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Pharmacological potential of Maytenus species and isolated constituents, especially tingenone, for treatment of painful inflammatory diseases

ABSTRACT

Uses of medicinal plants by people around the world significantly contribute and guide biologically active compounds research that can be useful in the combat against various diseases. Due to a great chemical and structural variety found in their vegetal structures it consolidates ethnopharmacology as an important science for the pharmaceutical section. Inserted in the diversity of medicinal plants, is the Maytenus genus, whose research has already revealed lots of isolated substances which are responsible for a great variety of biological activities, among which we cite analgesic and anti-inflammatory, for the treatment of inflammatory diseases such as rheumatoid arthritis, gastritis, ulcers and gastrointestinal disorders. The aim of this review article is to make a compendium of the Maytenus genus and its isolated chemical compounds, among them tingenone. The elucidation of its mechanism of action reveals promising sources for the development of new drugs specially targeted for the treatment of painful inflammatory diseases.

Keywords:
Maytenus; Tingenone; Inflammation; Pain

Medicinal plants: source for discovery of new drugs

Research for the treatment of the main diseases that affect the humankind is a constant concern of the population, whose information is proven by the numerous records found in the first civilizations that lived on Earth (Calixto and Siqueira, 2008Calixto, J.B., Siqueira Jr., J.M., 2008. Desenvolvimento de Medicamentos no Brasil: Desafios. Gazeta Médica da Bahia 78, 98-106.). Ancient civilization such as Chinese, Indian and North African have provided written evidence from the origin of man using plants for the treatment of a great variety of diseases. In Old Greece, for example, scholars classified plants and gave descriptions that helped in the identification process (Phillipson, 2001Phillipson, J.D., 2001. Phytochemistry and medicinal plants. Phytochemistry 56, 237-243.).

Nowadays, treatment through medicinal plants plays a fundamental role in the health systems of many countries (Bhatia et al., 2014Bhatia, H., Sharma, Y.P., Manhas, R.K., Kumar, K., 2014. Ethnomedicinal plants used by the villagers of district Udhampur, J&K, India. J. Ethnopharmacol. 151, 1005-1018.). Researches of medicinal plants are becoming more important in the development of health care and maintenance programs in different parts of the world (Shil et al., 2014Shil, S., Choudhury, M.D., Das, S., 2014. Indigenous knowledge of medicinal plants used by the Reang tribe of Tripura state of India. J. Ethnopharmacol. 152, 135-141.).

Brazilian biodiversity comprises more than 50,000 species of vascular plants (20–22% of the existent total in the planet) and, due to this, the interest in studies of medicinal properties of plants are explored by Brazilian researchers and the pharmaceutical industry (Calixto and Siqueira, 2008Calixto, J.B., Siqueira Jr., J.M., 2008. Desenvolvimento de Medicamentos no Brasil: Desafios. Gazeta Médica da Bahia 78, 98-106.). Plant-derived medicines form a significant segment related to pharmaceutical products, since, 25% of prescribed drugs are originating from plants (Schmidt et al., 2007Schmidt, B.M., Ribnicky, D.M., Lipsky, P.E., Raskin, I., 2007. Revisiting the ancient concept of botanical therapeutics. Nat. Chem. Biol. 3, 360-366.). Therefore, natural products are still representing a valuable source of inspiration for chemicals, working with synthesis of biological active compounds, developing new drugs (Ji et al., 2009Ji, H.-F., Li, J.-X., Zhang, H.-Y., 2009. Natural products and drug discovery: can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO Rep. 10, 194-200.).

Materials and methods

This review was prepared by databases Pubmed, Google Scholar, ScienceDirect and SciFinder on period September 2014 to January 2017. The keywords utilized were Maytenus, chemical compounds, tingenone and pharmacological activities.

The Celastraceae family

The Celastraceae family is formed by 106 genera and 1300 species, that are widely distributed in tropical and subtropical regions of the world, including North Africa, South America and east Asia, mainly China (Spivey et al., 2002Spivey, A.C., Weston, M., Woodhead, S., 2002. Celastraceae sesquiterpenoids: biological activity and synthesis. Chem. Soc. Rev. 31, 43-59.; Simmons et al., 2008Simmons, M.P., Cappa, J.J., Archer, R.H., Ford, A.J., Eichstedt, D., Clevinger, C.C., 2008. Phylogeny of the Celastreae (Celastraceae) and the relationships of Catha edulis (qat) inferred from morphological characters and nuclear and plastid genes. Mol. Phylogenet. Evol. 48, 745-757.; Núñez et al., 2016Núñez, M.J., Jiménez, I.A., Mendonza, C.R., Chavez-Sifontes, M., Martinez, M.L., Ichiishi, E., Tokuda, R., Tokuda, H., Bazzocchi, I.L., 2016. Dihydro-β-agarofuran sesquiterpenes from Celastraceae species as anti-tumor-promoting agents: structure–activity relationship. Eur. J. Med. Chem. 111, 95-102.). It is also commonly known, as a bittersweet family, due to its fruits’ flavor (Gonzalez et al., 2000Gonzalez, A.G., Bazzocchi, I.L., Moujir, L., Jimenez, I.A., 2000. Ethnobotanical uses of Celastraceae bioactive metabolites. Stud. Nat. Prod. Chem. 23, 649-738.). The plants of this family are in general, characterized by small trees, bushes or lianas (Spivey et al., 2002Spivey, A.C., Weston, M., Woodhead, S., 2002. Celastraceae sesquiterpenoids: biological activity and synthesis. Chem. Soc. Rev. 31, 43-59.). Representative genus of this family are Maytenus, Euonymus, Cassine and Celastrus (Perestelo, 2009Perestelo, N.I.R., 2009. Metabolitos secundarios aislados de Maytenus jelskii (Celastraceae). Estudio de relación estructura-actividad. Tesis Doctoral, Universidad de La Laguna, La Laguna, 387p.), that are studied not only because of their use in popular medicine, but also, because of the large geographical distribution, diversity and structural complexity of the isolated secondary metabolites (Coppede et al., 2014Coppede, J.S., Pina, E.S., Paz, T.A., Fachin, A.L., Marins, M.A., Bertoni, B.W., França, S.C., Pereira, A.M.S., 2014. Cell cultures of Maytenus ilicifolia Mart. are richer sources of quinone-methide triterpenoids than plant roots in natura. Plant Cell Tissue Org. Cult. 118, 33-43.). Many species from the Celastraceae family are widely studied, except for Zinowiewia genus whose studies are very out dated probably due to its poor phytochemical and ethnopharmacological characterization (Núñez et al., 2016Núñez, M.J., Jiménez, I.A., Mendonza, C.R., Chavez-Sifontes, M., Martinez, M.L., Ichiishi, E., Tokuda, R., Tokuda, H., Bazzocchi, I.L., 2016. Dihydro-β-agarofuran sesquiterpenes from Celastraceae species as anti-tumor-promoting agents: structure–activity relationship. Eur. J. Med. Chem. 111, 95-102.).

The Celastraceae family includes various plants species, and its extracts have been used for the treatment of stomach complications, fever, appetite suppressants, rheumatoid arthritis and cancer (Spivey et al., 2002Spivey, A.C., Weston, M., Woodhead, S., 2002. Celastraceae sesquiterpenoids: biological activity and synthesis. Chem. Soc. Rev. 31, 43-59.). The Tripterygium wilfordii specie, largely used in China due to its insecticidal properties, is one of the most studied from this family and has several isolated bioactive substances (Brinker et al., 2007Brinker, A.M., Ma, J., Lipsky, P.E., Raskin, I., 2007. Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 68, 732-766.). Extracts of this species are used for the rheumatoid arthritis, autoimmune sicknesses and skin infections (Wang and Xie, 1999Wang, X.W., Xie, H., 1999. C-1027: antineoplastic antibiotic. Drug Future 24, 991-997.).

Examples of isolated compounds from the Celastraceae family and their respective biological activity, are: (-)-epicatequin-5-O-β-d-glucosyl 3-benzoate (1) (antioxidant activity) (Hwang et al., 2001Hwang, B.Y., Kim, H.S., Lee, J.H., Hong, Y.S., Ro, J.S., Lee, K.S., Lee, J.J., 2001. Antioxidant benzoylated flavan-3-ol glycoside from Celastrus orbiculatus. J. Nat. Prod. 64, 82-84.), triptolide (2) (insecticidal activity) (Luo et al., 2004Luo, D.Q., Zhang, X., Tian, X., Liu, J.K., 2004. Inseticidal compounds from Tripterygium wilfordii active against Mythimna separata. Z. Naturforsch. 59, 421-426.), oppositine A (3) (cytotoxic activity against tumor cells in human colon) (Whitson et al., 2006Whitson, E.L., Damayanthi Mala, S.M.V., Veltri, C.A., Bugni, T.S., Dilip de Silva, E., Ireland, C.M., 2006. Oppositines A and B, sesquiterpenes pyridine alkaloids from a Sri Lankan Pleurostylia opposita. J. Nat. Prod. 69, 1833-1835.), tingenone (4) (antimicrobial and antinociceptive activities) (Mena-Rejón et al., 2007Mena-Rejón, G.J., Pérez-Espadas, A.R., Moo-Puc, R.E., Cedillo-Rivera, R., Bazzocchi, I.L., Jiménez-Diaz, I.A., Quijano, L., 2007. Antigiardial activity of triterpenoids from root bark of Hippocratea excelsa. J. Nat. Prod. 70, 863-865.; Veloso et al., 2014aVeloso, C.C., Rodrigues, V.G., Azevedo, A.O., Oliveira, C.O., Gomides, L.F., Duarte, L.P., Duarte, I.D., Klein, A., Perez, A.C., 2014a. Antinociceptive effects of Maytenus imbricata Mart. ex. Reissek (Celastraceae) root extract and its tingenone constituent. J. Med. Plants Res. 8, 68-76., 2014bVeloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2014b. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to opioidergic activation. Planta Med. 80, 1615-1621., 2015Veloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2015. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP – sensitive K(+) channels pathway activation in mice. Eur. J. Pharmacol. 755, 1-5.), 1-acetyloxy-9-benzoyloxy-8-cinamoyloxy-4,6-dihydro-β-agarofuran (5) (inhibition of photosynthesis) (Torres-Romero et al., 2008Torres-Romero, D., King-Díaz, B., Jiménez, I.A., Lotina-Hennsen, B., Bazzocchi, I.L., 2008. Sesquiterpenes from Celastrus vulcanicola as photosynthetic inhibitors. J. Nat. Prod. 71, 1331-1335.) and elaeodendroside W (6) (antiproliferative activity against human ovarian cancer) (Hou et al., 2009Hou, Y., Cão, S., Brodie, P., Callmander, M., Ratovoson, F., Randrianaivo, R., Rakotobe, E., Rasamison, V.E., Rakotonandrasana, S., TenDyke, K., Suh, E.M., Kingston, D.G.I., 2009. Antiproliferative cardenolide glycosides of Elaeodendron alluaudianum from the Madagascar Rainforest. Bioorg. Med. Chem. 17, 2215-2218.).


The Maytenus genus

In Brazil, 76 species were found in different habitats, like the Atlantic forest (M. distichophylla, M. macrophylla), altitude forest (M. erythroxylon), rock fields (M. opaca) and in regions with caatinga vegetation (M. truncata, M. imbricata, M. ilicifolia, M. catingarum, M. impressa, M. obtusifolia), predominantly distributed between Bahia and Ceará state (Rocha et al., 2004Rocha, C.S., Pimentel, R.M.M., Randau, K.P., Xavier, H.S., 2004. Morfoanatomia de folhas de Maytenus rigida Mart. (Celastraceae); uma espécie utilizada como medicinal no nordeste do Brasil. Acta Farm. Bonaer. 23, 472-476.; Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.).

The name Maytenus is derived from the word "Maytén", used by the "Mapuche" population from Chile, which means "man of the land" (Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.). Numerous medicinal uses are associated to the Maytenus genus species, with the use of roots, barks and leaves for the treatment of gastric ulcers, anti-inflammatory, analgesic, anti-allergy, antitumor, among others in South America (Sosa et al., 2007Sosa, S., Morelli, C.F., Tubaro, A., Cairoli, P., Speranza, G., Manitto, P., 2007. Anti-inflammatory activity of Maytenus senegalensis root extracts and of maytenoic acid. Phytomedicine 14, 109-114.; Baggio et al., 2009Baggio, C.H., Freitas, C.S., Mayer, B., Dos Santos, A.C., Twardowschy, A., Potrich, F.B., Cipriani, T.R., de Souza, L.M., Sassaki, G.L., lacomini, M., Marques, M.C., Mesia-Vela, S., 2009. Muscarinic-dependent inhibition of gastric emptying and intestinal motility by fractions of Maytenus ilicifolia Mart ex. Reissek. J. Ethnopharmacol. 123, 385-391.; Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.; Martins et al., 2012Martins, M.V., Estevam, C.S., Santos, A.L.L.M., Dias, A.S., Cupertino-da-Silva, Y.K., Araújo-Júnior, J.X., Miranda, A.L.P., Barreiro, E.J., Pizza, C., Piacente, S., Montoro, P., Quintans-Júnior, L.J., Araujo, B.S., Alexandre-Moreira, M.S., Sant’Ana, A.E.G., 2012. Antinociceptive effects of an extract, fraction and an isolated compound of the stem bark of Maytenus rigida. Rev. Bras. Farmacogn. 22, 598-603.). The leaves of the several existent species of Maytenus in Brazil, are traditionally used by Indians as infusion against gastric affections (hyperacidity, gastric ulcers, duodenal and chronic gastritis) (Rocha et al., 2004Rocha, C.S., Pimentel, R.M.M., Randau, K.P., Xavier, H.S., 2004. Morfoanatomia de folhas de Maytenus rigida Mart. (Celastraceae); uma espécie utilizada como medicinal no nordeste do Brasil. Acta Farm. Bonaer. 23, 472-476.). As shown in Box 1, Maytenus genus is widely used in folk medicine for the treatment of various diseases.

Box 1
The Maytenus genus and its uses in folk medicine.

Extracts and isolated substances of the Maytenus genus species present a range of biological activities. Among the 76 known species of the Maytenus found in Brazil, only 15% had their pharmacological effects studied (Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.), and most of these were performed in animal models of pain and inflammation. According to the literature, the ethanolic extract of the M. putterlickoides roots presents antileukemic activity (Schneberg et al., 2001Schneberg, B.T., Green, D.K., Sneden, A.T., 2001. Dihydroagarofuran sesquiterpene alkaloid from Maytenus putterlickoides. J. Nat. Prod. 64, 624-626.), the methanol extract of M. senegalensis roots’ barks shows antibacterial activity (Lindsey et al., 2006Lindsey, K.L., Budesinsky, M., Kohout, L., Staden, J.V., 2006. Antibacterial activity of maytenonic acid isolated from the root-bark of Maytenus senegalensis. S. Afr. J. Bot. 72, 473-477.) and the chloroform, hexane and methanolic extracts of the roots present anti-inflammatory activity, decreasing ear edema induced by croton oil in mice (Sosa et al., 2007Sosa, S., Morelli, C.F., Tubaro, A., Cairoli, P., Speranza, G., Manitto, P., 2007. Anti-inflammatory activity of Maytenus senegalensis root extracts and of maytenoic acid. Phytomedicine 14, 109-114.). Another study showed that the hydroalcoholic extract of M. robusta leaves presents gastroprotective property (De Andrade et al., 2007De Andrade, S.F., Lemos, M., Comunello, E., Noldin, V.F., Filho, V.C., Niero, R., 2007. Evaluation of the antiulcerogenic activity of Maytenus robusta (Celastraceae) in different experimental ulcer models. J. Ethnopharmacol. 113, 252-257.). The ethyl-acetate and methanolic extracts of the leaves of M. truncata show analgesic and antiulcer activities (Fonseca et al., 2007Fonseca, A.P.N.D., Silva, G.D.F., Carvalho, J.J., Salazar, G.C.M., Duarte, L.P., Silva, R.P., Jorge, R.M., Tagliati, C.A., Zani, C.L., Alves, T.M.A., Peres, V., Vieira Filho, S.A., 2007. Estudo fitoquímico do decocto das folhas de Maytenus truncata Reissek e avaliação das atividades antinociceptiva, antiedematogênica e antiulcerogênica de extratos do decocto. Quim. Nova 30, 842-847.), the ethanolic extract of the M. rigida leaves presents anti-inflammatory, antiulcer and antidiarrheal activities (Santos et al., 2007Santos, V.L., Costa, V.B.M., Agra, M.F., Silva, B.A., Batista, L.M., 2007. Pharmacological studies of ethanolic extracts of Maytenus rigida Mart (Celastraceae) in animal models. Rev. Bras. Farmacogn. 17, 336-342.). In addition to these effects, M. rigida also presented antinociceptive effect (Martins et al., 2012Martins, M.V., Estevam, C.S., Santos, A.L.L.M., Dias, A.S., Cupertino-da-Silva, Y.K., Araújo-Júnior, J.X., Miranda, A.L.P., Barreiro, E.J., Pizza, C., Piacente, S., Montoro, P., Quintans-Júnior, L.J., Araujo, B.S., Alexandre-Moreira, M.S., Sant’Ana, A.E.G., 2012. Antinociceptive effects of an extract, fraction and an isolated compound of the stem bark of Maytenus rigida. Rev. Bras. Farmacogn. 22, 598-603.) and M. heterophylla specie showed anti-inflammatory effect (Da Silva et al., 2011Da Silva, G., Taniça, M., Rocha, J., Serrano, R., Gomes, E.T., Sepodes, B., Silva, O., 2011. In vivo anti-inflammatory effect and toxicological screening of Maytenus heterophylla and Maytenus senegalensis extracts. Hum. Exp. Toxicol. 30, 693-700.).

Biological activities of various species of Maytenus genus plants are being studied. A large number of studies on M. ilicifolia are found in literature, one of the most commonly used, and herbal medicine prepared from this specie is already commercially available for the treatment of gastric ulcers. This specie is native to the Southern part of Brazil, Paraguay, Uruguay and northern Argentina and has biological activities besides its ornamental use. Preliminary studies of the hexane and ethyl acetate extracts of M. ilicifolia leaves inhibited the second phase of the formalin test in mice and paw edema induced by carrageenan in rats. Beside these effects, protection against gastric lesions was also observed (Jorge et al., 2004Jorge, R.M., Leite, J.P.V., Oliveira, A.B., Tagliati, C.A., 2004. Evaluation of antinociceptive, anti-inflammatory and antiulcerogenic activities of Maytenus ilicifolia. J. Ethnopharmacol. 94, 93-100.; Leme et al., 2013Leme, T.S.V., Prando, T.B.L., Gasparotto, F.M., Souza, P., Crestani, S., Souza, L.M., Cipriani, T.R., Lourenço, E.L.B., Junior, A.G., 2013. Role of prostaglandin/Camp pathway in the diuretic and hypotensive effects of purified fraction of Maytenus ilicifolia Mart ex Reissek (Celastraceae). J. Ethnopharmacol. 150, 154-161.). This plant is popularly known as "erva-cancerosa", "espinho-de-deus", "salva-vidas", "espinheira-santa", among other names (Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.). Espinheira-santa is also a popular name for other species, such as: M. aquifolium, M. robusta and M. truncada, because of their marked morphological similarity. These plants have the traditional use for the treatment of diabetes, kidney problems, treatment of gastric ulcers, as anti-inflammatory and analgesic (Rocha et al., 2004Rocha, C.S., Pimentel, R.M.M., Randau, K.P., Xavier, H.S., 2004. Morfoanatomia de folhas de Maytenus rigida Mart. (Celastraceae); uma espécie utilizada como medicinal no nordeste do Brasil. Acta Farm. Bonaer. 23, 472-476.; Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.; Leme et al., 2013Leme, T.S.V., Prando, T.B.L., Gasparotto, F.M., Souza, P., Crestani, S., Souza, L.M., Cipriani, T.R., Lourenço, E.L.B., Junior, A.G., 2013. Role of prostaglandin/Camp pathway in the diuretic and hypotensive effects of purified fraction of Maytenus ilicifolia Mart ex Reissek (Celastraceae). J. Ethnopharmacol. 150, 154-161.). M. obtusifolia, M. heterophylla, M. undata and M. putterlickioides species present antiplasmodial activity. M. heterophylla is used in Africa by healers for the treatment of hernia and syphilis and anthelmintic (Muthaura et al., 2015Muthaura, C.N., Keriko, J.M., Mutai, C., Yenesew, A., Gathirwa, J.W., Irungu, B.N., Nyangacha, R., Mungai, G.M., Derese, S., 2015. Antiplasmodial potential of traditional phytotherapy of some remedies used in treatment of malaria in Meru-Tharaka Country of Kenya. J. Ethnopharmacol. 175, 315-323.). Maytenus gonoclada, known as "tiuzinho", is a Brazilian plant found in cerrado and rupestrian fields. Some triterpenes of this specie were isolated and evaluated, proving a giardicidal activity (Silva et al., 2012Silva, F.C., Busatti, H.G.N.O., Gomes, M.A., Duarte, L.P., Silva, G.D.F., Filho, S.A.V., 2012. Antigiardial activity of the hexane extracts of Maytenus gonoclada Mart. Int. J. Pharm. Pharm. Sci. 4, 638-639.).

Thinking about possible new and future treatments for the Alzheimer's disease, Rodrigues et al. (2014)Rodrigues, V.G., Silva, F.C., Duarte, L.P., Takahashi, J.A., Matildes, B.L.G., Silva, G.D.F., Silva, R.R., Vieira-Filho, S.A., 2014. Pentacyclic triterpenes from Maytenus genus as acetylcholinesterase inhibitors. Int. J. Pharm. Pharm. Sci. 6, 918-920. analyzed some triterpenes isolated from M. imbricata and M. gonoclada. Some of these compounds exhibited acetylcholinesterase inhibition properties.

Some studies have reported biological activities related to Maytenus triterpenic compounds in the central nervous system. A study performed using the roots of M. obtusifolia revealed antipsychotic effect in the model of catalepsy (De Sousa and De Almeida, 2005De Sousa, D.P., De Almeida, R.N., 2005. Neuroleptic-like properties of the chloroform extract of Maytenus obtusifolia Mart. Biol. Pharm. Bull. 28, 224-225.). Santoyo et al. (2015)Santoyo, C.Z., Espinoza, L.Z., Puente, R.Z., Sánchez, J.Z., Quispe, N.Z., Medina, C.P., Granara, S.A., 2015. Antipsychotic and behavior effect of the ethanolic extract from the bark of Maytenus macrocarpa (Ruiz & Pav.) Briq. in mice. Pharmacogn. Commun. 5, 244-249. demonstrated antipsychotic effect and behavior modifying effect in a study using the Maytenus macrocarpa ethanolic extract.

Chemical compounds

Isolated constituents from species of Maytenus genus (Box 2) subjected to laboratorial tests also showed biological effects. Through phythochemical studies of plants of the Maytenus genus, many compounds classes were isolated, including flavonoids, pentacyclic triterpenes, alkaloids and condensed tannins (Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.).

Box 2
Isolated compounds from Maytenus genus.

Among the isolated secondary metabolites of these species, the fridelane pentacyclic triterpenes, quinonamethides and lupanes have been isolated. Lupanes and quinonamethides deserve special mention for presenting important biological activities (Vellosa et al., 2009Vellosa, J.C.R., Khalil, N.M., Gutierres, V.O., Santos, V.A.F.F.M., Furlan, M., Brunetti, I.L., Oliveira, O.M.M.F., 2009. . Braz. J. Pharm. Sci. 45, 99-107.; Martucciello et al., 2010Martucciello, S., Balestrieri, M.L., Felice, F., Estevam, C.S., Sant’Ana, A.E.G., Pizza, C., Piacente, S., 2010. Effects of triterpene derivatives from Maytenus rigida on VEGF-induced Kaposi's sarcoma cell proliferation. Chem.-Biol. Interact. 183, 450-454.).

Phytochemical studies performed from leaves, branches, stems and roots of M. imbricata showed six pentacyclic triterpenes isolated from the roots: 11α-hydroxylup-20(29)-en-3-one; 6-oxotingenol; 3,7-dioxofriedelane; 3-oxo-29-hydroxyfriedelane; 3β,11α-di-hydroxylup-20(29)-en and tingenone (Silva, 2007Silva, S.R.S., 2007. Estudo químico e avaliação do potencial farmacológico e herbicida de Maytenus imbricata Mart. ex. Reissek. Belo Horizonte 2007. Tese de Doutorado, Universidade Federal de Minas Gerais.; Rodrigues et al., 2012Rodrigues, V.G., Duarte, L.P., Silva, G.D.F., Silva, F.C., Góes, J.F., Takahashi, J.A., Pimenta, L.P.S., 2012. Evaluation of antimicrobial activity and toxic potential of extracts and triterpenes isolated from Maytenus imbricata. Quim. Nova 35, 1375-1380.).

Triterpenes are targeted because they present broad spectrum of activities, such as: analgesic, anticancer, anti-allergy, antiviral, among others (Patočka, 2003Patočka, J., 2003. Biologically active pentacyclic triterpenes and their current medicine signification. J. Appl. Biomed. 1, 7-12.). Tingenone expressed insecticidal activity in in vivo essays (Avilla et al., 2000Avilla, J., Teixidò, A., Velázquez, C., Alvarenga, N., Ferro, E., Canela, R., 2000. Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae). J. Agric. Food Chem. 48, 88-92.), potent activity against T. cruzi (Duarte et al., 2002Duarte, L.P., Vieira Filho, S.A., Silva, G.D., de Sousa, J.R., Pinto, A.S., 2002. Anti-trypanosomal activity of pentacyclic triterpenes isolated from Austroplenckia populnea (Celastraceae). Rev. Inst. Med. Trop. São Paulo 44, 109-112.), antitumor activity (Gomes et al., 2011Gomes, J.P.M., Cardoso, C.R.P., Varanda, E.A., Molina, J.-M., Fernandez, M.F., Olea, N., Carlos, I.Z., Vilegas, W., 2011. Antitumoral, mutagenic and (anti)estrogenic activities of tingenone and pristimerin. Rev. Bras. Farmacogn. 21, 963-971.) and antibacterial and antifungal properties (Rodrigues et al., 2012Rodrigues, V.G., Duarte, L.P., Silva, G.D.F., Silva, F.C., Góes, J.F., Takahashi, J.A., Pimenta, L.P.S., 2012. Evaluation of antimicrobial activity and toxic potential of extracts and triterpenes isolated from Maytenus imbricata. Quim. Nova 35, 1375-1380.).

Sesquiterpenes with basic skeleton dihydro-β-agarofuran, presented inhibitory activity for Leishmania parasite resistant to other drugs (Delgado-Méndez et al., 2008Delgado-Méndez, P., Herrera, N., Chávez, H., Estévez-Braun, A., Ravelo, A.G., Cortes, F., Castanys, S., Gamarro, F., 2008. New terpenoids from Maytenus apurimacensis as MDR reversal agents in the parasite Leishmania. Bioorg. Med. Chem. 16, 1425-1430.) and fridelane triterpenes revealed antiulcer activity (Andrade et al., 2008Andrade, S.F., Comunello, E., Noldin, V.F., Monache, F.D., Cechinel Filho, V., Niero, R., 2008. Antiulcerogenic activity of fractions and 3,15-Dioxo-21α-hydroxyfriedelane isolated from Maytenus robusta (Celastraceae). Arch. Pharm. Res. 31, 41-46.).

A research by Andrade et al. (2008)Andrade, S.F., Comunello, E., Noldin, V.F., Monache, F.D., Cechinel Filho, V., Niero, R., 2008. Antiulcerogenic activity of fractions and 3,15-Dioxo-21α-hydroxyfriedelane isolated from Maytenus robusta (Celastraceae). Arch. Pharm. Res. 31, 41-46. verified the antiulcerogenic activity of 3,15-dioxo-21α-hydroxy friedelane (7), a triterpene isolated from M. robusta. This compound significantly reduced lesion area induced by HCl/ethanol. The effect of 3,15-dioxo-21α-hydroxy friedelane (7) as an antiulcer drug is due to triterpenes’ ability to strengthen the defenses of the gastrointestinal tract by raising prostaglandin production, which is important for gastric mucosa protection.

Type II arabinogalactan is a polysaccharide found in plants cell walls. Baggio et al. (2012)Baggio, C.H., Freitas, C.S., Twardowschy, A., Dos Santos, A.C., Mayer, B., Potrich, F.B., Cipriani, T.R., Sassaki, G.L., Iacomini, M., Marques, M.C.A., Mesia-Vela, S., 2012. In vivo/in vitro studies of the effects of the type II arabinogalactan isolated from Maytenus ilicifolia Mart. Ex Reissek on the gastrointestinal tract of rats. Z. Naturforsch. 67, 405-410. evaluated the protective effect of this compound isolated from M. ilicifolia in models of gastric hypersecretion and ulcer. The results showed that type II arabinogalactan protected the mucosa against gastric ulcers in oral and intraperitoneal routes.

A friedelane derived, 3-oxofriedelane (friedelin), presents potent antiproliferative activity (Roberts, 2007Roberts, S.C., 2007. Production and engineering of terpenoids in plant cell culture. Nat. Chem. Biol. 3, 387-395.) and a large spectrum of antimicrobial activity (against six gram positive bacteria, four gram negative and two fungi (Kuete et al., 2007Kuete, V., Nguemwving, J.R., Beng, V.P., Azebaze, A.G., Etoa, F.X., Meyer, M., Nkengfack, A.E., 2007. Antimicrobial activity of the methanolic extracts and compounds from Vismia laurentii De Wild (Guttiferae). J. Ethnopharmacol. 109, 372-379.). Another fridelane derived, 1,3-dioxofriedelane, has inhibitory activity against tumor cells (Bishayee et al., 2011Bishayee, A., Ahmed, S., Brankov, N., Perloff, M., 2011. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front. Biosci. 16, 980-996.).

Lupane derivatives have many biological activities, such as, anti-HIV, anticancer and anti-inflammatory (Xiong et al., 2010Xiong, J., Kashiwada, Y., Chen, C.-H., Qian, K., Morris-Natschke, S.L., Lee, K.H., Takaishi, Y., 2010. Conjugates of betulin derivatives with AZT as potent anti-HIV agentes. Bioorg. Med. Chem. 18, 6451-6469.). The betulinic acid, lupane derivative, has anti-HIV activity. Bevirimat, a synthetic derivative of betulinic acid, is in the phase II clinical assays. This derivative is the first of a new anti-HIV agent class, known as maturation inhibitors (Lee, 2010Lee, K.-H., 2010. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J. Nat. Prod. 73, 500-516.).

Lupane triterpenes showed potent anti-inflammatory activity (Reyes et al., 2006Reyes, C.P., Núñez, M.J., Jiménez, I.A., Busserolles, J., Alcaraz, M.J., Bazzocchi, I.L., 2006. Activity of lupane triterpenoids from Maytenus species as inhibitors of nitric oxide and prostaglandin E2. Bioorg. Med. Chem. 14, 1573-1579.), while secotriterpene acid compound from M. undata presented some effect in thromboxane B2 inhibition and in decreasing the superoxide anion formation (Muhammad et al., 2000Muhammad, I., El Sayed, K.A., Mossa, J.S., Al-Said, M.S., El-Feraly, F.S., Clark, A.M., Hufford, C.D., Oh, S., Mayer, A.M.S., 2000. Bioactive 12-oleanene triterpene and secotriterpene acids from Maytenus undata. J. Nat. Prod. 63, 605-610.).

Secondary metabolites, such as flavonoids, triterpenes, steroids, among others, are found in Maytenus genus species (Niero et al., 2011Niero, R., de Andrade, S.F., Filho, V.C., 2011. A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus Genus. Curr. Pharm. Des. 17, 1851-1871.). Their anti-inflammatory mechanism of action is reported on literature. Among the effects, stand out: reduction of chemokines production and reduction of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β, inhibitory activity against the nuclear factor κB (NF-κB), a factor that activates the transcription of cytokines (Matsusaka et al., 1993Matsusaka, T., Fujikawa, K., Nishio, Y., Mukaida, N., Matsushima, K., Kishimoto, T., Akira, S., 1993. Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc. Natl. Acad. Sci. U.S.A. 90, 10193-10197.; Pinto et al., 2008Pinto, S.A.H., Pinto, L.M.S., Cunha, G.M.A., Chaves, M.H., Santos, F.A., Rao, V.S., 2008. Anti-inflammatory effect of α, β-amyrin, a pentacyclic triterpene from Protium heptaphyllum in rat model of acute periodontitis. Inflammopharmacology 16, 48-52.; Dat et al., 2009Dat, N.T., Thao, N.P., Quynh, L.T.P., Minh, C.V., Bach, T.T., Joon, L.J., 2009. Flavonoids from Eupatorium odoratum as inhibitors of NF-KB. J. Sci. Technol. 47, 1-6.; Valerio and Awad, 2011Valerio, M., Awad, A.B., 2011. β-Sitosterol down-regulates some pro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP-1 in J774A.1 murine macrophages. Int. Immunopharmacol. 11, 1012-1017.; Choi et al., 2012Choi, J.N., Choi, Y.-H., Lee, J.-M., Noh, I.C., Park, J.W., Choi, W.S., Choi, J.H., 2012. Anti-inflammatory effects of β-sitosterol-β-d-glucoside from Trachelospermum jasminoides (Apocynaceae) in lipopolysaccharide-stimulated RAW 264.7 murine macrophages. Nat. Prod. Res. 26, 2340-2343.; Fan et al., 2012Fan, S.-Y., Zeng, H.-W., Pei, Y.-H., Li, L., Ye, J., Pan, Y.-X., Zhang, J.-G., Yuan, X., Zhang, W.-D., 2012. The anti-inflammatory activities of an extract and compounds isolated from Platycladus orientalis (Linnaeus) Franco in vitro and ex vivo. J. Ethnopharmacol. 141, 647-652.).

To some isolated triterpenoids from Maytenus species, was assigned inhibitory effects of E2 prostaglandin (PGE2) in macrophages stimulated with bacterial endotoxin (Reyes et al., 2006Reyes, C.P., Núñez, M.J., Jiménez, I.A., Busserolles, J., Alcaraz, M.J., Bazzocchi, I.L., 2006. Activity of lupane triterpenoids from Maytenus species as inhibitors of nitric oxide and prostaglandin E2. Bioorg. Med. Chem. 14, 1573-1579.). Antinociceptive effect was demonstrated for the triterpenes in the formalin test (Lima et al., 2005Lima, F.V., Malheiros, A., Otuki, M.F., Calixto, J.B., Yunes, R.A., Filho, V.C., Monache, F.D., 2005. Three triterpenes from the resinous bark of Protium kleinii and their antinociceptive activity. J. Brazil. Chem. Soc. 16, 578-582.; Gaertner et al., 1999Gaertner, M., Muller, L., Roos, J.F., Cani, G., Santos, A.R.S., Niero, R., Calixto, J.B., Yunes, R.A., Monache, F.D., Cechinel-Filho, V., 1999. Analgesic triterpenes from Sebastiania schottiana roots. Phytomedicine 1, 41-44.). Longhi-Balbinot et al. (2011)Longhi-Balbinot, D.T., Martins, D.F., Lanznaster, D., Silva, M.D., Facundo, V.A., Santos, A.R.S., 2011. Further analyses of mechanisms underlying the antinociceptive effect of the triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene in mice. Eur. J. Pharmacol. 653, 32-40. showed the involvement of the opioid system in the mechanism of action of a triterpene in the formalin test, in which the antinociception was reverted by nonspecific and specific µ, δ and κ opioid receptors antagonism.

In a study of isolated compounds from M. senegalensis, Sosa et al. (2007)Sosa, S., Morelli, C.F., Tubaro, A., Cairoli, P., Speranza, G., Manitto, P., 2007. Anti-inflammatory activity of Maytenus senegalensis root extracts and of maytenoic acid. Phytomedicine 14, 109-114. demonstrated anti-inflammatory activity for three triterpenes derivatives, which were the maytenoic acid (8), the lupenone and the β-amyrin. These substances significantly inhibited edema in a dose-dependent relationship. In this research, the maytenoic acid showed effectiveness, being twice as active as indomethacin and even though lupenone and β-amyrin had less effectiveness, they demonstrated a good biological activity.


Mattos et al. (2006)Mattos, W.M., Campos, M.M., Fernandes, E.S., Richetti, G.P., Niero, R., Yunes, R.A., Calixto, J.B., 2006. Anti-edematogenic effects of velutinol A isolated from Mandevilla velutina: evidence for a selective inhibition of kinin B1 receptor-mediated responses. Regul. Pept. 136, 98-104. reported antiedematogenic effect from am steroid that was able to reduce the edematogenic response induced by carrageenan. Flavonoids exert important effect in many biologic systems, such as antitumor, anti-allergy, and anti-inflammatory, among others (Di Carlo et al., 1999Di Carlo, G., Mascolo, N., Izzo, A.A., Capasso, F., 1999. Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci. 65, 337-353.). A previous study showed that a flavonoid compound presented inhibitory activity against the NF-κB, a protein that regulates the pro-inflammatory and inflammatory cytokines transcription (Schmidt et al., 2010Schmidt, C.A., Murillo, R., Bruhn, T., Bringmann, G., Goettert, M., Heinzmann, Brecht, V., Laufer, S.A., Merfort, I., 2010. Catechin derivatives from Parapiptadenia rigida with in vitro wound-healing properties. J. Nat. Prod. 73, 2035-2041.). Landolfi et al. (1984)Landolfi, R., Mower, R.L., Steiner, M., 1984. Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Biochem. Pharmacol. 32, 1525-1530. reported that some flavonoids block the lipoxygenase and cyclooxygenase (COX) pathways, inhibiting the inflammatory mediators such as leukotrienes and prostaglandins.

Veloso et al. (2014a)Veloso, C.C., Rodrigues, V.G., Azevedo, A.O., Oliveira, C.O., Gomides, L.F., Duarte, L.P., Duarte, I.D., Klein, A., Perez, A.C., 2014a. Antinociceptive effects of Maytenus imbricata Mart. ex. Reissek (Celastraceae) root extract and its tingenone constituent. J. Med. Plants Res. 8, 68-76. verified antinociceptive effect of the extracts and tingenone obtained from the M. imbricata roots. The antinociceptive peripheral mechanism of action of tingenone was also demonstrated. It involves opioidergic pathways activation and nitric oxide (NO)/cyclic guanosine monophosphate (GMPc)/channels for sensitive potassium ATP (KATP) (Veloso et al., 2014bVeloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2014b. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to opioidergic activation. Planta Med. 80, 1615-1621., 2015Veloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2015. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP – sensitive K(+) channels pathway activation in mice. Eur. J. Pharmacol. 755, 1-5.) against mechanical hyperalgesia induced by E2 prostraglandin (PGE2). Cunha et al. (2010)Cunha, T.M., Roman-Campos, D., Lotufo, C.M., Duarte, H.L., Souza, G.R., Verri Jr., W.A., Funez, M.I., Dias, Q.M., Schivo, I.R., Domingues, A.C., Sachs, D., Chiavegatto, S., Teixeira, M.M., Hothersall, J.S., Cruz, J.S., Cunha, F.Q., Ferreira, S.H., 2010. Morphine peripheral analgesia depends on activation of the PI3Kγ/AKT/nNOS/KATP signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 107, 4442-4447. demonstrated that activation of the nitric oxide pathway by morphine was dependent on an initial stimulation of PI3Kγ/AKT protein kinase B (AKT) that in turn might cause the stimulation of nNOS and an increase in NO production.

In a study performed by Veloso et al. (2014b)Veloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2014b. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to opioidergic activation. Planta Med. 80, 1615-1621., it was showed that tingenone, when administrated in the right hind paw, induced local antinociceptive effect that was antagonized by naloxone, a nonspecific antagonist for the opioid receptors. Clocinnamox, naltrindole and nor-binaltorphimine, which are specific antagonists for the µ, δ and κ receptors, respectively, reverted the peripheral antinociception induced by tingenone. Bestatin, an aminopeptidase inhibitor, an enzyme that degrades opioid peptides, intensified the antinociceptive effect of tingenone. Thus, the results suggested the participation of the opioidergic system in the peripheral antinociception induced by tingenone.

Tingenone, when administrated in the right hind paw, also induced a local antinociceptive effect that was antagonized by l-NOArg, a nonspecific inhibitor of nitric oxide sintase (NOS), and by L-NPA, an specific inhibitor of neuronal NOS (Veloso et al., 2015Veloso, C.C., Rodrigues, V.G., Ferreira, R.C.M., Duarte, L.P., Klein, A., Duarte, I.D., Romero, T.R.L., Perez, A.C., 2015. Tingenone, a pentacyclic triterpene, induces peripheral antinociception due to NO/cGMP and ATP – sensitive K(+) channels pathway activation in mice. Eur. J. Pharmacol. 755, 1-5.). l-NIO, an specific inhibitor of the endothelial isoform, and the l-NIL, an specific inhibitor of the inducible form, did not change the peripheral antinociceptive effect of tingenone (4). ODQ, an specific inhibitor of soluble guanylate cyclase, prevented the peripheral antinociceptive effect of tingenone, and zaprinast, a phosphodiesterase inhibitor, enzyme that degrades GMPc, intensified the peripheral antinociceptive effect of the lowest dose of tingenone. Glibenclamide, a KATP channel blocker, but not tetraethylammonium chloride, a blocker of the voltage-dependent channels for potassium; dequalinium chloride, a blocker of the activated by small conductance calcium channels for potassium, and paxillin, a potent blocker of the channels for potassium activated by high conductance calcium, prevented the peripheral antinociceptive effect of tingenone (Fig. 1). The results showed that tingenone induced a peripheral antinociceptive effect by activation of the l-arginine/NO/GMPc/KATP pathway, revealing a potential to become a new analgesic drug.

Fig. 1
Mechanism of action proposed for tingenone. nNOS, neuronal nitric oxide sintase; l-Arg, l-arginine; NO, nitric oxide; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; KATP, channels for sensitive potassium ATP.

Conclusion

Studies of natural products are multidisciplinary. The path involves preliminary experimental tests of a plant crude extract and several steps that cost a lot of time and investment, before the main objective, that is the development of a drug (herbal or traditional) that can reach a population in need. This is very important in poor or under developed countries such as Brazil that presents a big biodiversity and a poor population.

Due to the popular use of Maytenus species for the treatment of inflammatory diseases, studies of pharmacological properties and characterization of the chemical compounds in the extracts and infusions are necessary to define and elucidate a safe and non-toxic use. This is also the base for the development of new drugs from natural products, but always targeting to elucidate the mechanism of action and to disclose the biological activity and the chemical structure responsible.

Tingenone has a big potential to become an analgesic, as demonstrated by its biological activities evaluation. It was demonstrated the opioidergic pathway activation by tingenone, whose peripheral antinociceptive action occurs by activation of l-arginine/NO/cGMP/KATP pathway. This mechanism of action is associated with various opioid analgesics. However, more studies are required to further elucidate its mechanism of action and new therapeutic actions.

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Publication Dates

  • Publication in this collection
    Jul-Aug 2017

History

  • Received
    27 Sept 2016
  • Accepted
    14 Feb 2017
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