Effects of Pregnane Glycosides on Food Intake Depend on Stimulation of the Melanocortin Pathway and BDNF in an Animal Model

Abstract

Pregnane glycosides appear to modulate food intake by possibly affecting the hypothalamic feeding circuits; however, the mechanisms of the appetite-regulating effect of pregnane glycosides remain obscure. Here, we show that pregnane glycoside-enriched extracts from swamp milkweed Asclepias incarnata at 25-100 mg/kg daily attenuated food intake (up to 47.1 ± 8.5% less than controls) and body weight gain in rats (10% for males and 9% for females, respectively) by activating melanocortin signaling and inhibiting gastric emptying. The major milkweed pregnane glycoside, ikemagenin, exerted its appetite-regulating effect by decreasing levels of agouti-related protein (0.6-fold) but not NPY satiety peptides. Ikemagenin treatment also increased secretion of brain-derived neurotropic factor (BDNF) downstream of melanocortin receptors in the hypothalamus (1.4-fold) and in the C6 rat glioma cell culture in vitro (up to 6-fold). These results support the multimodal effects of pregnane glycosides on feeding regulation, which depends on the activity of the melanocortin signaling pathway and BDNF.

Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus

“…Ikemagenin (IC 50 value of 13.2 µM) was 15 times more effective than glycyrrhetinic acid and three times more effective than carbenoloxone, but approximately 300‐fold less effective than corticosterone and 10,000‐fold less effective than dexamethasone in competing for [ 3 H] dexamethasone binding sites (Soro et al, 1997). It is not clear whether this affinity accounts for some or any of the direct in vitro effects on steroidogenesis observed in this study, increased vacuolization of the adrenal cortex in vivo (Komarnytsky et al, 2013a), or reductions in food intake and weight gain associated with pregnane glycoside administration (Komarnytsky et al, 2013b).…”

“…While major swamp milkweed pregnane glycoside ikemagenin is analogous to the major bioactive P57AS3 pregnane glycoside isolated from H. gordonii (van Heerden et al, 2007), it possesses several unique structural properties. These include a bulky lipophilic cinnamoyl moiety attached at C12 position, additional hydroxylation at C18 position, and a different set of rare deoxysugar moieties (oleandrose, digitoxose, and cymarose) attached at the C3 position (Komarnytsky et al, 2013b). A number of other bioactive compounds possess deoxysugars attached to their aglycones; in many cases, these deoxysugars are essential for their biological activity as in case of cardiac glycosides (Schoner and Scheiner‐Bobis, 2007), antibiotics (Salah‐Bey et al, 1998), or antitumor agents (Otten et al, 1997).…”

“…Pregnane glycoside‐enriched extract from Rutgers University greenhouse‐grown H. gordonii plants was prepared as described previously using methanol–dichloromethane extraction followed by solvent–solvent partitioning (van Heerden et al, 2007) and contained 25% (w:w) pregnane glycosides. Pregnane glycoside‐enriched extract from Rutgers University greenhouse‐grown A. incarnata plants was prepared using two‐step process that included defatting and methanol extraction, resulting in 30% (w:w) total pregnane glycoside content and 3.5% (w:w) of major pregnane glycoside, 3,8,12,14‐tetrahydroxypregn‐5‐en‐20‐one; (3β,12β,14β,17α)‐form, 12‐cinnamoyl, 3‐O‐[β‐ D ‐oleandropyranosyl‐(1 → 4)‐ D ‐digitoxopyranosyl‐(1 → 4)‐β‐digitoxopyranosyl‐(1 → 4)‐β‐ D cymaropyranoside (ikemagenin; Komarnytsky et al, 2013b). Incarnatin extract was further used to isolate eight pregnane glycosides to at least 85% purity, as shown on Figure 1A.…”

“…Incarnatin extract was further used to isolate eight pregnane glycosides to at least 85% purity, as shown on Figure 1A. Total pregnane content and individual pregnane glycosides were estimated by a xanthydrol‐based colorimetric assay (Aitova et al, 1973), HPLC, and LCMS/ESI analysis (Komarnytsky et al, 2013b). Absence of cardiac glycosides from the pregnane glycoside‐enriched extracts was confirmed by a negative Kedde reaction (Stahl, 1973).…”

Caralluma fimbriata extract activity involves the 5‐HT2c receptor in PWS Snord116 deletion mouse model

“…Studies in animals report similar attenuation of food intake, and importantly comprehensive toxicity assessments assure the safety of treatment CFE (Odendaal et al, ; Sakore, Patil, & Surana, ). However, characterization of the mechanism of action of CFE remains hypothetical (Kamalakkannan, Rajendran, Venkatesh, Clayton, & Akbarsha, ; Komarnytsky, Esposito, Rathinasabapathy, Poulev, & Raskin, ; Rajendran et al, ). Observations in animals include improvements in the lipid profile and reduction in levels of leptin and/or blood glucose (Ambadasu, Dange, & Wali, ).…”