Avaliação dos efeitos antinociceptivo, anti-inflamatório e antiartrite do LQB-118 em camundongos

Abstract

Rheumatoid arthritis, a chronic and progressive inflammatory autoimmune disease, leads to bone erosion, cartilage destruction and loss of function, leading to severe joint pain. In the development of arthritis, macrophages are responsible for producing and secreting inflammatory cytokines that are able to activate immune system cells, expanding the inflammatory process. In addition, after the menopause period, the incidence of arthritis is three times higher in women when compared to men and women with arthritis show improvement in the health state during pregnancy, which suggests that sex hormones have some protective effect on the disease. Although there are many pharmacological tools for the treatment of arthritis, these drugs cause many side effects or are very expensive. Therefore, the present study aimed to evaluate the antinociceptive and antiarthritis potential of LQB-118, a pterocarpaquinone designed from the combination of lapachol and pterocarpan, as well as the involvement of estrogen receptors in the mechanism of action of this compound. For this, experimental models that evaluate the nociceptive behavior and the model of zymosan- induced arthritis in mice were used. In the acetic acid-induced writhing, LQB-118 (3, 10 and 30 mg/kg, s.c.) reduced the number of writhings in a dose-dependent manner (25.4%, 55.6% and 68.7 %, respectively), indicating an antinociceptive effect. In the formalin test, LQB-118 (30 mg/kg, s.c.) did not change the reactivity time of nociceptive behavior during neurogenic pain, but reduced the reactivity of the animals by 46.6% during the inflammatory pain, suggesting an antinociceptive effect involving anti-inflammatory mechanisms. The hot plate test ruled out the involvement of central antinociceptive mechanisms, since LQB-118 (30 mg/kg, s.c.) did not change the fall time of the mice. In addition, the rota rod test ruled out changes in the animal motor functions, as the mice's falling time was not altered by LQB-118 (30 mg/kg, s.c.). In the zymosan-induced arthritis, LQB-118 (30 mg/kg, s.c.) increased the nociceptive threshold by 50.2%, while lapachol and lausone did not change this parameter. Treatments with LQB-118, lapachol and lausone significantly and similarly reduced zymosan-induced leukocyte migration into the joint cavity. The treatment of ovariectomized animals (OVX) with LQB-118 (10 and 30 mg/kg, s.c.) did not alter the estrous cycle phases of these animals, which remained in metestrus and diestrus, ruling out a possible agonist action on estrogen receptors. In contrast, LQB-118 (30 mg/kg) significantly reduced the uterine weight of OVX animals by 47.4%, suggesting a possible antagonistic effect on estrogen receptors. Corroborating this hypothesis, in OVX animals that received estradiol cypionate, treatment with LQB (30mg/kg, s.c.) reversed the increase in uterine weight by 29.4% and maintained 75% of the animals in metestrus or diestrus. In vitro, LQB-118 (10-100 µM) reduced the cytokine synthesis (TNF-α, IL-6 and IL-10) and the proliferation of LPS-stimulated primary macrophages. This dataset suggests that LQB-118 has antinocieptive, antiarthritis and antiproliferative effects, indicating this compound as a promising pharmacological tool for the treatment of arthritis. Our data also suggest that LQB-118 may act as an estrogen receptor antagonist. However, further studies need to be carried out to better investigate its mechanism of action.