Erythromycin as an antiinflammatory/treatment of diabetic nephropathy
Today's edition of DailyUpdates from LeadDiscovery highlights what we felt to be a particularly interest study demonstrating the efficacy of erythromycin in diabetic rats. In particular, this study shows that erythromycin is able to ameliorate renal injury through the modulation of inflammation. The title of the study is "Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats" and it was published in Diabetologia. 2005 Oct 18; [Epub ahead of print]. The abstract is below.
One of the reasons why we found this report so interesting was that diabetic nephropathy remains a serious clinical concern. In fact in their in depth evaluation of this field Diabetic Nephropathy: Prevalence, Progression, Prevention and Potential conclude that diabetic nephropathy is the most common cause of end-stage renal disease in the US and Europe. Despite the efforts to address the increasing incidence of both type 1 and type 2 diabetes, the diabetic population is set to increase by 72% between 2003 and 2025 and therefore diabetic nephropathy is likely to remain a major cause of death unless improved treatments are identified.
The Diabetologia study featured in DailyUpdates is therefore of interest since it may hold the key to improved therapeutics. The data suggest that companies may wish to evaluate the therapeutic potential of erythromycin-like molecules, outside the field of infectious diseases, in greater detail. Presumably this is relevant to inflammatory diseases in general and not just the inflammatory component of diabetic nephropathy.
Having conducted a very preliminary search of PubMed we were unable to find much in the way of information on the anti-inflammatory properties of erythromycin. We aim to expand on this over the next few hours but if any visitors to this forum would like to provide information on this topic it will be gratefully received.
Likewise, since erythromycin has been known for a long time libraries of erythromycin-like molecules are sure to exist somewhere - does anyone know of such a library and has this been screened for anti-inflammatory activity? We will also be chasing up this information but feel free to post a comment if you know of such libraries.
Publisher's Abstract
AIMS/HYPOTHESIS: Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. METHODS: STZ-induced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks. To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-kappaB) activity. RESULTS: Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-beta1), type IV collagen protein production and NF-kappaB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. CONCLUSIONS/INTERPRETATION: Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-kappaB activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.
posted by Jon Goldhill at 2:49 PM
4 Comments:
An older paper by Adachi et al. (J Allergy Clin Immunol 98:S207-15,1996) describes the ability of erythromycin and clarithromycin to reverse Interleukin-5-afforded survival of eosinophils by inducing apoptosis in vitro. Not known whether this effect is limited just to eosinophils.
Erythromycin has also been demonstrated to reduce the release of eosinophil chemotactic agents (Sato et al, 2001). The possible modification of eosinophil migration/function/survival by macrolides is interesting and supports further studies in asthma models or patients. A quick inspection of the literature reveals that this concept has already attracted some attention.
A study by Kostadima et al (2004) reported that clarithromycin reduces the degree of bronchial hyperresponsiveness in patients with asthma. Furthermore Spahn et al (2001) reported that clarithromycin potentiates glucocorticoid responsiveness in patients. Whether these effects are specific to clarithromycin has not to our knowledge been investigated although in vitro studies have demonstrated that the macroclides in general (including erythromycin) inhibit cholinergic control of brochoconstriction (Tamaoki et al, 1995).
If the macrolides do block airway hyper-responsiveness as well as eosinophil function, chemical optimization of this family may yield novel therapeutics that are of benefit to the treatment of asthma as well as being of use in renal disease as suggested in the original post.
doxycyclin potently reduces VEGF levels as well, suggesting a general antiinflammatory action.
Interesting point on the VEGF effect - this may suggest dual efficacy in rheumatoid arthritis through anti-inflammatory activity plus inhibition of angiogenesis
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