Atividade imunomoduladora de derivado sintético

Abstract

The immune system consists of a complex, articulated organization which maintains homeostasis modulating the immune response when necessary, stimulating or suppressing a response mediated by microorganisms, plants and/ or synthetic derivatives. The development of small immunomodulatory molecules is necessary because rational planning provides new therapeutics, aiming for greater selectivity and lower adverse effects, which are limiting factors of some therapies. From this perspective, LASSBio-596, a structural hybrid of thalidomide, sildenafil, and arylsulfonamide, which was rattionally designed as an immunomodulator, is described in the literature with antiangiogenic and anti-inflammatory activities. In this sense, the present study aimed to evaluate in experimental models the antinociceptive, acute and chronic anti-inflammatory and antitumoral activities for glioblastoma, of LASSBio-596 aiming at the development of a potential candidate drug prototype. Chapter I. LASSBio-596, new thalidomide hybrid, induces antinociceptive and antirheumatic effects on mice: In the nociception tests, LASSBio-596 treatment inhibited: the response to writhing in 39.9%; the lick times in the formalin test at 25.7% (1st stage) and 23.9% (2nd phase); as well as in glutamate-induced nociception (31.9%); in addition to statistically increasing pain latency in the hot plate assay. In the acute inflammation model of zymosan-induced peritonitis, leukocyte recruitment was reduced by 39.9% post-treatment with LASSBio-596. In chronic inflammation induced by Freund’s complete adjuvant, treatment with LASSBio-596 reduced the volume of paw edema from the first day of treatment regrowing until the last. In addition, it reduced serum levels of IL-17A, IFN-γ, and TNF-α by 79.0%, 55.4% and 67.1%, respectively. No hepatic or renal damage was observed, whereas cellularity and extracellular matrix of the paws were better preserved in the mice treated with LASSBio-596 than thalidomide. No motor impairment was observed in the motor performance test. The data demonstrated the antinociceptive effect of LASSBio- 596 and reinforces its anti-inflammatory property in a model of chronic autoimmune disease, which amplify the therapeutic potential of this molecule. Chapter II. In vitro therapeutic potential of thalidomide-hybrid, LASSBio-596, in glioblastoma: In the current study LASSBio-596, rationally designed as a hybrid of thalidomide, was tested in vitro assays to assess its activity on tumor growth, representing an important findings about antitumor effects of this analogue on solid tumors. In the viability assay for MTT, LASSBio-596 significantly reduced cell viability at all times tested, whose maximum effect was found at the concentration of 100 μM with higher activity after 72h of treatment, reducing mitochondrial metabolic activity by 52.2 ± 1.2%. PBMC viability, also was reduced with the same treatments, however LASSBio-596 induced a toxicity three times lower compared to thalidomide, and two times lower than TMZ. Whereas the maximum effect for LASSBio-596 was also statistically lower than TMZ and thalidomide on PBMC demonstrating in fact this hybrid exhibited a greater selectivity in inhibiting tumor cells than PBMC. Althought these preliminar promissors results, others in vitro studies are necessaries for comprovation of mechanism of action of this compound as well the evaluation in animal models in order to confirm the potential of LASSBio-596 in the treatment of glioblastoma. In view of the results it is possible to conclude that the thalidomide derivative LASSBio-596 induced antinociceptive and anti-inflammatory effects in in vivo models, as well as reduced the cell viability of GBM02 in in vitro models with lower selectivity for leukocytes in the same model.