Atividades do RI75, um análogo da curcumina, em modelo de neuropatia induzida por quimioterápico.

Abstract

The management of chemotherapy-induced neuropathic pain (CIPN) is still challenging due to the lack of drugs that effectively prevent or alleviate this condition. Modifying the chemical structure of substances with therapeutic potential represents a promising strategy in the development of new drugs. Curcumin, a natural polyphenol abundant in the rhizome of Curcuma longa, is used in traditional medicine due to its therapeutic properties, especially the anti-inflammatory one. Due to the low bioavailability of curcumin, analogues have been synthesized in an attempt to obtain improvements in biopharmaceutical characteristics and increase biological effects. Preclinical trials have demonstrated that curcumin and its analogues exhibit activities in different pain models. In the present study, we evaluated the effect of RI75, a thiazolyl hydrazone analogue of curcumin, in a murine model of neuropathic pain induced by repeated administrations of paclitaxel and investigated possible mechanisms that mediate this effect. Intraperitoneal (i.p.) administration of RI75 (20 and 40 mg/kg) reduced paclitaxel induced mechanical allodynia. This activity was attenuated by prior administration of AM251 (4 and 8 mg/kg, i.p.), naltrexone (5 and 10 mg/kg, i.p.) or cyproheptadine (5 or 10 mg/kg, i.p.), but not glibenclamide (20 or 40 mg/kg, per os). RI75 (40 mg/kg) reduced the concentrations of tumor necrosis factor (TNF-α) and CXCL-1 in the sciatic nerve, dorsal root ganglia and thalamus and attenuated the histological changes of the sciatic nerve induced by paclitaxel. In RAW 264.7 cells stimulated by lipopolysaccharide, RI75 reduced the concentrations of TNFα and interleukin-1β (IL-1β). In a model with Artemia salina L., RI75 did not induce toxicity. In the preliminary assessment of systemic toxicity in mice, RI75 (40 or 80 mg/kg, i.p.) did not induce significant hematological or biochemical changes. In an in vitro assay, RI75 exhibited marked antioxidant activity. In conclusion, the results demonstrate that RI75, a curcumin analogue, exhibits antinociceptive activity in a model of neuropathic pain induced by paclitaxel. The activity of RI75 is probably associated with the activation of cannabinoidergic, opioidergic and serotonergic mechanisms and the reduction of pro-inflammatory cytokines, as well as neuroprotective and antioxidant activities.