Evaluation of antioxidant, photoprotective and antinociceptive activities of Marcetia macrophylla extract: potential for formulation of sunscreens / Avaliação da atividade antioxidante, photoprotetora e antinociceptiva de Marcetia macrophylla: potencial formulação fotoprotetora

Abstract The antioxidant, photoprotective and antinociceptive Marcetia macrophylla active extract was investigated as an active ingredient in a sunscreen cream formulation. Thus, the M. macrophylla extract showed IC50 of 3.43 mg/ml of the antioxidant (DPPH∙ scavenging test) and Sun Protection Factor of 20.25 (SPF/UV-B, at 250 µg/ml) and UV-A of 78.09% (photobleaching trans-resveratrol test). The antinociceptive activity was superior to all standards tested using the in vivo acetic acid-induced writhing test (99.14% at the dose of 200 mg/kg) and the high-performance liquid chromatography coupled with diode array detector and mass spectroscopy multi-stage (HPLC-DAD-MS/MS) enabled the structural characterization of the quercetin-3-O-hexoside, quercetin-3-O-pentoside and quercetin-3-O-desoxihexoside. The pharmaceutical formulation containing the Marcetia macrophylla crude active extract was prepared and the physicochemical tests (organoleptic characteristics, pH analysis and centrifugation), the in vitro UVB (sun protection factor, SPF) and UVA (β-carotene) using the spectroscopic method were investigated. The formulation showed satisfactory results concerning the physicochemical parameters evaluated and active against the UV test. Thus, M. macrophylla showed biological activities with potential use in pharmaceutical preparations.

Resumo O extrato bruto de Marcetia macrophylla mostrou atividade antioxidante, fotoprotetora e antinociceptiva, sendo em seguida investigado como ingrediente ativo em uma formulação fotoprotetora. Assim, o extrato de M. macrophylla apresentou atividade antioxidante com IC50 de 3,43 mg/mL (teste de sequestro do DPPH∙) e Fator de Proteção Solar de 20,25 (FPS/UV-B, 250 µg/mL) e UV-A de 78,09% (teste de fotobranqueamento do trans-resveratrol). A atividade antinociceptiva usando o teste in vivo de contorções abdominais induzidas por ácido acético foi superior a todos os padrões testados (99,14% na dose de 200 mg/Kg). A análise por cromatografia líquida de alta eficiência acoplada a detector de fotodiodos e espectroscopia de massas multi-estágio (CLAE-DAD-EM/EM) possibilitou a caracterização dos flavonoides quercetina-3-O-hexosídeo, quercetina-3-O-pentosídeo e quercetina-3-O-desoxihexosídeo. A formulação farmacêutica contendo o extrato ativo bruto de Marcetia macrophylla foi preparada e os testes físico-químicos (características organolépticas, análise de pH e centrifugação), o UVB in vitro (fator de proteção solar, FPS) e UVA (β-caroteno) foram investigados. A formulação apresentou resultados satisfatórios frente aos parâmetros físico-químicos avaliados e ativos contra UV. Assim, M. macrophylla apresentou atividades biológicas com potencial uso em preparações fitofarmacêuticas.

Antinociceptive and anti-inflammatory activities of Hymenaea martiana Hayne (Fabaceae) in mice / Atividade antinociceptiva e anti-inflamatória de Hymenaea martiana Hayne (Fabaceae) em camundongos

Hymenaea martiana is a species popularly known in Northeastern Brazil as "jatobá" and used in folk medicine to treat pain and inflammation. The aim of this work was to evaluate the antinociceptive and anti-inflammatory activity of H. martiana. In the present study, we carried out an investigation about the effects of the crude ethanolic extract (Hm-EtOH) and the ethyl acetate fraction (Hm-AcOEt) in models of nociception and inflammation in mice. Chemical (acetic acid-induced writhing and formalin) and thermal stimuli (hot plate) were used for the evaluation of antinociceptive activity, while for the anti-inflammatory profile paw edema induced by carrageenan was used, along with leukocyte migration to the peritoneal cavity. The presence of the flavonoid astilbin in the samples was characterized through HPLC-DAD-MS analysis. Hm-EtOH and Hm-AcOEt (100, 200 and 400 mg.kg-1, i.p.) significantly reduced the number of abdominal contortions and decreased the paw licking time in the formalin test. In the hot plate, the extract increased the latency time of animals. Hm-EtOH and Hm-AcOEt inhibited significantly the increase in the edema after the administration of carrageenan. Hm-EtOH and Hm-AcOEt inhibited leukocyte migration in the peritonitis test. HPLC-DAD-MS analysis of Hm-EtOH and Hm-AcOEt revealed the presence of the flavonoid astilbin in the samples. According to the results of this study, both Hm-EtOH and Hm-AcOEt have antinociceptive and anti-inflammatory activities, which could be related with the presence of flavonoid in the extracts. The results reinforce the popular use of this plant.

Hymenaea martiana é uma espécie popularmente conhecida no Nordeste do Brasil como "jatobá" e usada na medicina popular para tratar a dor e a inflamação. O objetivo deste trabalho foi avaliar a atividade antinociceptiva e antiinflamatória de H. martiana. No presente estudo, foram avaliados os efeitos do extrato etanólico bruto (Hm-EtOH) e da fração acetato de etila (Hm-AcOEt) em modelos de nocicepção e inflamação em camundongos. Foram utilizados estímulos químicos (contorções abdominais induzidas por ácido acético e teste da formalina) e estímulo térmico (teste da placa quente) para avaliação da atividade antinociceptiva, enquanto no perfil anti-inflamatório foi utilizado o teste do edema de pata induzido por carragenina e migração de leucócitos para a cavidade peritoneal. A presença do flavonoide astilbina nas amostras foi caracterizada através de análise por CLAE-DAD-EM. Hm-EtOH e o Hm-AcOEt (100, 200 e 400 mg.kg-1, i.p.) reduziram significativamente o número de contorções abdominais e diminuíram o tempo de lambida da pata no teste da formalina. No teste da placa quente, houve aumento do tempo de latência dos animais. Hm-EtOH e Hm-AcOEt inibiram significativamente o aumento do edema após a administração de carragenina, bem como inibiram a migração de leucócitos no teste de peritonite. A análise por CLAE-DAD-EM de Hm-EtOH e Hm-AcOEt revelou a presença do flavonoide astilbina nas amostras. De acordo com os resultados deste estudo, tanto Hm-EtOH quanto o Hm-AcOEt possuem atividades antinociceptiva e anti-inflamatória, o que pode estar relacionado à presença do flavonoide. Os resultados reforçam o uso popular desta planta.

Essential Oil from the Stem Bark of Casuarina equisetifolia Exerts Anti-inflammatory and Anti-nociceptive Activities in Rats

Abstract Herein the chemical constituents and the anti-pain properties of the essential oil from the stem bark of Casuarina equisetifolia L. (Casuarinaceae) grown in Nigeria were evaluated. The essential oil was obtained by hydrodistillation method in an all glass Clevenger-type apparatus, and characterized by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). The hot plate method was used to determine the anti-nociceptive property whereas the anti-inflammatory activity was evaluated by carrageenan-induced and formalin experimental models. The pale-yellow essential oil was obtained in yield of 0.21% (v/w), calculated on a dry weight basis. The main constituents of the essential oil were methyl salicylate (30.4%), a-zingiberene (15.5%), (E)-anethole (9.5%), b-bisabolene (8.6%), b- sesquiphellandrene (6.9%), and ar-curcumene (6.2%). In the anti-nociceptive study, the rate of inhibition increases as the doses of essential oil increases with optimum activity at the 30th and 60th min for all tested doses. The essential oil displayed anti-nociceptive activity independently of reaction time at the highest tested dose (200 mg/kg). The essential oil of C. equisetifolia moderately reduced pain responses in early and late phases of the formalin test. The oil inhibited the paw licking in the neurogenic phase (60-63%) compared to the late phase of the formalin test. The carrageenan- induced oedema model revealed the suppression of inflammatory mediators within the 1st - 3rd h. Thus, C. equisetifolia essential oil displayed both anti-nociceptive and anti-inflammatory activities independent of the dose tested. The anti-inflammatory and anti-nociceptive activities of C. equisetifolia essential oil are herein reported for the first time

Mechanism of emodin in relieving neuropathic pain by regulating serum metabolism / 中国中药杂志

The present study investigated the effect of emodin on the serum metabolite profiles in the chronic constriction injury(CCI) model by non-target metabolomics and explored its analgesic mechanism. Twenty-four Sprague Dawley(SD) rats were randomly divided into a sham group(S), a CCI group(C), and an emodin group(E). The rats in the emodin group were taken emodin via gavage once a day for fifteen days(50 mg·kg~(-1)) on the first day after the CCI surgery. Mechanical withdrawal threshold(MWT) and thermal withdrawal threshold(TWL) in each group were performed before the CCI surgery and 3,7, 11, and 15 days after surgery. After 15 days, blood samples were collected from the abdominal aorta. The differential metabolites were screened out by non-target metabolomics and analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG) and ingenuity pathway analysis(IPA). From the third day after CCI surgery, the MWT and TWL values were reduced significantly in both CCI group and emodin group, compared with the sham group(P<0.01). At 15 days post-surgery, the MWT and TWL values in emodin group increased significantly compared with the CCI group(P<0.05). As revealed by non-target metabolomics, 72 differential serum metabolites were screened out from the C-S comparison, including 41 up-regulated and 31 down-regulated ones, while 26 differential serum metabolites from E-C comparison, including 10 up-regulated and 16 down-regulated ones. KEGG analysis showed that the differential metabolites in E-C comparison were enriched in the signaling pathways, such as sphingolipid metabolism, arginine biosynthesis, glycerophospholipid metabolism, and tryptophan metabolism. IPA showed that the differential metabolites were mainly involved in the lipid metabolism-molecular transport-small molecule biochemistry network. In conclusion, emodin can exert an analgesic role via regulating sphingolipid metabolism and arginine biosynthesis.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2

ABSTRACT Purpose To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. Methods Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine β synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). Results Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. Conclusions Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

Network pharmacological analysis and experimental verification of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium / 中国中药杂志

To explore the mechanism of anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium based on network pharmacology and inflammatory or pain mouse models. The effective components of Zanthoxyli Pericarpium were screened out by TCMSP database. And their potential corresponding targets were predicted by PharmMapper software. The possible targets relating to inflammation and pain were mainly collected through DrugBank, TTD and DisGeNET databases. The "active ingredient-gene-disease" network diagram was constructed by Cytoscape 3.7.0 software. The network pharmacology results showed 5 potential effective compounds, which were related to 29 targets; 132 targets relating to inflammation and pain were screened out in the DrugBank, TTD and DisGeNET databases. The network analysis results indicated that the phosphatidylinositol 3-kinase catalytic subunit gamma isoform(PIK3 CG) gene may be the key to the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium. The anti-inflammatory and analgesic effects of essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium were explored through the mouse model of inflammation induced by xylene or carrageenan and the mouse model of pain induced by acetic acid or formalin. The experimental results showed that essential oil extract and dichloromethane extract of Zanthoxyli Pericarpium could reduce xylene-induced ear swelling and carrageenan-induced paw swelling and decrease the number of writhing responses in mice induced by acetic acid and the licking foot time of mice in phase Ⅱ induced by formalin. Western blot results showed that Zanthoxyli Pericarpium extract could inhibit the expressions of PIK3 CG, phosphonated nuclear factor kappaB(p-NF-κB) and phosphonated p38(p-p38 MAPK) protein. The present study showed the anti-inflammatory and analgesic effect of Zanthoxyli Pericarpium through multiple components and targets, so as to provide a pharmacodynamic basis for the study of Zanthoxyli Pericarpium and its mechanism.

Quantitative Electrophysiological Evaluation of the Analgesic Efficacy of Two Lappaconitine Derivatives: A Window into Antinociceptive Drug Mechanisms / 神经科学通报·英文版

Quantitative evaluation of analgesic efficacy improves understanding of the antinociceptive mechanisms of new analgesics and provides important guidance for their development. Lappaconitine (LA), a potent analgesic drug extracted from the root of natural Aconitum species, has been clinically used for years because of its effective analgesic and non-addictive properties. However, being limited to ethological experiments, previous studies have mainly investigated the analgesic effect of LA at the behavioral level, and the associated antinociceptive mechanisms are still unclear. In this study, electrocorticogram (ECoG) technology was used to investigate the analgesic effects of two homologous derivatives of LA, Lappaconitine hydrobromide (LAH) and Lappaconitine trifluoroacetate (LAF), on Sprague-Dawley rats subjected to nociceptive laser stimuli, and to further explore their antinociceptive mechanisms. We found that both LAH and LAF were effective in reducing pain, as manifested in the remarkable reduction of nocifensive behaviors and laser-evoked potentials (LEPs) amplitudes (N2 and P2 waves, and gamma-band oscillations), and significantly prolonged latencies of the LEP-N2/P2. These changes in LEPs reflect the similar antinociceptive mechanism of LAF and LAH, i.e., inhibition of the fast signaling pathways. In addition, there were no changes in the auditory-evoked potential (AEP-N1 component) before and after LAF or LAH treatment, suggesting that neither drug had a central anesthetic effect. Importantly, compared with LAH, LAF was superior in its effects on the magnitudes of gamma-band oscillations and the resting-state spectra, which may be associated with their differences in the octanol/water partition coefficient, degree of dissociation, toxicity, and glycine receptor regulation. Altogether, jointly applying nociceptive laser stimuli and ECoG recordings in rats, we provide solid neural evidence for the analgesic efficacy and antinociceptive mechanisms of derivatives of LA.

Spinal protein kinase A and phosphorylated extracellular signal-regulated kinase signaling are involved in the antinociceptive effect of phytohormone abscisic acid in rats / A proteína quinase A da medula espinhal e a sinalização da quinase fosforilada regulada por sinal extracelular estão envolvidas no efeito antinociceptivo do ácido fito-hormônio abscísico em ratos

Abstract Objective: The phytohormone abscisic acid (ABA) as a signaling molecule exists in various types of organisms from early multicellular to animal cells and tissues. It has been demonstrated that ABA has an antinociceptive effect in rodents. The present study was designed to assess the possible role of PKA and phosphorylated ERK (p-ERK) on the antinociceptive effects of intrathecal (i.t.) ABA in male Wistar rats. Methods: The animals were cannulated intrathecally and divided into different experimental groups (n=6‒7): Control (no surgery), vehicle (received ABA vehicle), ABA-treated groups (received ABA in doses of 10 or 20 µg/rat), ABA plus H.89 (PKA inhibitor)-treated group which received the inhibitor 15 min prior to the ABA injection. Tail-flick and hot-plate tests were used as acute nociceptive stimulators to assess ABA analgesic effects. p-ERK was evaluated in the dorsal portion of the spinal cord using immunoblotting. Results: Data showed that a microinjection of ABA (10 and 20 µg/rat, i.t.) significantly increased the nociceptive threshold in tail flick and hot plate tests. The application of PKA inhibitor (H.89, 100 nM/rat) significantly inhibited ABA-induced analgesic effects. Expression of p-ERK was significantly decreased in ABA-injected animals, which were not observed in the ABA+H.89-treated group. Conclusions: Overall, i.t. administration of ABA (10 µg/rat) induced analgesia and p-ERK down-expression likely by involving the PKA-dependent mechanism.

Resumo Objetivo: O ácido fito-hormônio abscísico (ABA) existe como molécula sinalizadora em vários tipos de organismos, de multicelulares a células e tecidos animais. Foi demonstrado que o ABA tem efeito antinociceptivo em roedores. O presente estudo foi desenhado para avaliar o possível papel da PKA e da ERK fosforilada (p-ERK) nos efeitos antinociceptivos do ABA intratecal (i.t.) em ratos Wistar machos. Métodos: Os animais foram canulados por via i.t. e divididos em diferentes grupos experimentais (n=6‒7): controle (sem cirurgia), veículo (veículo ABA recebido), grupos tratados com ABA (recebeu ABA em doses de 10 ou 20 µg/rato), grupo tratado com ABA mais H.89 (inibidor de PKA) que recebeu o inibidor 15 minutos antes da injeção de ABA. Os testes de movimento da cauda e placa quente foram utilizados como estimuladores nociceptivos agudos para avaliar os efeitos analgésicos da ABA. A p-ERK foi avaliada na porção dorsal da medula espinhal por imunotransferência. Resultados: A microinjeção de ABA (10 e 20 µg/rato, i.t.) aumentou significativamente o limiar nociceptivo nos testes de movimento da cauda e placa quente. A aplicação de inibidor de PKA (H.89, 100 nM/rato) inibiu significativamente os efeitos analgésicos induzidos por ABA. A expressão de p-ERK diminuiu significativamente em animais injetados com ABA que não foram observados no grupo tratado com ABA+H.89. Conclusões: No geral, a administração i.t. de ABA (10 µg/rato) induziu a analgesia e expressão negativa de p-ERK provavelmente envolvendo mecanismo dependente de PKA.

Anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide in mice

Several isatin derivatives have shown important biological activities, which have attracted interest from researchers. For this reason, the present study aimed to evaluate the anti-inflammatory and antinociceptive effects of the isatin derivative (Z)-2-(5-chloro-2-oxoindolin-3-ylidene)-N-phenyl-hydrazinecarbothioamide (COPHCT) in mice. Three doses of this compound were tested: 1.0, 2.5, and 5.0 mg/kg. The anti-inflammatory activity was assessed using the carrageenan-induced paw edema model and the zymosan-induced air pouch model. The evaluation of the antinociceptive effect was performed through the formalin test and the acetic acid-induced abdominal writhing test. The paw edema assay demonstrated that all doses of the compound showed a significant reduction of the edema in the second hour evaluated, but a better response was observed in the fourth hour. The zymosan-induced air pouch model indicated that the compound, in all doses, significantly reduced leukocyte migration and total protein concentration levels. In the formalin test, the doses 1.0, 2.5, and 5.0 mg/kg of COPHCT showed activity only in the second phase, with reduction in paw pain time of 73.61, 79.46, and 73.85%, respectively. The number of abdominal writhings decreased with the increasing dose, but only 5.0 mg/kg COPHCT exhibited a significant response, with a reduction of 24.88%. These results demonstrated the ability of this compound to interfere in the anti-inflammatory activity of edema, vascular permeability, and cell migration. In addition, its possible antinociceptive effect may be related to the dose used.

Phytochemical and morpho-anatomical study of the vegetative organs of Psychotria fractistipula L. B.Sm., R.M. Klein & Delprete (Rubiaceae)

Psychotria fractistipula L.B.Sm, R.M. Klein & Delprete (Rubiaceae) is found in the existing Atlantic Forest in the South of Brazil, in the Paraná and Santa Catarina States. The members of Rubiaceae are characterized chemically by the presence of alkaloids, some pharmacological properties of which include antifungal, antibacterial, analgesic, antioxidant, antimutagenic, and antiviral activities. In this study, we report the results of anatomical, morphological, and histochemical analyses of the leaves and stems of the Rubiaceae family member, P. fractistipula. The anatomical analysis involved of light microscopy and scanning electron microscopy. Morpho-anatomical and histochemical characterization were made using standard methodology. The isolated compounds were identified by Nuclear Magnetic Resonance spectroscopic analysis. The following structures are highlighted as the distinctive features of the species: presence of petiolate leaves and a petiole base, leaf blade with smooth cuticle on both surfaces, paracytic stomata, and, dorsiventral mesophyll and presence of trichomes on the leaves and stems. Phytosteroids, identified as β-sitosterol and campesterol, were observed in the hexane fraction of the stem. Future studies should focus on the isolation of other fractions of interest and their characterization through specific biological and cytotoxicity assays.

Investigation of New Benzimidazole Derivative Compounds Effects on A549 Cell Line

Abstract Chronic inflammation is a common indication of several diseases, e.g. asthma, chronic obstructive pulmonary disease (COPD), atherosclerosis, etc. Benzimidazole derivatives are preferable compounds to design new analgesic and anti-inflammatory substances due to their unique biological features. We aimed to investigate the effect of a newly synthesized benzimidazole derivative, ORT-83, on A549 human lung adenocarcinoma cell line. ORT-83 was synthesized, and a non-cytotoxic concentration of ORT-83 on A549 cells was detected with MTT assay. To analyze the anti-inflammatory effect of ORT-83, an inflammatory cell culture model was established by stimulating A549 cell line with IL1-β (10 ng/ml). After 2 hours of treatment with IL1-β to induce inflammation, A549 cells were exposed to ORT-83 (0.78 µg/ml) for 24 hours. Thereafter gene expression analyses were performed with qRT-PCR. We found that ORT-83 significantly suppressed the gene expression levels of the proinflammatory cytokines; IL-6, NFkB, and TNF-α. However, the increased levels of IL-10 (2.8 folds) by IL-1β induction did not change after ORT-83 and/or dexamethasone (Dex: positive control) treatments. While Dex; a COX-2 inhibitor, reduced the COX-2 expression level in inflammatory cells from 10.03 folds to 0.71 folds, ORT-83 reduced its level to 4.37 folds. iNOS expression levels did not change in any experimental groups. In conclusion, we showed that ORT-83 exerted its anti-inflammatory effects by repressing the gene expression of proinflammatory cytokines in the inflammation-induced A549 cell line. Although ORT-83 had a weaker COX-2 inhibitory effect compared to Dex, it was shown to be still a strong anti-inflammatory compound.

Calcitonin as an analgesic agent: review of mechanisms of action and clinical applications / Calcitonina como agente analgésico: revisão dos mecanismos de ação e das aplicações clínicas

Abstract Background and objectives: Calcitonin is a polypeptide hormone regulating the metabolism of calcium in the body. For many years calcitonin has been used to maintain and improve bone mineral density and to reduce the fracture rate. Many studies showed that calcitonin had analgesic role in several painful circumstances. This pain-ameliorating effect is irrelevant to its osteoclastic inhibitory effect and mechanisms like altering Na+ channel and serotonin receptor expression or hypothesis including the endorphin-mediated mechanism were used to explain this effect. In this study we performed a thorough review on the role of calcitonin as an analgesic agent in different scenarios and investigated the fact that calcitonin can be a feasible medication to relieve pain. Method: Many studies focused on the analgesic effect of calcitonin in several painful circumstances, including acute pains related to vertebral fractures, metastasis, migraine and reflex sympathetic dystrophy as well as neuropathic pains related to spinal injuries or diabetes, and phantom pain. Also, calcitonin was showed to be a useful additive to local anesthesia in the case of controlling postoperative pain or trigeminal neuralgia more effectively. However we faced some contradictory data for conditions like lumbar canal stenosis, complex regional pain syndrome, phantom pain and malignancies. Conclusion: This study showed that calcitonin could be helpful analgesic agent in different painful situations. Calcitonin can be considered an eligible treatment for acute pains related to vertebral fractures and a feasible alternative for the treatment of the acute and chronic neuropathic pains where other medications might fail.

Resumo Justificativa e objetivos: A calcitonina é um hormônio polipeptídico que regula o metabolismo do cálcio no organismo. Por muitos anos a calcitonina tem sido usada para manter e melhorar a densidade mineral óssea e reduzir a incidência de fraturas. Muitos estudos mostraram que a calcitonina teve efeito analgésico em várias condições físicas de dor. Esse efeito de melhoria da dor é irrelevante diante de seu efeito inibidor osteoclástico e de mecanismos, tais como a alteração do canal de Na+ e da expressão do receptor de serotonina, inclusive a hipótese do mecanismo mediado pela endorfina, que foram usados para explicar esse efeito. Neste estudo, fizemos uma revisão completa sobre o papel da calcitonina como agente analgésico em diferentes cenários e investigamos o fato de que a calcitonina pode ser uma medicação viável para aliviar a dor. Método: Muitos estudos centraram no efeito analgésico da calcitonina em várias condições de dor, inclusive dores agudas relacionadas a fraturas vertebrais, metástases, enxaqueca e distrofia simpática reflexa, bem como dores neuropáticas relacionadas a lesões medulares ou ao diabetes e dor fantasma. Além disso, a calcitonina mostrou ser um aditivo útil à anestesia local para o controle mais efecaz da dor pós-operatória ou neuralgia do trigêmeo. Porém, nos deparamos com alguns dados contraditórios em condições como estenose do canal lombar, síndrome complexa da dor regional, dor fantasma e malignidades. Conclusão: Este estudo mostrou que a calcitonina pode ser um analgésico útil em diferentes condições de dor. A calcitonina pode ser considerada um tratamento elegível para as dores agudas relacionadas a fraturas vertebrais e uma opção viável para o tratamento das dores neuropáticas agudas e crônicas em que outros medicamentos podem falhar.

Anti-inflammatory and anti-nociceptive activities of essential oil of Waltheria indica / Actividades antiinflamatorias y nociceptivas del aceite esencial de Waltheria indica

This paper reports for the first time volatile compounds, anti-nociceptive and anti-inflammatory activities of essential oils from the leaves of Waltheria indica L. (Stericullaceae) growing in Nigeria. The essential oil was hydro-distilled and characterized by gas chromatography-flame ionization detection (GC-FID) and gas chromatography coupled with mass spectrometry (GC-MS) analyses. The anti-inflammatory activity was evaluated on carrageenan induced rat paw edema while the anti-nociceptive test was based on hot plate model. The hydro-distillation afforded 0.41% (dry weight basis) of light green oil. Forty compounds representing 99.8% were identified in the oil. The main constituents of the oil were limonene (34.7%), sabinene (21.2%) and citronellal (9.7%). The anti-nociceptive property of the essential oils statically inhibited edema development (p<0.001) at a dose of 200 and 400 mg/kg independent of time of exposure. However, the 100 mg/kg Waltheria indica essential oils (WIEO) displayed a relatively low inhibition (p<0.01-p>0.5) which declines as exposure time increases. The anti-inflammatory activities shows a steady rate and non-dose dependent activity (p<0.001) up to the 3rd h of inflammation study. Conversely, a sharp reduction at the rate of p<0.5, 0.1 and 0.01 for the 100, 200 and 400 mg/kg WIEO doses respectively. Overall, the results presented sustain and establish the anti-nociceptive and anti-inflammatory properties and justifies the need for further evaluation and development of the essential oils from this plant.

Este artículo informa por primera vez de compuestos volátiles, actividades anti-nociceptivas y antiinflamatorias de aceites esenciales de las hojas de Waltheria indica L. (Stericullaceae) que crecen en Nigeria. El aceite esencial fue hidro-destilado y se caracterizó por cromatografía de gases-detección de ionización de llama (GC-FID) y cromatografía de gases junto con análisis de espectrometría de masas (GC-MS). La actividad antiinflamatoria se evaluó en el edema de pata de rata inducido por carragenano, mientras que la prueba antinociceptiva se basó en el modelo de placa caliente. La destilación hidráulica proporcionó 0,41% (en peso seco) de aceite verde claro. Cuarenta compuestos que representan el 99.8% fueron identificados en el aceite. Los principales componentes del aceite fueron el limoneno (34,7%), el sabineno (21,2%) y el citronelal (9,7%). La propiedad anti-nociceptiva de los aceites esenciales inhibió estáticamente el desarrollo del edema (p<0.001) a una dosis de 200 y 400 mg/kg independientemente del tiempo de exposición. Sin embargo, los aceites esenciales de Waltheria indica de 100 mg/kg (WIEO) mostraron una inhibición relativamente baja (p<0.01-p>0.5) que disminuye a medida que aumenta el tiempo de exposición. Las actividades antiinflamatorias muestran una tasa constante y una actividad no dependiente de la dosis (p<0.001) hasta la tercera hora del estudio de inflamación. Por el contrario, una fuerte reducción a una tasa de p<0.5, 0.1 y 0.01 para las dosis de 100, 200 y 400 mg/kg de WIEO respectivamente. En general, los resultados presentados sostienen y establecen las propiedades anti-nociceptivas y antiinflamatorias y justifican la necesidad de una mayor evaluación y desarrollo de los aceites esenciales de esta planta.

Basil, tea tree and clove essential oils as analgesics and anaesthetics in Amphiprion clarkii (Bennett, 1830) / Óleos essenciais de manjericão, melaleuca e cravo como anestésicos e analgésicos em Amphiprion clarkii (Bennett, 1830)

Abstract In this study were evaluated the anaesthesia and analgesic effects of clove Eugenia caryophyllata, tea tree Melaleuca alternifolia and basil Ocimum basilicum essential oils (EO) during handling of yellowtail clownfish Amphiprion clarkii. Juveniles (3.70 ± 0.75 cm and 1.03 ± 0.50 g; mean ± standard deviation) were submitted to concentrations of 40, 50, 60, 70 and 80 µl L-1 of clove, 150, 200, 250, 300 and 350 µl L-1 of basil and 200, 300, 400, 500 and 600 µl L-1 of tea tree oils (n=10/concentration), previously defined in pilot tests. Individually and only once, fish from each treatment were placed in a glass recipient containing 1 L of seawater at a temperature of 25 °C, salinity of 35 g L-1 and the specific concentration of diluted EO (stock solution). Control (only seawater) and blank (seawater and ethanol at the highest concentration used to dilute the oils) treatments were also conducted. After reaching the stage of surgical anaesthesia, fish were submitted to biometry and a sensibility test. After that, they were transferred to clean seawater for anaesthesia recovery. The times of induction needed to reach each anaesthesia stage and anaesthesia recovery were recorded. Animals were observed for 72 hours after the procedures. All the EO provoked anaesthesia and analgesic effects in A. clarkii, but basil oil is not recommended because it caused involuntary muscle contractions and mortality in 100% and 12% of fish, respectively. The lower concentrations that promote suitable induction and recovery times are 50 µl L-1 of clove oil and 500 µl L-1 of tea tree oil. However, due to its complementary high analgesic efficiency, clove oil is recommended as the ideal anaesthetic for A. clarkii.

Resumo Neste estudo foram avaliados os efeitos anestésicos e analgésicos dos óleos essenciais (OE) de cravo Eugenia caryophyllata, melaleuca Melaleuca alternifolia e manjericão Ocimum basilicum durante manejo de peixes-palhaços Amphiprion clarkii. Juvenis (3.70 ± 0.75 cm e 1.03 ± 0.50 g; média ± desvio padrão) foram submetidos às concentrações de 40, 50, 60, 70 e 80 µl L-1 de cravo, 150, 200, 250, 300 e 350 µl L-1 de manjericão e 200, 300, 400, 500 e 600 µl L-1 de melaleuca (n=10/concentração), previamente definidas em testes pilotos. Individualmente e somente uma vez, os peixes de cada tratamento foram colocados em recipiente de vidro contendo 1 L de água salgada, em temperatura de 25 °C, salinidade de 35 g L-1 e a concentração específica de OE diluída (solução estoque). Tratamentos controle (apenas água marinha) e branco (água marinha e a maior concentração de etanol utilizada para diluição dos óleos) também foram conduzidos. Após atingirem o estágio de anestesia cirúrgica, os peixes foram submetidos à biometria e teste de sensibilidade. Em seguida, foram transferidos para água marinha limpa. Os tempos necessários para atingir cada estágio anestésico e recuperação foram registrados. Os animais foram observados por 72 horas após os procedimentos. Todos os OE provocaram anestesia e analgesia em A. clarkii, porém o óleo de manjericão não é recomendado, pois causou contrações musculares involuntárias e mortalidade em 100% e 12% dos animais, respectivamente. As menores concentrações que promovem indução anestésica e recuperação em tempos adequados são 50 µl L-1 de óleo de cravo e 500 µl L-1 de óleo de melaleuca. Entretanto, devido à sua alta eficiência analgésica complementar, o óleo de cravo é recomendado como o anestésico ideal para A. clarkii.

Efecto analgésico, caracterización fitoquímica y análisis toxicológico del extracto etanólico de hojas de pereskia lychnidiflora / Analgesic effect, phytochemical characterization and toxicological analysis of ethanolic extract of pereskia lychnidiflora leaves

RESUMEN Objetivo Evaluar el efecto analgésico del extracto etanólico de las hojas de Pereskia lychnidiflora, la prospección de metabolitos secundarios y el análisis toxicológico. Materiales y métodos La actividad analgésica fue evaluada mediante la prueba del ácido acético y la formalina en ratones NIH a una concentración de 30, 50 y 100 mg/kg de peso corporal, utilizando como control Ibuprofeno a 200 mg/kg y agua destilada como blanco. La prospección de metabolitos secundarios se realizó por el método de cromatografía de capa fina y la toxicidad del extracto fue evaluada in vivo según la dosis máxima de 2000 mg/kg de peso corporal. Resultados La prospección fitoquímica determinó la presencia de alcaloides, taninos, triterpenos y esteroles como mayores constituyentes químicos. Se determinó que el extracto etanólico de Pereskia lychnidiflora posee una actividad analgésica similar al Ibuprofeno. No se observaron signos de toxicidad en los ratones de experimentación y se clasifica el extracto como no tóxico con una DL50 mayor de 2000 mg/kg. Conclusión El extracto etanólico de Pereskia lychnidiflora tiene un efecto analgésico antiinflamatorio que podría estar condicionado por la presencia de alcaloides, taninos y esteroles (terpenoides) presentes en esta especie vegetal y puede ser clasificado como no tóxico.

ABSTRACT Objective To evaluate the analgesic effect of the ethanolic extract of the leaves of Pereskia lychnidiflora, the prospection of secondary metabolites and the toxicologic analysis. Materials and Methods Analgesic activity was evaluated by testing acetic acid and formalin in NIH mice at a concentration of 30, 50 and 100 mg/kg body weight, using Ibuprofen control at 200 mg/kg and distilled water as the target. Secondary metabolites were prospected using the thin layer chromatography method and the toxicity of the extract was evaluated in vivo according to the maximum dose of 2,000 mg/kg body weight. Results Phytochemical prospecting determined the presence of alkaloids, tannins, triterpenes, and sterols as major chemical constituents. The ethanolic extract of Pereskia lychnidiflora was found to have an analgesic activity similar to ibuprofen. No signs of toxicity were observed in the experimental mice and the extract is classified as non-toxic with a DL50 greater than 2,000 mg/kg. Conclusions The ethanolic extract of Pereskia lychnidiflora has an anti- inflammatory analgesic effect that could be conditioned by the presence of alkaloids, tannins, and sterols (terpenoids) present in this species and can be classified as non-toxic.

Polygala anatolica Boiss. et Heldr.: is a potential remedy for inflammation and pain? / Polygala anatolica Boiss. et Heldr.: ¿es un remedio potencial para la inflamación y el dolor?

Species of Polygala genus have been used for the treatment of inflamation and pain in Turkish traditional medicine. The aim of the present study is to assess the anti-inflammatory and analgesic activities of P. anatolica. n-Hexane, ethyl acetate and methanol extracts of the aerial parts and roots of P. anatolica were investigated for their anti-inflammatory and analgesic effects. The methanol extracts prepared from the aerial parts and roots of P. anatolica were found to be active in carrageenan- and PGE2-induced paw edema models and in Whittle method. Methanolic extract of the aerial part inhibited serotonin-induced hind paw edema, while the root extract did not exert inhibitory effect in the same model. In addition, Fr. B and C obtained from the methanol extract of P. anatolica aerial parts showed significant anti- inflammatory activity. Morover, the analgesic effect of the methanol extracts prepared from the roots and aerial parts and Fr.B and Fr.C were found to be statistically significant without inducing ulceration. The methanol extract obtained from the aerial parts of the plant and its saponoside and flavonoid fractions showed anti-inflammatory and analgesic activities in the trials.

Las especies del género Polygala se han utilizado para el tratamiento de la inflamación y el dolor en la medicina tradicional turca. El objetivo del presente estudio es evaluar las actividades antiinflamatorias y analgésicas de P. anatolica. Se investigaron los extractos de n-hexano, acetato de etilo y metanol de las partes aéreas y raíces de P. anatolica por sus efectos antiinflamatorios y analgésicos. Los extractos de metanol preparados a partir de las partes aéreas y raíces de P. anatolica se encontraron activos en modelos de edema de pata inducidos por carragenina y PGE2 por el método de Whittle. El extracto metanólico de la parte aérea inhibió el edema de la pata trasera inducido por serotonina, mientras que el extracto de raíz no ejerció un efecto inhibidor en el mismo modelo. En suma, la fracción B y C obtenidos a partir del extracto metanólico de partes aéreas de P. anatolica mostraron actividad antiinflamatoria significativa. Además, el efecto analgésico de los extractos de metanol preparados a partir de las raíces y las partes aéreas y la fracción B y C resultaron ser estadísticamente significativas sin inducir la ulceración. El extracto de metanol obtenido de las partes aéreas de la planta y sus fracciones de saponósidos y flavonoides mostraron actividades antiinflamatorias y analgésicas en los ensayos.

Essential oil of Pterodon polygalaeflorus Benth attenuates nociception in mice

Essential oils (EO) are volatile liquids responsible for the aroma of plants. Pterodon polygalaeflorus seeds have received widespread use in folk medicine for the treatment of inflammatory diseases. For this reason and because Pterodon polygalaeflorus seeds have great EO content, which is frequently pharmacologically active, the present study aimed to evaluate the antinociceptive effect of EO from Pterodon polygalaeflorus (EOPPgfl) and its acute toxic effects. The EEOPPgfl sample, which was extracted by steam distillation of the seeds, had a yield of 2.4% of the seeds weight and had, as major constituents, beta-elemene (48.19%), trans-caryophyllene (19.51%), and epi-bicyclosesquiphellandrene (12.24%). The EOPPgfl sample showed mild acute toxicity and its calculated median lethal dose (LD50) was 3.38 g/kg. EOPPgfl (20-60 mg/kg) showed antinociceptive activity as evidenced by several tests and inhibited writhing induced by acetic acid. The maximum effect was obtained with the 30 mg/kg dose and at 60 min after its administration. EOPPgfl also decreased formalin-induced nociception, as verified by the inhibition of the first and second phase of the formalin test. At 30 mg/kg, EOPPgfl also decreased thermally stimulated nociception. Nociception may be related to inflammatory and antiedematogenic activity and at doses ranging 10-100 mg/kg, EOPPgfl blocked dextran- and carrageenan-induced edema. The results demonstrated that EOPPgfl presented, at doses approximately 100 times smaller than LD50, an antinociceptive effect that probably was due to anti-inflammatory activities.

Analgesic effects of Marasmius androsaceus mycelia ethanol extract and possible mechanisms in mice

Marasmius androsaceus is a medicinal fungus mainly used to treat various forms of pain in China. This study investigated the analgesic effects of an ethanol extract of M. androsaceus (MAE) and its potential molecular mechanisms. Oral administration of MAE (50, 200, and 1000 mg/kg) had significant analgesic effects in an acid-induced writhing test, a formalin test, and a hot-plate test, with effectiveness similar to tramadol (the positive control drug). The autonomic activity test showed that MAE had no harmful effects on the central nervous system in mice. MAE resulted in significantly enhanced levels of noradrenalin and 5-hydroxytryptamine in serum but suppressed both of these neurotransmitters in the hypothalamus after 30 s of hot-plate stimulation. Co-administration with nimodipine (10 mg/kg; a Ca2+ channel blocker) strongly enhanced the analgesic effect in the hot-plate test compared to MAE alone. Moreover, MAE down-regulated the expression of calmodulin-dependent protein kinase II (CaMKII) in the hypothalamus after a 30-s thermal stimulus. These results suggested that the analgesic ability of MAE is related to the regulation of metabolism by monoamine neurotransmitters and Ca2+/CaMKII-mediated signaling, which can potentially aid the development of peripheral neuropathic pain treatments obtained from M. androsaceus.

Manejo farmacológico del dolor en la odontología actual / Pharmacological management of pain in today´s dentistry

Una de las principales preocupaciones de los pacientes que van a ser sometidos a un procedimiento odontológico es el dolor que dicho procedimiento pueda ocasionar. Por lotanto, lograr un control eficaz y seguro de ese dolor es una parte esencial de la práctica odontológica diaria. Los fármacos de primera elección para el tratamiento del dolor y el edemason, sin lugar a dudas, los antiinflamatorios no esteroideos(AINEs). Principios activos como el ibuprofeno (y sus congéneres) o sus derivados permiten controlar simultáneamente el dolor y el edema posquirúrgicos de una forma eficaz y segura. En muchas ocasiones, el AINE prescrito para mantener al paciente asintomático o con síntomas tolerables es suficiente. Sin embargo, cuando esto no ocurre, debemos recurrir a otrosfármacos, o realizar asociaciones con fármacos que complementen el efecto analgésico y trabajen logrando un sinergismo de potenciación que incremente el efecto buscado y disminuya los efectos adversos de cada una de las sustancias por separado, utilizando menores dosis. Un ejemplo comprobado de esas asociaciones es la de ibuprofeno con paracetamol. En el presente artículo se sugieren diversas estrategias pre- y posoperatorias para el manejo del dolor de origen inflamatorio, y un protocolo para su tratamiento.