov and Syrov, 1988; Fomovska et al., 1992) and turkesterone improves lung defence mechanisms in diabetic rats (Najmutdinova and Saatov, 1999). 20E was shown to inhibit in a dose-dependent fashion (10−9–10−4 M) histamine release from rat peritoneal mast cells induced by anti-IgE or concanavailin A (Takei et al., 1991). Taniguchi et al. (1997), however, could not observe any antiinflammatory effect of 20E given orally to rats (5 mg/kg/day for 7 days).
Ecdysteroids have antioxidant properties: 20E has antioxidative and anti-free radical properties (Osynska et al., 1992) and it can thus reduce lipid peroxidation (Kuzmenko et al., 1997, 2001). Several models were used in these studies, as the chemiluminescence of blood serum induced by H2O2 using rats receiving a vitamin D-deficient diet eventually supplemented with 0.1 mg 20E/kg per day, or the uptake of oxygen by methyl linoleate micelles in the presence or absence of 20E.
Are ecdysteroids toxic to microorganisms?: there are a few reports about antimicrobial activity of ecdysteroids. However, Ahmad et al. (1996) reported antifungal and antibacterial activity of 20E at rather high concentrations (between 100 and 400 µg/ml, i.e. 2–8 × 10−4 M). An antimicrobial activity of 20E and its acetates was also observed by Volodin et al. (1999). Toxic effects on protozoa have also been reported; rabbits receiving 20E per os (5 mg/g/day for 3 months) showed a reduced infection with Lamblia duodenalis (Syrov et al., 1990), and the improvement of ruminant productivity by ecdysone was also interpreted by its toxicity towards rumen protozoa (Purser and Baker, 1994).
Ecdysteroids are not toxic to vertebrates: ecdysteroids have a very low toxicity (LD50 > 6g/kg), they are not hypertensive and, in spite of their anabolic action, they would have neither androgenic nor oestrogenic (or antioestrogenic) effects; they induce no virilisation and they do not induce significant changes in castrated animals (e.g. Prabhu and Nayar, 1974). All together this suggests that ecdysteroids are attractive compounds for a wide array of uses, which have been proposed, and of course it would be of particular interest to understand more precisely their mode(s) of action in mammals.
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