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Erik Walum - One of the best experts on this subject based on the ideXlab platform.

  • Polygodial induced noradrenaline release in human neuroblastoma sh sy5y cells
    Toxicology in Vitro, 1997
    Co-Authors: M I Andres, A Forsby, Erik Walum
    Abstract:

    Polygodial is a natural sesquiterpene which exhibits pronounced pungency and a powerful antifeedant activity. At low concentrations, which do not alter general cell membrane permeability, Polygodial increases the intracellular concentration of free calcium ([Ca(2+)](i)). Sensory neurotransmission depends on noradrenaline (NA) release, and vesicular exocytosis, in turn, is dependent on an increase in [Ca(2+)](i). The nociceptive response induced by Polygodial could therefore be directly linked to intracellular calcium levels. Consequently, the objective of this work was to investigate the effect of Polygodial on NA release. The human neuroblastoma cell line SH-SY5Y was selected as an in vitro model for sensory neurones. Semiconfluent cells were preloaded with tritiated NA ([(3)H]NA). After 3 min exposure of Polygodial to the cells, released and unreleased radioactivity were measured. Polygodial induced a significant [(3)H]NA release at concentrations between 0.1 and 0.5 mug/ml with a maximum effect at 0.2 mug/ml (40% increased release of [(3)H]NA as compared with unstimulated control cells). No Polygodial-induced transmitter release was seen at 3.5 and 5 mug/ml. For comparison, carbachol (1 rim) increased [(3)H]NA release by 10% and the KCl-induced (100 mm) [(3)H]NA release increased by 8% as compared with unstimulated SH-SY5Y cells. In conclusion Polygodial, at the concentrations 0.1-0.5 mug/ml (equal to 0.4-2 mum), induces NA release which is dependent on Polygodial-induced increase in [Ca(2+)](i).

  • Polygodial induces inositol phosphate turnover in human neuroblastoma sh sy5y cells
    Neuroscience Letters, 1996
    Co-Authors: A Forsby, Erik Walum
    Abstract:

    The pungent sesquiterpenoid unsaturated dialdehydes Polygodial and isovelleral, have previously been shown to increase the intracellular free calcium concentration [Ca2+]i in human neuroblastoma SH-SY5Y cells, partly by a release from intracellular Ca2+ stores, whereas the non-pungent compound epiPolygodial, had no effect on the [Ca2+]i. In this study, we investigated the effect of isovelleral, Polygodial and epiPolygodial on inositol phosphate (IP) formation on the assumption that there might be a correlation between the release of intracellular Ca2+ and pungency of the compounds. It was found that Polygodial induced IP mobilization in a concentration dependent way, whereas isovelleral had no effect on the IP formation in the SH-SY5Y cells. Phosphoinositide (PPI) turnover was activated by epiPolygodial, but only at concentrations 40-fold higher than for Polygodial, which emphasizes the importance of the correct stereometry in the dialdehyde configuration for the biological activity of Polygodial. The Polygodial-induced formation of IP1 was reduced by 71% under extracellular calcium-free conditions, which suggests feedback interactions between the IP formation and the increase in [Ca2+]i to account for a periodic activation of phospholipase C(PLC).

Joao B Calixto - One of the best experts on this subject based on the ideXlab platform.

  • the sesquiterpenes Polygodial and drimanial in vitro affect glutamatergic transport in rat brain
    Neurochemical Research, 2006
    Co-Authors: Lucia Helena Martini, Rosendo A. Yunes, Joao B Calixto, Lucas Dos Santos Cereser, Isaac Zanonato, Fluvia Melina Alves Jardim, Deusa Vendite, Marcos Emilio Dos Santos Frizzo, Susana Tchernin Wofchuk, Diogo O Souza
    Abstract:

    Natural products including those derived from plants, have over the years greatly contributed to the development of therapeutic drugs. Polygodial and drimanial are sesquiterpenes isolated from the bark of the plant Drymis Winteri (Winteraceae) that exhibit antinociceptive properties. Since peripheral glutamate presents nociceptive actions, in this study it was investigated the effects of hydroalcooholic extracts from Drymis winteri (Polygodial and drimanial) on the glutamatergic system in rat brain. Polygodial and drimanial inhibited glutamate uptake by astrocytes, as well as by cortical, hippocampal and striatal slices, and increased synaptosomal glutamate release. These concurrent effects would predispose to an increase in the extracellular glutamate concentrations, leading to possible neurotoxic effects (excitotoxicity) of these natural compounds, which would suggest the need for some caution in their therapeutic application.

  • pharmacological characterisation of the plant sesquiterpenes Polygodial and drimanial as vanilloid receptor agonists
    Biochemical Pharmacology, 2006
    Co-Authors: Eunice Andre, Angela Malheiros, Rosendo A. Yunes, Joao B Calixto, Barbara Campi, Marcello Trevisani, Juliano Ferreira, Pierangelo Geppetti
    Abstract:

    This study was designed to assess the participation of transient receptor potential vanilloid 1 (TRPV1) in the biological effects induced by the plant-derived sesquiterpenes Polygodial and drimanial. In rat isolated urinary bladder, Polygodial and drimanial produced a tachykinin-mediated contraction that was inhibited by combination of NK(1) and NK(2) tachykinin receptor antagonists, SR 140333 and SR 48968. Furthermore, two different TRPV1 antagonists, capsazepine and ruthenium red prevented the contraction induced by both compounds. In addition, capsaicin, Polygodial and drimanial displaced in a concentration-dependent manner the specific binding sites of [(3)H]-resiniferatoxin to rat spinal cord membranes, with a IC(50) values of 0.48, 4.2 and 3.2 microM, respectively. Likewise, capsaicin, Polygodial and drimanial promoted an increase of [(45)Ca(2+)] uptake in rat spinal cord synaptosomes. In cultured rat trigeminal neurons, Polygodial, drimanial and capsaicin were also able to significantly increase the intracellular Ca(2+) levels, effect that was significantly prevented by capsazepine. Together, the present results strongly suggest that the pharmacological actions of plant-derived sesquiterpenes Polygodial and drimanial, seem to be partially mediated by activation of TRPV1. Additional investigations are needed to completely define the pharmacodynamic properties of these sesquiterpenes.

  • evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes Polygodial and drimanial in rats
    Neuropharmacology, 2004
    Co-Authors: Eunice Andre, Angela Malheiros, Rosendo A. Yunes, Juliano Ferreira, Joao B Calixto
    Abstract:

    Abstract This study investigated whether or not the neonatal treatment of rats with the sesquiterpenes Polygodial or drimanial could cause persistent antinociception similar to that induced by capsaicin. Rats were injected subcutaneously 48 h after birth with capsaicin (50 mg/kg), Polygodial (150 mg/kg), drimanial (150 mg/kg) or vehicle (1ml/kg). Six to eight weeks later, rats were tested in models of nociception. Treatment of rats with capsaicin, Polygodial or drimanial produced significant inhibition of the first phase and, to a lesser extent, the second phase of formalin-induced nociception. A significant reduction in Complete Freund’s Adjuvant and capsaicin-induced hyperalgesia was observed in the animals neonatally treated with capsaicin, Polygodial or drimanial compared with vehicle-treated rats. Moreover, both sesquiterpenes caused inhibition of plasma extravasation induced by injection of capsaicin. The neonatal treatment with capsaicin, Polygodial or drimanial significantly decreased [3H]-resiniferatoxin binding sites in the rat spinal cord, but only capsaicin neonatal treatment significantly reduced the expression of TRPV1 in dorsal root ganglia (DRG) when assessed by Western blot. These results extend our previous findings demonstrating that the neonatal treatment of rats with Polygodial or drimanial, similar to that reported for capsaicin, produced persistent antinociception in adult animals associated with TRPV1 down-regulation in the spinal cord, but not TRPV1 expression in DRG.

  • role of nitric oxide and k channels in relaxation induced by Polygodial in rabbit corpus cavernosum in vitro
    Journal of Cardiovascular Pharmacology, 2003
    Co-Authors: Eunice Andre, Angela Malheiros, Rosendo A. Yunes, Valdir Cechinelfilho, Joao B Calixto
    Abstract:

    This study examines the relaxation produced by the sesquiterpene Polygodial and compares its action with those caused by acetylcholine (ACh) and sodium nitroprusside (SNP) in the rabbit corpus cavernosum (RbCC) in vitro. RbCC was set up in a 5-ml bath containing Krebs solution at 37 degrees C, at pH 7.2, and under 2 g of tension. Polygodial, ACh, and SNP elicited graded relaxation in RbCC with mean EC50 values of 46.70 microM, 0.38 microM, and 0.30 microM, respectively. The nitric oxide (NO) synthase inhibitor L-NOARG and the guanylate cyclase inhibitors LY 83583 and ODQ markedly inhibited the relaxation induced by Polygodial (% of inhibition of 79, 48, and 51, respectively) and those caused by ACh (% of inhibition of 100, 49, and 32, respectively). Tetraethylammonium (TEA) and glibenclamide inhibited the relaxation induced by Polygodial (52% and 43%, respectively), but only TEA caused shift to the right on ACh-mediated relaxation. In contrast, apamin, charybdotoxin, and 4-aminopyridine or the protein kinase A inhibitor KT 5720 all failed to affect either Polygodial or ACh-mediated relaxation in these preparations. The authors concluded that Polygodial produced graded relaxation in the RbCC in vitro via a mechanism that was partially dependent on the release of NO or a NO-derived substance through an activation of guanylate cyclase but was independent of adenylate cyclase mechanism. In addition, the opening of K+ channels sensitive to TEA and glibenclamide, but not those sensitive to apamin, 4-aminopyridine, or charybdotoxin, also contributed to the relaxant action produced by Polygodial in the RbCC.

  • Additional evidence for the anti-inflammatory and anti-allergic properties of the sesquiterpene Polygodial
    Life sciences, 2001
    Co-Authors: Fernanda Marques Da Cunha, Valdir Cechinel Filho, Angela Malheiros, Rosendo A. Yunes, Gilboe L Mendes, Tânia S. Fröde, Joao B Calixto
    Abstract:

    This study evaluates further the anti-inflammatory and anti-allergic properties of Polygodial, a sesquiterpene extracted from the barks plant Drymis winteri (Winteraceae). Polygodial (12.8-128.1 micromol/kg, i.p.) 30 min prior, inhibited significantly the mouse paw oedema induced by prostaglandin E2, bradykinin (BK) substance P (SP), dextran, platelet activating factor (PAF) or carrageenan. Polygodial also inhibited arachidonic acid-, capsaicin- and croton oil-induced ear oedema in mice. Polygodial (42.7 micromol/kg, i.p.), significantly inhibited both exudation and cell influx when assessed in the pleurisy induced by SP and histamine, and to a less extent the inflammatory response caused by carrageenan, PAF, BK and des-Arg9-BK. Finally, Polygodial (4.2-42.7 micromol/kg, i.p.) produced dose-related inhibition of paw oedema induced by ovalbumin, protecting in a time-dependent manner the anaphylactic shock induced by endovenous administration of ovalbumin in animals which had been actively sensitised by this antigen. These and our previous results indicate that the major component present in the bark of the plant D. winteri, the sesquiterpene Polygodial exerts an interesting anti-inflammatory and anti-allergic properties when assessed in rats and mice.

Isao Kubo - One of the best experts on this subject based on the ideXlab platform.

  • combination effect of miconazole with Polygodial against candida albicans
    Open Journal of Medical Microbiology, 2011
    Co-Authors: Isao Kubo, Sang Hwa Lee, Kuniyoshi Shimizu
    Abstract:

    The combination effect of miconazole with Polygodial against Candida albicans was investigated by an in vitro checkerboard method. Isobolograms, fractional inhibitory concentration (FIC), and fractional fungicidal concentration (FFC) indices were used for evaluating the interaction between compounds combined. The combination of miconazole with Polygodial exhibited strong synergism on both fungistatic and fungicidal action against this opportunistic pathogen.

  • multifunctional action of antifungal Polygodial against saccharomyces cerevisiae involvement of pyrrole formation on cell surface in antifungal action
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Ken-ichi Fujita, Isao Kubo
    Abstract:

    The antifungal activity of Polygodial against Saccharomyces cerevisiae involves multifunctions. Polygodial first acts as a surface-active agent (surfactant) and then becomes involved in biochemical processes. The ability to form a pyrrole derivative with a primary amine group of phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the outer monolayer of the plasma membrane is likely, in part, an initial step in the antifungal action of Polygodial. In the lipid fraction derived from cells treated with Polygodial, no PE and PS were detected, indicating a disturbance in the balance of the plasma membrane. The primary antifungal action of Polygodial comes from its ability to act as a surfactant that nonspecifically disrupts the lipid-protein interface of integral proteins, denaturing their functioned conformation. Once Polygodial enters the cytoplasm by destroying the membrane barrier, it reacts with L-cystein-containing cytoplasmic materials, such as a small molecule, glutathione, and a protein, alcohol dehydrogenase, to potentiate the antifungal action.

  • antibacterial activity of Polygodial
    Phytotherapy Research, 2005
    Co-Authors: Isao Kubo, Ken-ichi Fujita, Sang Hwa Lee
    Abstract:

    Polygodial was found to possess moderate antibacterial activity against gram-positive bacteria including Bacillus subtilis, Staphylococcus aureus and gram-negative bacteria including Escherichia coli and Salmonella choleraesuis with minimum bactericidal concentrations (MBC) of 100 and 100 microg/mL (0.34 mm) and 100 and 50 microg/mL, respectively. The time kill curve study showed that Polygodial was bactericidal against B. subtilis and S. choleraesuis. However, there was a difference in its bactericidal action against endospore-forming B. subtilis and food-borne S. choleraesuis.

  • Naturally Occurring Antifungal Agents against Zygosaccharomyces bailii and Their Synergism
    Journal of agricultural and food chemistry, 2005
    Co-Authors: Ken-ichi Fujita, Isao Kubo
    Abstract:

    Polygodial was found to exhibit a fungicidal activity against a food spoilage yeast, Zygosaccharomyces bailii, with the minimum fungicidal concentration (MFC) of 50 microg/mL (0.17 mM). The time-kill curve study showed that Polygodial was fungicidal at any growth stage. The primary action of Polygodial comes from its ability to disrupt the native membrane-associated function of integral proteins as nonionic surface active agents (surfactants) followed by a decrease in plasma membrane fluidity. The fungicidal activity of Polygodial was increased 128-fold in combination with a sublethal amount (equivalent of 1/2 MFC) of anethole and vice versa relative to the fungicidal activity of anethole. The fungicidal activity of sorbic acid was enhanced 512-fold in combination with 1/2 MFC of Polygodial. Conversely, the fungicidal activity of Polygodial was enhanced 128-fold in combination with 1/2 MFC of sorbic acid.

  • Synergism of Polygodial and trans-Cinnamic Acid on Inhibition of Root Elongation in Lettuce Seedling Growth Bioassays
    Journal of Chemical Ecology, 2003
    Co-Authors: Ken-ichi Fujita, Isao Kubo
    Abstract:

    A bicyclic sesquiterpene dialdehyde, Polygodial did not inhibit root elongation up to a concentration of 12.5 μg/ml in a lettuce seedling assay: trans -Cinnamic acid inhibited the elongation by 50% at 1.2 μg/ml (8.1 μM). The inhibitory activity of trans -cinnamic acid was enhanced 17-fold when used in combination with 6.25 μg/ml (26.5 μM) of Polygodial. A decrease in the pH of the medium was observed during normal seedling growth, indicating transport of protons from the cells by a plasma membrane H^+-ATPase. The inhibitory effect of trans -cinnamic acid on the elongation was reduced to some extent in 2 mM phosphate buffer (pH 7.0) during seedling growth. Although Polygodial did not inhibit the activity of H^+-ATPase in the plasma membrane fraction of roots in normally growing seedlings, a decrease in activity was found in the fraction obtained from seedlings incubated with 20 μg/ml of Polygodial. These results suggest that Polygodial functions synergistically with trans -cinnamic acid in the inhibition of root elongation via restriction of proton transport from the cytoplasm of germinated cells.

João Henrique G. Lago - One of the best experts on this subject based on the ideXlab platform.

  • Sesquiterpene Polygodial from Drimys brasiliensis (Winteraceae) Down-Regulates Implant-Induced Inflammation and Fibrogenesis in Mice.
    Journal of natural products, 2020
    Co-Authors: Bruno Antonio Ferreira, João Henrique G. Lago, Anderson Ferraz Norton Filho, Simone Ramos Deconte, Tatiana Carla Tomiosso, Fernanda Thevenard, Silvia Passos Andrade, Fernanda De Assis Araújo
    Abstract:

    Drimys brasiliensis (Winteraceae) has been investigated in traditional medicine for its anti-inflammatory properties to treat gastric ulcers and allergic and respiratory system diseases as well as for cancer treatment. In this work, we investigate the ability of the sesquiterpene Polygodial, isolated from D. brasiliensis stem barks, to modulate the chronic inflammatory response induced by polyester-polyurethane sponge implants in C57BL/6J mice. Daily treatment with Polygodial inhibited the macrophage content in the implants as determined by the activity of the N-acetyl-β-d-glucosaminidase enzyme as well as decreased the levels of CXCL1/KC and CCL2/JE/MCP-1 pro-inflammatory chemokines and the presence of mast cells along the formed fibrovascular tissue. Similarly, the deposition of a new extracellular matrix (total collagen and type I and III collagen fibers) as well as the production of the TGF-β1 cytokine were attenuated in implants treated with Polygodial, showing for the first time its antifibrogenic capacity. The hemoglobin content, the number of newly formed vessels, and the levels of VEGF cytokine, which were used as parameters for the assessment of the neovascularization of the implants, did not change after treatment with Polygodial. The anti-inflammatory and antifibrogenic effects of Polygodial over the components of the granulation tissue induced by the sponge implant indicate a therapeutic potential for the treatment of inflammatory diseases associated with the development of fibrovascular tissue.

  • antitrypanosomal activity of epi Polygodial from drimys brasiliensis and its effects in cellular membrane models at the air water interface
    Bioorganic Chemistry, 2019
    Co-Authors: Giulia E G Goncalves, André G. Tempone, João Henrique G. Lago, Thiago R Morais, Kaio S Gomes, Thais A Costasilva, Luciano Caseli
    Abstract:

    Abstract Epi-Polygodial, a drimane sesquiterpene was isolated from Drimys brasiliensis (Winteraceae). This compound demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (IC50 = 5.01 μM) with a selectivity index higher than 40. These results were correlated with the effects observed when this compound was incorporated in cellular membrane models of protozoans, represented by Langmuir monolayers of dipalmitoylphosphoethanolamine (DPPE). Surface pressure-area isotherms showed that epi-Polygodial expands DPPE monolayers at higher areas and condenses them at lower areas, which was attributed to the preferential interaction with the polar heads of the lipid. This mechanism of action could be corroborated with Polarization-Modulation Reflection-Absorption Spectroscopy and Brewster Angle Microscopy. These results pointed to the fact that the interaction of epi-Polygodial with DPPE monolayers at the air-water interface affects the physical chemical properties of the mixed film, which may be important to comprehend the interaction of this drug with cellular membranes at the molecular level.

  • incorporation of Polygodial in langmuir films of selected lipids
    Thin Solid Films, 2019
    Co-Authors: Giulia E G Goncalves, João Henrique G. Lago, Thiago R Morais, Luciano Caseli
    Abstract:

    Abstract Identification of membrane sites capable of drug binding is important to understand the interaction of bioactive compounds with biointerfaces such as microbial cellular membranes. As the exact molecular mechanism of action is yet to be fully understood for many drugs, in this study, Polygodial, an antimicrobial compound, was incorporated in Langmuir monolayers of selected lipids that served as cell membrane models. Results from pressure-area isotherms, specific vibrational spectroscopy and Brewster angle microscopy revealed the expansion of the lipid monolayers, but with distinctive effects for each lipid in terms of film compressibility, stability, order of alkyl chains, and topographical morphology. These data can be therefore correlated with the possible bioactivity effect of Polygodial in lipidic surfaces of mammalian and microbial membranes.

  • Polygodial, a sesquiterpene isolated from Drimys brasiliensis (Winteraceae), triggers glucocorticoid-like effects on pancreatic β-cells.
    Chemico-biological interactions, 2016
    Co-Authors: Kaidu H. Barrosa, Patricia Sartorelli, Murilo C. Mecchi, João Henrique G. Lago, Daniela Gonçales Rando, Ari J. S. Ferreira, Maíra Mello Rezende Valle, Silvana Bordin, Luciana C. Caperuto, Camilo Lellis-santos
    Abstract:

    Despite its common use, the synthetic glucocorticoid dexamethasone can cause several adverse effects, such as diabetes and insulin-related metabolic impairment. Thus, research on molecules that could provide the same anti-inflammatory response with milder side effects is constant. In this work the anti-inflammatory activity of the natural sesquiterpene Polygodial, extracted from the endemic Brazilian plant Drimys brasiliensis Miers (Winteraceae), was investigated. Employing a pancreatic β-cell model (INS 1E), the effect of Polygodial on signaling pathways is similar to that caused by dexamethasone - both increased MKP1 and decreased ERK1/2 expression in a dose-response and time-dependent manner. Relating to such finding, nuclear translocation of the glucocorticoid receptor was also discovered to be induced by the sesquiterpene. Molecular modeling results indicated that Polygodial was capable of docking to the glucocorticoid receptor, but presented preference for the Arg611 binding site rather than Thr739 when set to bind freely inside the pocket. At last, fragmentation of DNA was verified as consequence of sesquiterpene-induced cell death. Altogether, our results suggest that, like dexamethasone, Polygodial interacts the glucocorticoid receptor ligand binding domain but create fewer ligand-protein interactions at the site, yielding a weaker effector response. Such property provides an advantage when regarding the adverse effects resulting from stronger affinity ligands of the glucocorticoid receptor, such as in the case of the current standard dexamethasone-based treatment. This aspect, also, turns Polygodial an interesting hit compound to the development of new drugs based on its backbone structure providing less harmful anti-inflammatory treatments.

  • Anti-leishmanial and anti-trypanosomal potential of Polygodial isolated from stem barks of Drimys brasiliensis Miers (Winteraceae)
    Parasitology Research, 2011
    Co-Authors: Daniela S. Corrêa, André G. Tempone, Juliana Q. Reimão, Noemi N. Taniwaki, Paulete Romoff, Oriana A. Fávero, Patricia Sartorelli, Murilo C. Mecchi, João Henrique G. Lago
    Abstract:

    Parasitic protozoan diseases affect the poorest population in developing countries. Leishmaniasis and Chagas disease have been included among the most important threats for public health in Central and South American continent, with few therapeutic alternatives and highly toxic drugs. In the course of selection of novel drug candidates, we studied the anti-protozoal potential of Drimys brasiliensis . Thus, the crude hexane extract from stem bark as well as its main derivative, the sesquiterpene Polygodial, were tested using in vitro assays. The crude hexane extract and Polygodial showed activity against Leishmania spp. in the range between 22 and 62 μg/mL, but Polygodial demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (2 μg/mL), with a selectivity index of 19. Finally, Polygodial showed a leishmanicidal effect, inducing intense ultrastructural damages in Leishmania in short-time incubation. The obtained results suggested that Polygodial could be used as a tool for drug design studies against protozoan diseases and as a candidate molecule for further in vivo studies against T. cruzi .

Angela Malheiros - One of the best experts on this subject based on the ideXlab platform.

  • Drimanes from Drimys brasiliensis with leishmanicidal and antimalarial activity
    Memorias do Instituto Oswaldo Cruz, 2013
    Co-Authors: Vanessa Duarte Claudino, Valdir Cechinel Filho, Franco Delle Monache, Rosendo A. Yunes, Kesia Caroline Da Silva, Alberto Giménez, Efrain Salamanca, David Gutierrez-yapu, Angela Malheiros
    Abstract:

    This paper evaluates CHCl3 and CH3OH extracts of the stem bark, branches and leaves of Drimys brasiliensis and drimane sesquiterpenes isolated from the stem bark against strains of Leishmania amazonensis and Leishmania braziliensis promastigotes and Plasmodium falciparum trophozoites. All of the extracts and compounds were tested in cell lines in comparison with reference standards and cell viability was determined by the XTT method. The CHCl3 and CH3OH extracts from the stem bark and branches yielded promising results against two strains of Leishmania, with 50% inhibitory concentrations (IC50 ) values ranging from 39-100 µg/mL. The CHCl3 extract of the stem bark returned IC50 values of 39 and 40.6 µg/mL for L. amazonensis and L. braziliensis, respectively. The drimanes were relatively effective: 1-β-(p-coumaroyloxy)-Polygodial produced IC50 values of 5.55 and 2.52 µM for L. amazonensis and L. braziliensis, respectively, compared with 1-β-(p-methoxycinnamoyl)-Polygodial, which produced respective IC50 values of 15.85 and 17.80 µM. The CHCl3 extract demonstrated activity (IC50 of 3.0 µg/mL) against P. falciparum. The IC50 values of 1-β-(p-cumaroyloxyl)-Polygodial and 1-β-(p-methoxycinnamoyl)-Polygodial were 1.01 and 4.87 µM, respectively, for the trophozoite strain. Therefore, the results suggest that D. brasiliensis is a promising plant from which to obtain new and effective antiparasitic agents.

  • Presence of Polygodial and drimenol in Drimys populations from Chile
    Biochemical Systematics and Ecology, 2007
    Co-Authors: Diego Muñoz-concha, Rosendo A. Yunes, Hermine Vogel, Iván Razmilic, Louisiane F.v. Bresciani, Angela Malheiros
    Abstract:

    Drimys winteri (Winteraceae) is a tree with medicinal properties native to Chile. Its bark contains Polygodial and drimenol in unknown quantities, with antimicrobial and antinociceptive activity. The purpose of the present study was to quantify Polygodial and drimenol concentrations in leaves of five populations of D. winteri and one of Drimys andina from different regions of Chile, by GC analysis of the hexane extract. The concentration of these compounds was also determined in the bark of one of the D. winteri populations. In dried leaves mean concentrations of 0.99% for Polygodial and 0.011% for drimenol could be observed, both differing significantly among the studied populations. It is concluded that Polygodial and drimenol are present in the leaves and the bark of D. winteri and in D. andina leaves, this being the first report of the presence of these compounds in the latter species.

  • pharmacological characterisation of the plant sesquiterpenes Polygodial and drimanial as vanilloid receptor agonists
    Biochemical Pharmacology, 2006
    Co-Authors: Eunice Andre, Angela Malheiros, Rosendo A. Yunes, Joao B Calixto, Barbara Campi, Marcello Trevisani, Juliano Ferreira, Pierangelo Geppetti
    Abstract:

    This study was designed to assess the participation of transient receptor potential vanilloid 1 (TRPV1) in the biological effects induced by the plant-derived sesquiterpenes Polygodial and drimanial. In rat isolated urinary bladder, Polygodial and drimanial produced a tachykinin-mediated contraction that was inhibited by combination of NK(1) and NK(2) tachykinin receptor antagonists, SR 140333 and SR 48968. Furthermore, two different TRPV1 antagonists, capsazepine and ruthenium red prevented the contraction induced by both compounds. In addition, capsaicin, Polygodial and drimanial displaced in a concentration-dependent manner the specific binding sites of [(3)H]-resiniferatoxin to rat spinal cord membranes, with a IC(50) values of 0.48, 4.2 and 3.2 microM, respectively. Likewise, capsaicin, Polygodial and drimanial promoted an increase of [(45)Ca(2+)] uptake in rat spinal cord synaptosomes. In cultured rat trigeminal neurons, Polygodial, drimanial and capsaicin were also able to significantly increase the intracellular Ca(2+) levels, effect that was significantly prevented by capsazepine. Together, the present results strongly suggest that the pharmacological actions of plant-derived sesquiterpenes Polygodial and drimanial, seem to be partially mediated by activation of TRPV1. Additional investigations are needed to completely define the pharmacodynamic properties of these sesquiterpenes.

  • inhibition of the mitochondrial atp synthesis by Polygodial a naturally occurring dialdehyde unsaturated sesquiterpene
    Biochemical Pharmacology, 2005
    Co-Authors: Maria Victoria Castelli, Angela Malheiros, Anabella F Lodeyro, Susana Zacchino, Oscar A Roveri
    Abstract:

    Abstract Polygodial is a naturally occurring sesquiterpene dialdehyde that exhibits several pharmacologically interesting activities. Among them, its antifungal properties have been more thoroughly studied. The mitochondrial ATPase has been suggested as one of the possible targets for Polygodial action. However, its mechanism of action is not well defined yet. The effect of Polygodial on the mitochondrial energy metabolism is described in this paper. Polygodial inhibited ATP synthesis coupled to succinate oxidation in beef-heart submitochondrial particles at concentrations (IC 50  = 2.4 ± 0.1 μM) which marginally affected electron transport and ATPase activity (IC 50  = 97 ± 4 μM). A transitory stimulation of the electron transport in intact rat liver mitochondria in state 4 was also obtained at low Polygodial concentrations (EC 50  = 20 ± 4 μM). These results suggest that Polygodial uncouples ATP synthesis from electron transport at low concentrations. Similar concentrations of Polygodial partially abolished the ANS fluorescence enhancement (IC 50  = 2.2 ± 0.4 μM) induced by succinate oxidation in submitochondrial particles but did not collapse the ΔpH. We postulate that Polygodial uncouples mitochondrial ATP synthesis by affecting the electrical properties of the membrane surface and consequently collapsing the membrane potential (Δ ψ ) and/or the localized transmembrane pH difference (ΔpH S ) without affecting the ΔpH between the two bulk aqueous phases (ΔpH B ). The relevance of these findings for the understanding of the biochemical basis of the antifungal activity of Polygodial and the evaluation of its potentiality as a therapeutic agent are discussed.

  • evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes Polygodial and drimanial in rats
    Neuropharmacology, 2004
    Co-Authors: Eunice Andre, Angela Malheiros, Rosendo A. Yunes, Juliano Ferreira, Joao B Calixto
    Abstract:

    Abstract This study investigated whether or not the neonatal treatment of rats with the sesquiterpenes Polygodial or drimanial could cause persistent antinociception similar to that induced by capsaicin. Rats were injected subcutaneously 48 h after birth with capsaicin (50 mg/kg), Polygodial (150 mg/kg), drimanial (150 mg/kg) or vehicle (1ml/kg). Six to eight weeks later, rats were tested in models of nociception. Treatment of rats with capsaicin, Polygodial or drimanial produced significant inhibition of the first phase and, to a lesser extent, the second phase of formalin-induced nociception. A significant reduction in Complete Freund’s Adjuvant and capsaicin-induced hyperalgesia was observed in the animals neonatally treated with capsaicin, Polygodial or drimanial compared with vehicle-treated rats. Moreover, both sesquiterpenes caused inhibition of plasma extravasation induced by injection of capsaicin. The neonatal treatment with capsaicin, Polygodial or drimanial significantly decreased [3H]-resiniferatoxin binding sites in the rat spinal cord, but only capsaicin neonatal treatment significantly reduced the expression of TRPV1 in dorsal root ganglia (DRG) when assessed by Western blot. These results extend our previous findings demonstrating that the neonatal treatment of rats with Polygodial or drimanial, similar to that reported for capsaicin, produced persistent antinociception in adult animals associated with TRPV1 down-regulation in the spinal cord, but not TRPV1 expression in DRG.