Info

This may reflect a wider genotoxic concern, that in the development of novel treatment paradigms for oncology, disabling a genomic surveillance system may be an acceptable approach to acute therapy. In the context of chronic inflammatory diseases, this may be less desirable, but clearly further preclinical safety and efficacy data are awaited to place the importance of this approach alongside others for the treatment of IBD.

6.28.8.2.6 Cannabinoid receptor agonists/fatty acid amide hydrolase (FAAH) inhibitors

While it is well accepted that cigarette smoking protects against the development of UC, historically marijuana has also been used as adjunctive therapy to CD, to inhibit GI motility and secretion and to treat diarrhea, as well as to elicit anti-inflammatory and analgesic activity. Naturally occurring endocannabinoids are produced by the cleavage of membrane fatty acids, in particular arachidonic acids, that have varying specificities for the two cannabinoid 7 transmembrane (7TM) receptors, CB1 and CB2. Arachidonoyl ethanolamide (also referred to as anandamide) is produced and released by activated immune cells; its degradation is regulated by FAAH.

The tissue distribution of CB1 receptors accounts for the well-known psychotropic and peripheral effects of the cannabinoids. CB1 is abundantly expressed in the CNS, but it is also expressed in the human ileum and colon, and expression increases at sites of inflammation. CB1 and CB2 are both expressed on immune cells, where the effects of D9-tetrahydrocannabinol (THC) (27), the psychoactive component in marijuana, are to reduce a range of pro-inflammatory cytokines including TNF-a, IL10, IL6, IL12, and GM-CSF.

HU-210 (28), a nonselective cannabinoid agonist and THC derivative, reduces colonic inflammation, decreases the inflammatory cell influx, and reverses the electrophysiological signs of smooth muscle excitability, which mimic the intestinal dysmotility that is typical of the clinical condition, when administered to DNBS-induced colitic mice.78 In the same study, CB1 _/_ mice or wild-type mice treated with the CB1 antagonist SR141716A/Acomplia developed a more severe inflammatory response to DNBS or DSS, while FAAH "/" animals were significantly protected. Collectively, these data indicate that the endocannabinoid system, through ligation of CB1 receptors, performs a protective role in the GI system during inflammation. However, anandamide has affects on other receptors and it cannot be excluded that decreased inflammation in FAAH-/- mice and the anti-inflammatory actions of HU-210 are due to CB2 receptor or TRPV1 calcium channel activation (see Section 6.28.8.4.2).

Treating a chronic inflammatory disease by stimulating CB1 receptors may be somewhat undesirable given the psychosocial, behavioral, and addictive properties of marijuana, unless their efficacy can be peripherally restricted. However, recent evidence has suggested that enhancing endocannabinoid activity by inhibition of FAAH activity may not have the same potential for abuse.79

FAAH is a membrane-bound enzyme, and uniquely within the serine hydrolase family, it bears an unusual Ser-Ser-Lys triad catalytic mechanism. As a class, URB597 (29, IC50 = 4nM) is one of the best-characterized FAAH inhibitors,79 but LY-2077855 (30, IC50 = 41 nM) is also reported to inhibit anandamide uptake in RBL-2H3 cells and inhibits FAAH activity,80 and a series of exceptionally potent and selective 2-pyridyloxazole derivatives, typified by 31, (IC50 = 4.7 nM) have also been described.81 An assessment in against hyperalgesic and inflammatory endpoints in colitic models for this class of molecules is awaited.

27 28

6.28.8.2.7 Peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor (RXR) agonists

Recent evidence has suggested that the cyclopentenone prostaglandin 15-deoxy-A12'14 PGJ2 functions as an early anti-inflammatory signal, by directly regulating the activation of IKKb and subsequently NFkB (see ).

15-Deoxy-D12,14 PGJ2 is a somewhat selective eicosanoid ligand for PPAR-g, the nuclear receptor that plays a central role in adipocyte differentiation and insulin sensitivity, and is an important therapeutic target for diabetes. To activate transcription, PPAR-g requires heterodimerization with RXR. The RXR-PPARg heterodimers are permissive to activation by both PPAR-g and RXR ligands, and several of the biological effects of PPAR-g activation can be reproduced by specific RXR agonists or rexinoids.

PPAR-g is activated by fatty acid derivatives and the class of insulin-sensitizing thiazolidinediones, such as troglitazone (32), rosiglitazone (33), and pioglitazone (34). In addition to its role in glucose homeostasis, PPAR-g is expressed at high levels in colonic epithelium. Delivery of a replication-deficient adenovirus overexpressing PPAR-g reduces TNBS-induced colitis,83 and in contrast either PPAR-g or RXRa+'_ mice display a significantly enhanced susceptibility to TNBS-induced colitis compared with their wild-type littermates.84 When administered to either DSS-or TNBS-treated mice, troglitazone (100mgkg_ 1 day_ 1, orally) or rosiglitazone (20mgkg_ 1 day_ 1, orally) are effective in reducing histological lesions and intestinal bleeding.84,85 A synergistic improvement in the extent of colonic inflammation induced by TNBS could be achieved by coadministering the RXRa agonist LG-101305,84 a synergy that has been observed in a number of preclinical inflammatory, diabetes, and oncology models.

The significance of these preclinical observations is emphasized by further clinical findings. Firstly, PPAR-g expression levels in patients with UC appear to be impaired compared to normals or patients with CD. In a 12-week open label study with 15 UC patients with mild-to-moderate disease, rosiglitazone (4mg twice per day orally) was able to induce clinical remission in 27% of patients.87 Perhaps the most compelling evidence, however, of the role for PPAR-g agonists has emerged from studies which have dissected the mechanism of action of the 5-ASA class of anti-inflammatory agents that are used extensively to treat IBD.88 Desreumaux et al. demonstrated that PPAR-g+'_ mice treated with TNBS are refractory to the effects of 5-ASA and that 5-ASA is able to displace rosiglitazone from PPAR-g with a value of Ki that is similar to the clinical exposure levels which are needed for efficacy data that collectively point to PPAR-g being the possible molecular target of the 5-ASA drugs.84 This observation could lead to the development of second-generation PPAR-g ligands, as the clinical utility of the 5-ASA class of drugs is limited by their efficacy and side effect profile.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook


Post a comment