Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

Liu, Jilin; Li, Hui; Burstein, Sumner; Zurier, Robert B.; Chen, J. Don

doi:10.1124/mol.63.5.983

Cited by 121 publications

(93 citation statements)

References 48 publications

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“…We have shown [Liu et al, 2003] that AjA activates PPARg in HEK293 cells, and we have observed the same effect of AjA in human FLS (unpublished). PPARs were first cloned as nuclear receptors that mediate the effects on gene transcription of synthetic compounds called peroxisome proliferators.…”

Section: Discussionsupporting

confidence: 67%

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Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

Johnson

Stebulis

Rossetti

et al. 2006

J of Cellular Biochemistry

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Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARg directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARg in the mechanism of action of AjA. FLS, treated or not with a PPARg antagonist, were treated with AjA then stimulated with TNFa or IL-1a. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARg positive (PPAR þ/À ) and PPARg null (PPAR À/À ) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARg activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFa-and IL-1a-stimulated PPARg þ/À and PPARg À/À MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARg independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.

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Section: Discussionsupporting

confidence: 67%

“…AjA binds to and activates the nuclear receptor peroxisome proliferator activated receptor gamma (PPARg) in vitro [Liu et al, 2003]. Therefore, we investigated the influence of AjA on release of MMPs from stimulated human FLS and mouse embryonic fibroblasts (MEF), and we examined the role of PPARg in the mechanism of action of AjA.…”

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confidence: 99%

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

Johnson

Stebulis

Rossetti

et al. 2006

J of Cellular Biochemistry

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“…These remarkable results are potentially important in light of accumulating evidence that the timing of COX-2 expression may determine its potential to promote either induction or resolution of inflammation by regulating the production of prostaglandins, depending on the stage and progression of the inflammatory response (Willoughby et al, 2000). Although an earlier report suggests a mechanism for AJA involving PPAR-g (Liu et al, 2003), a more recent study shows that this is not always the case (Johnson et al, 2007) so that AJA may act by either PPAR-g dependent or independent mechanisms.…”

Section: Ajulemic Acid (Aja)mentioning

confidence: 94%

The elmiric acids: Biologically active anandamide analogs

Burstein

2008

Neuropharmacology

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SummaryAs chemical entities, lipoamino acids have been known for some time. However, more recently their occurrence and importance in mammalian species has been discovered. They appear to have close relationships with the endocannabinoids not only structurally but also in terms of biological actions. The latter include analgesia, anti-inflammatory effects, inhibition of cell proliferation and calcium ion mobilization. To date about 40 naturally occurring members of this family have been identified and, additionally, several synthetic analogs have been prepared and studied. To facilitate their identity, a nomenclature system has been suggested based on the name elmiric acid (EMA). The prototypic example, N-arachidonoyl glycine does not bind to CB1, however it does inhibit the glycine transporter GLYT2a and also appears to be a ligand for the orphan G-protein-coupled receptor GPR18. It may also have a role in regulating tissue levels of anandamide by virtue of its inhibitory effect on FAAH the enzyme that mediates inactivation of anandamide. Its concentration in rat brain is several fold higher than anandamide supporting its possible role as a physiological mediator. Future studies should be aimed at elucidating the actions of all of the members of this interesting family of molecules. Keywordsendocannabinoid; lipoamino acid; eicosanoid; elmiric acid; inflammation; anandamide Lipoamino acids (fatty acid-amino acid conjugates): general considerationsThe older literature on this topic is mainly concerned with lipoamino acids of bacterial origin (Batrakov et al., 2000;Kawai et al., 1990;Kawazoe et al., 1991;Lerouge et al., 1988;Miyazaki et al., 1993). These involve amino acid conjugation with complex and unusual fatty acids and little is known about their function in bacteria.More recently, attention has been given to lipoamino acids present in mammalian species in part because of their possible relationships to the endocannabinoids. The closely related analog of anandamide, N-arachidonylglycine (NAGly), is in a sense, a comparable acid analog to anandamide as the THC metabolite, THC-11-oic acid is to THC. NAGly is an endogenous substance found in rat brain and other sites that occurs in amounts greater than the closely related endocannabinoid, anandamide (Huang et al., 2001). However, the origin of NAGly in vivo is not completely understood. Sumner.Burstein@umassmed.edu, Tel: 508-856-2850, Fax: 508-856-2003. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Prior reports (Burstein et al. 1997;Huang et al., 2001), suggest that NAGly might have analgesic properties similar to tho...

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“…13,44 Indeed, PPAR␥ agonists ameliorate experimental colitis, [45][46][47] and PPAR␥ expression is reduced in patients with ulcerative colitis. 20 To verify whether PPAR␥ was also involved in colitis improvement after BCP treatment, the PPAR␥ antagonist GW9662 (1 mg/kg, i.p.)…”

Section: Beneficial Effects Of ␤-Caryophyllene On Dss-induced Colitismentioning

confidence: 99%

“…13,14 PPAR␥ is a member of the superfamily of nuclear receptors and has important anti-inflammatory activity, 15,16 because it inhibits the activation of nuclear factor B (NF B) and the expression of the proinflammatory cytokines IL-1␤ and tumor necrosis factor-␣ (TNF-␣). [17][18][19] The colon expresses a high density of PPAR␥, 20,21 and much evidence points to the involvement of the PPAR␥ receptor in the regulation of intestinal inflammation.…”

mentioning

confidence: 99%

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

Bento

Marcon

Dutra

et al. 2011

The American Journal of Pathology

208

145

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Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-␥ (PPAR␥) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-␤-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the antiinflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPAR␥. Oral treatment with BCP reduced disease activity, colonic macro-and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-␣, IL-1␤, interferon-␥, and keratinocyte-derived chemokine. Inflammatory bowel diseases (IBDs) are a group of chronic diseases that affect the gastrointestinal tract and have been mainly subdivided as ulcerative colitis and Crohn's disease. 1 The IBDs are characterized by a strong leukocyte activation and infiltration into the intestinal tissues, the release of proinflammatory cytokines 2 and enzymes, and the formation of reactive oxygen species. All of these events can induce an extensive and unbalanced activation of the mucosal immune system, driven by the commensal flora. 3 Recent evidence suggests a role for the cannabinoid system in IBD regulation. Cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed in normal human colon 4,5 and are up-regulated in IBD colonic tissue. In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis. 5 It is thought that CB1 activation results in a decrease of intestinal hypermotility and hypersecretion, whereas the activation of CB2 results in the inhibition of proinflammatory mediators. In addition, both CB2 and CB1 knockout mice are more susceptible to the development of experimental colitis, and the activation of these receptors is extremely important for the abrogation of intestinal inflammation. 6 The role of CB2, however, is directly involved with innate immune system, because CB2 is primarily expressed in immune cells, such as macrophages, CD4 ϩ and CD8 ϩ T cells, monocytes, and polymorphonuclear neutro-

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Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid

Cited by 121 publications

References 48 publications

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid

The elmiric acids: Biologically active anandamide analogs

β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway

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