Retraction: The Dietary Polyphenols trans-Resveratrol and Curcumin Selectively Bind Human CB1 Cannabinoid Receptors with Nanomolar Affinities and Function as Antagonists/Inverse Agonists

Abstract

The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examined whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act as ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal Gprotein activity in membranes prepared from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body weight in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, transresveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/ inverse agonists at CB1 receptors at dietary relevant concentrations. Therefore, these polyphenols and their derivatives might be developed as novel, nontoxic CB1 therapeutics for obesity and/or drug dependence.Dietary polyphenols, such as resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol] (found in red wine) and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders), have been used safely for centuries as traditional medicines. As a consequence, increasing scientific investigation suggests that they may prove useful as therapeutics for a broad range of conditions (Scalbert et al., 2005), from inflammatory diseases (Rahman et al., 2006) to cancer (Hadi et al., 2007). The protective effects of resveratrol and curcumin seem to be related to their antioxidant (Fraga, 2007) and anti-inflammatory (Surh et al., 2005) properties. Although the specific mechanisms responsible for these beneficial effects remain unclear, the beneficial effects in vitro generally require relatively high concentrations (Ͼ1 M) and are thought to in- Article, publication date, and citation information can be found at

Targeting Inflammation-Induced Obesity and Metabolic Diseases by Curcumin and Other Nutraceuticals

“…Recent studies indicated that curcumin selectively binds to CB-1 with nanomolar affinity and acts as an antagonist. When administered to mice repeatedly (2–10 mg/kg; twice daily; IP × 3 days), curcumin significantly reduced body weight in a dose-dependent manner (160). Thus, curcumin could work against obesity by reducing food intake and body weight.…”

Biochemical effects of SIRT1 activators

“…Of course, many other targets of resveratrol could contribute to its effects on body weight. One such target is the cannabinoid receptor CB1 [89], which can regulate body weight through food intake and appetite-independent mechanisms.…”

“…In fact, the relationship between SIRT1 and AMPK is more complex, since each has been reported to influence the other [75, 99], however, activation of AMPK by resveratrol is at least partially independent of SIRT1 [74, 100]. Additional direct effects of resveratrol that could have important consequences in vivo include inhibition of kinases [101, 102], modulation of the estrogen receptor [103], the aryl hydrocarbon receptor [49], and a cannabinoid receptor [89], and inhibition of quinone reductase 2 [104], to name a few.…”

Medicinal and Nutritional Perspective of Cinnamon: A Mini-review

“…In vitro studies showed that polyphenolic compounds could inhibit differentiation of adipocyte; also they inhibited lipolysis [25], lipogenesis [26] or intestinal lipid absorption [27] that they tend to lower weight. Polyphenolic compounds are inducers of fatty acid oxidation [26] or antagonist at cannabinoid receptors [28] and attenuate the inflammatory changes [29].…”