Abstract
Thalidomide is an immunomodulatoryagent with anti-inflammatory activity, however it may also cause serious side effects. New compounds derived from thalidomide effective in modulating inflammatory responses and having an improved safety profile is being investigated. In this study, two thalidomide analogs, GI-16 and SC-15, were evaluated using the carrageenan-induced paw swelling and the lipopolysaccharide (LPS)-induced lung inflammation in mice. Acute and sub-chronic toxicity of the compounds were investigated in blood and serum samples of Wistar rats by measurements of hematological and biochemical parameters. Histopathological analyses were conducted to assess inflammatory cell infiltration in heart, liver and kidneys. Our results show that treatment with GI-16 and SC-15 reduced the carrageenan-induced paw edema over a 24 hour period. GI-16 and SC-15 treatments inhibited LPS-induced TNF-α and IL-6 in lung homogenates. In contrast, thalidomide and SC-15 enhanced IL-10 (p<0.05). Histopathological analysis showed reduction in LPS–induced lung inflammation after treatment with GI-16 and SC-15. Wistar rats treated with the compounds did not develop any clinical signs of acute or sub-chronic toxicity. No mortality occurred in both control and treated animals and body weight gain over time was similar in all groups. In addition, no significant alterations were detected in enzyme activity of aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase, and no significant alterations were found in glucose, urea, creatinine, total cholesterol or triglyceride levels. GI-16 and SC-15 treatments did not modify hemoglobin, red and white blood cell count, and sections of liver, kidneys and heart tissues showed no pathological alterations under light microscopy. In conclusion, the remarkable in vivo anti-inflammatory activity and low toxicity of SC-15 and GI-16 makes them promising drug candidates to treat inflammatory conditions.
Highlights
This study aimed to evaluate the in vivo effects of two selected compounds derived from thalidomide, namely GI-16 and SC-15
Treatment with the compounds caused a significant reduction in TNF-α at both dose levels, reaching values similar to those obtained by treatment with thalidomide or dexamethasone
The most salient findings of this work are that mice treated with the thalidomide analogs GI-16 and SC-15 have a significant decrease in carrageenan- induced paw edema and reduction in LPS–induced lung inflammation, showing lower levels of TNF-α and IL-6 in lungs
Summary
In order to improve the pharmacokinetic properties of thalidomide and reduce the incidence of side effects, several analogs have been developed with increasingly promising results [1,2,9]. The first studies with thalidomide analogs sought the relationship between chemical structure and biological activity [10]. Thalidomide analogs with open phtalimidic structure reduced TNF-α levels, and decreased interleukin-12 (IL-12) and IL-1β production in lipopolysaccharide (LPS)-stimulated monocytes [2]. In previous study from our laboratory it has been shown that thalidomide analogs containing diamines and open phthalimide structures with the presence of NO2 group showed high inhibitory in vitro activity in key molecules, such as TNFα, IL-12, IFN-γ, IL-6, CXCL9, CXCL10 and CD80 in J774 macrophages. Some compounds induced an increase in IL-10 production [1,2]
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