The same applies to the potential use of antioxidants such as antagonist of the effects of angiotensin-II (example: losartan) and U0126 substances like Nacetyl- cystein, epigallocatechin gallate (found in green tea), idebenone, resveratrol and BN82270. In terms of further antifibrotic effects, drugs countering cisplatin dna myostatin such as formeterol are promising candidates as well as the collagen type 1 synthesis inhibitor halofunginone. In addition, substances that enhance NO signalling such as sildenafil or poloxamer 188 are currently being investigated as potential future antifibrotic medications
(28, 30-32). Activation Inhibitors,research,lifescience,medical of cyclic AMP via forskolin has recently been indicated as a promising antifibrotic avenue (33). Application of this approach to DMD remains to be explored. Suramin, Inhibitors,research,lifescience,medical a TGF β1 blocker, effectively prevents muscle fibrosis in mdx mice (14). Eplerenone According to GeneNote, mineralocorticoid aldosterone receptor expression is not specific to the kidney but is instead found in many tissues including cardiac, skeletal,
and smooth muscle. Additionally, aldosterone appears to not only be synthesised in the adrenal gland but also locally in other organs such as the heart (34). In the heart, it upregulates Inhibitors,research,lifescience,medical proinflammatory molecules such as growth factor TGF-β, adhesion molecules, and plasminogen activator inhibitors through mechanisms that are both dependent on and independent from the mineralocorticoid
receptor, e.g. by osteopontin Inhibitors,research,lifescience,medical upregulation or through NF-κB activation (reviewed in 35). Additionally, aldosterone increases reactive oxygen species through NADPH oxidase activation (36, 37). Taken together, aldosterone induces inflammation and oxidative stress. Finally, aldosterone can induce fibrosis, an effect that can be inhibited by blocking the mineralocorticoid receptor with spironolactone (reviewed in 38). In skeletal muscle, a combination of an angiotensine-converting enzyme (ACE) inhibitor and Inhibitors,research,lifescience,medical spironolactone prevented fibrosis in a phenotypically very mild mouse model of Duchenne dystrophy (26). However, the many hormone side effects make it illadapted for the treatment of children. Eplerenone as a specific mineralcorticoid antagonist without the side effects of spironolactone has been shown to also inhibit fibrosis in tissues such as blood vessels, the heart and other internal GSK-3 organs (39, 40). Its use in Duchenne dystrophy is appealing and the single Duchenne patient in a very advanced disease stage that has been treated with eplerenone to date indeed showed increased mobility and strength (27). Nutrition While epigallocatechin gallate (green tea extract) seems to have promising antifibrotic effects, much higher concentrations than are usually used for food supplements seem to be required (40).