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Palicourea rigida Kunth is traditionally used for the treatment of skin diseases, kidney pains and ovarian inflammation. Based on these traditional uses, this study evaluated the topical anti-inflammatory activity of the ethanol extract from P. rigida leaves (EEPR) and identified bioactive compounds. Ear edema was induced in Swiss mice by the topical application of Croton oil, arachidonic acid, phenol and capsaicin. Histopathological analysis and myeloperoxidase and N-acetyl-β-D-glucosaminidase activities were determined. EEPR was characterized by UHPLC-UV-MS HPLC and the isolated compound was identified through H andC nuclear magnetic resonance and mass fragmentation. Interaction profiles between quercetin 3-O-β-D-glucoside and cyclooxygenase-1 and -2 were established by molecular docking. EEPR significantly inhibited ear edema induced by Croton oil (p < 0.001), arachidonic acid (p < 0.01), phenol (p < 0.001) and capsaicin (p < 0.01 or p < 0.001). Histopathological analysis showed a reduction of edema, inflammatory cell infiltration and vasodilation. Additionally, the myeloperoxidase and N-acetyl-β-D-glucosaminidase activities were decreased (p < 0.001). From spectroscopic data, quercetin 3-O-β-D-glucoside was the identified compound. This compound can to interact with cyclooxygenase-1 and -2 through van der Waals interactions and dipole-dipole and hydrogen bonding's, demonstrating inhibition of these enzymes. The results indicate that EEPR is a source of active compounds with topical anti-inflammatory activity, justifying the traditional use of P. rigida and showing that this species has a therapeutic potential to treat skin inflammatory processes.

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Palicourea rigida Kunth (Rubiaceae), also called "bate-caixa" or "douradão", has been used as antihypertensive, antiulcerogenic, anti-inflammatory and analgesic by traditional communities. Pharmacological potential of the ethanol extract from P. rigida (EEPR) and two quercetin derivatives were investigated. Using the high performance liquid chromatography (HPLC) assay, EEPR was analyzed. Phenolic contents (total phenolic and flavonoids) were quantified by spectrophotometric methods. 2,2-diphenyl-1-pycrilhydrazil (DPPH), iron reducing power and β-carotene/linoleic acid bleaching tests were applied to estimate the antoxidant capacity of EEPR. Nociception (acetic acidinduced writhing, formalin and hot plate) and inflammation (carrageenan-induced paw edema and pleurisy) assays were performed. Molecular docking was used to measure the interactions' profiles of ligands (rutin and quercetin) and cyclooxigenases (COX-1 and COX-2). HPLC analysis identified rutin and quercetin derivatives. Expressive levels of total phenolic and flavonoids and a promising antioxidant effect were measured. EEPR, rutin and quercetin reduced the abdominal contortions. EEPR was effective against both phases of formalin, while rutin and quercetin inhibited the second phase. The latency time on hot plate significantly increased after treatment with EEPR. Inflammatory parameters (paw edema, exudate volume and leukocyte infiltrate) were diminished by EEPR, rutin and quercetin. The molecular docking showed that rutin and quercetin are capable of complexing with COX-1 and COX-2 favorably through physical-chemical interactions. The results suggest that EEPR showed a relevant pharmacological potential, which may be related to action of rutin and quercetin derivatives.Key words: Palicourea rigida, rutin, quercetin, antioxidant, antinociception, inflammation. INTRODUCTIONIn the body, the imbalance between oxidant/antioxidant in favor of the oxidation promotes the oxidative stress that causes proteins, lipids and DNA damages, as well as induces a variety of cellular responses through the generation of reactive oxygen species (ROS) that may be originated from cellular metabolism or environmental sources (Nita and Grzybowski, 2016). ROS have become a concern among researchers because they have been associated with a significant number of diseases involving inflammatory and painful processes that affect humans and animals. In inflammation, for example, ROS cause vascular damage which allows the permeability of macromolecules and inflammatory cells from the blood to tissue (Mittal et al., 2014). This permeability is controlled by vasoactive and chemotactic mediators, which make the inflammatory process active, including the pain (Silva, 2015). Among the mediators that regulate the events of inflammation, vasoactive amines, lipid-derived eicosanoids, cytokines, chemokines and adhesion molecules have been highlighted (Silva, 2015). On the other hand, the inflammatory pain has been treated with non-steroidal anti-inflammatory agents, but present high prevalenc...

Study design and experimental tools are crucial for good quality science, and an important part of it is the choice of control groups to best test the hypothesis. Two of the most common control groups in research are needle prickling without substance injection (Sham) and/or vehicle injection (Saline). Very few studies investigated the behavioral effects of a single intraperitoneal (i.p) Sham and/or single i.p. Saline administration in mice, mostly using adult males. In this study, we investigated if a single i.p. Sham and/or i.p. Saline administration affects female and male prepubertal (4-weeks-old) mice behavior. After Sham or Saline injection, we examined exploratory/motor behavior (open field test; OFT), anxiety-like behavior (elevated plus-maze; EPM), and behavioral despair/depressive-like behavior (forced swimming test; FST). We observed that both Sham prepubertal females and males showed minor behavioral alterations in OFT and EPM, and Saline males showed behavioral alterations in OFT and FST. On the other hand, prepubertal Saline females showed an increase in exploratory behavior, risk assessment/anxiety-like behavior, and behavioral despair/depressive-like behavior. Thus, we observed that the experimental procedures used as control have mild (but not insignificant) consequences in prepubescent mice behavior. However, the consequences of control protocols in prepubescent females are stronger than in males. To the best of our knowledge, this is the first study investigating the consequences of Sham and Saline protocols in prepubertal mice. This study highlights how important is to include Naive animals (Negative control) together with Sham and/or Vehicle for a better and more honest interpretation of the data.