Tatiana M. Souza-Moreira1, Geisiany M. Queiroz-Fernandes2, Rosemeire C.L.R. Pietro1,*.
1Department ofDrugsand Medicines, SchoolofPharmaceuticalSciences, São Paulo StateUniversity-UNESP, Rodovia Araraquara-Jau, km 1, 14800-903, Araraquara, São Paulo,Brazil. E-mail: email@example.com. 2Pró Reitoria de Pesquisa e Pós-graduação, Universidade do Sagrado Coração, Bauru, 17011-160, São Paulo, Brazil. E-mail: firstname.lastname@example.org.
Abstract: Stryphnodendron spp, popularly known as “barbatimão”, is the native Brazilian tree most often employed to treat wounds and infections. The aim of the present study was to highlight the importance of S. adstringens, as well as other Stryphnodendron species recognized as "barbatimão", to human health, depicting the relevance of ethnopharmacological knowledge to scientific evidence for uses, related chemical compounds, development of pharmaceutical formulations, and the establishment of toxicity parameters. For this purpose, the literature databases Pubmed, Scielo, Lilacs, CAPES Thesis, and Google Scholar were searched until 2017. It was observed that stem bark was the primary part of the plant used, mainly as a decoction, for wound healing and treatment of infectious and inflammatory disorders. Confirmed biological activities, including wound healing, anti-inflammatory, antioxidant, and antimicrobial activities, were related to the presence of compounds from tannin class, mostly proanthocyanidins. Toxicity parameters for stem bark were inconclusive, but toxicity was observed to a significant extent when seeds were ingested by cattle or other animals. Due to these important and confirmed biological activities, government policy encourages the phytotherapic use of S. adstringens, and some formulations with stem bark extracts were developed and patented. Furthermore, antiprotozoal, hypoglycemic, and antiviral activities were identified as promising.
Plants are a source of molecules with a wide variety of applications, and humanity has learned to harness their benefits and to recognize their toxic effects throughout history. Ethnopharmacological uses of plants represent part of each culture around the world, so it is no wonder that isolated active molecules are being used in standard preparations [1, 2]. Today, natural drugs, including plants and their derivatives, are one of the biggest sources of approved medicines . Brazil has extensive biodiversity, and many exotic species have been introduced, reflecting a rich folk medicine with the influence of native, African, and European peoples [3, 4]. In that sense, government policies were established over the years to protect Brazilian biodiversity and to stimulate drug development and phytotherapy in the country’s health system [5-7].
In Brazil, one of the native trees commonly used is known as “barbatimão”, from which stem barks are prepared as decoctions or infusions with the main purpose of wound and infection healing [8, 9]. On the other hand, the broad beans are also recognized as an abortive for cattle when they are eaten in the field [10, 11]. Other popular names of these trees include "barbatimão-verdadeiro", "barba-de-timão", "chorãozinho-roxo" and "casca-da-virgindade". The scientific name of the species is Stryphnodendron adstringens (Mart.) Coville, with accepted synonyms Acacia adstringens Mart., Mimosa barbadetimam Vell., Mimosa virginalis Arruda, Stryphnodendron barbatimam Mart., and Stryphnodendron barbadetiman (Vell.) Mart. [12, 13]. However, other Stryphnodendron species are also popularly known as “barbatimão” as S. obovatum Benth. (synonym of S. rotundifolium Mart.), S. polyphyllum Mart., and S. rotundifolium Mart.. Other species such as Abarema cochliocarpos (Gomes) Barneby & Grimes, Pithecellobium cocliocarpum (Gomez) Macbr., and Dimorphandra mollis Benth. can be mistakenly referred in the literature as “barbatimão” but they are recognized as “falso-barbatimão” which could be freely translated as “fake-barbatimão”. There are 42 species in the Stryphnodendron genus presently, and they are disseminated in the Neotropical region, from Costa Rica in Central America to the south of Brazil, with the majority of species in Brazil present either in the rainforest or in the Brazilian savanna (“Cerrado”) . Phylogenetic analysis of the Stryphnodendron genus showed very short internal branches but clustered together savanna species as S. adstringens and S. rotundifolium, whereas species from the rainforest such as S. polyphyllum formed a different cluster, indicating rapid evolution and morphological diversification in the group. Abarema, Pithecellobium, and Dimorphandra were not included in this study as their genera were not closely related to Stryphnodendron .
Thus, data compilation reviewing the studies already done with Stryphnodendron spp barks will contribute to the phytotherapeutic use of “barbatimão” in the health care system and to the development of efficient formulations. In addition, this data compilation will also highlight the gaps still present in literature in order to elucidate the safe use of the barks in a sustainable way and to create a future in which the active molecules of the extract can be utilized as new drugs or new drug prototypes. Furthermore, by stimulating the conservation of the species and disseminating its benefits to the scientific community, more drugs can be developed for treatment of wounds as well as infectious and inflammatory disorders.
In that sense, the aim of the present work is to review the existing information available about the benefits of S. adstringens and other “barbatimão” species from the Stryphnodendron genus to human health, thereby demonstrating the relevance of folk knowledge to scientifically-proven biological activities, formulations developed, toxicity parameters, and the main compounds involved.
2. Data collection methodology
The scientific names of the Stryphnodendron genus referred to as “barbatimão” were selected for search in databases. Those names comprised S. adstringens, A. adstringens, M. barbadetimam, M. virginalis, S. barbatimam, S. barbadetiman, S. discolor, S. obovatum, S. polyphyllum, and S. rotundifolium. Searches were performed in the following databases: Pubmed (https://www.ncbi.nlm.nih.gov/pubmed/), Scielo (http://www.scielo.br/), Lilacs (http://lilacs.bvsalud.org/), and the CAPES Brazilian Thesis databank (http://bancodeteses.capes.gov.br/banco-teses/#!/)up to November 5, 2017. Complementary information was searched in Google (http://www.google.com).
3. General aspects on literature about Stryphnodendron
A survey of the databases Pubmed, Scielo, and Lilacs identified about 200 papers covering “barbatimão” species (S. adstringens, S. obovatum, S. polyphyllum, and S. rotundifolium, including synonyms), and more than 200 Master and PhD Theses in Brazil were found in CAPES. After the year 2000, the number of publications about Stryphnodendron spp known as “barbatimão” increased about 10 times and twice in journals indexed in Pubmed after 2010 (Figure 1A). Most of the publications were related to the biological properties of the species, mainly for the treatment of internal and external infectious and inflammatory diseases, but also for wound and ulcerative wound healing related to the astringent and cicatrization properties, highlighting the ethnopharmacological attributes of the species. Demonstrating the ethnopharmacological use of a plant requires well-conducted scientific studies correlating the plant results with a well-established standard . Attention should be payed to studies of biological activity with inconclusive data, which, while not confirming ethnopharmacological use, can be one step in the right direction . To that end, the Brazilian Pharmacopeia and Government have amassed the efforts of recognized scientific institutions and internationally published papers to enable proper identification of “barbatimão” species, their active chemical constituents, and their therapeutic uses according to the proven efficacy of the species [17-19].
Chemical composition and standardization of methods to analyze the barks constitution are expressive. Although there are some studies related to plant toxicity of “barbatimão” species for cattle, there are few studies focusing on toxicity levels and safety in humans. Different medicinal topical products derived from bark extracts are being developed, and their activity has been demonstrated (Figure 1B).
Figure 1. Number of publications in the searched databases according year (A) and research area (B).
4. Botanical features and sustainable management aspects
Plants from genus Stryphnodendron belongs to Fabaceae Lindl. family, which comprises more than 200 genera . Trees of the genus are small to medium evergreen-sized, with an unbranched trunk, and the stem generally has tortuous and thick rust-colored bark [13, 20]. S. adstringens trees have a low and round top, while S. polyphyllum has the top large, and the top of S. rotundifolium is round and diffuse .
S. polyphyllum has the shortest petiole at 3-6.5 cm, which contrasts with S. adstringens at 6.5-9 cm and S. rotundifolium at 2.5-10 cm. Species are more easily differentiated by their bipinnate compound leaves; S. adstringens has 5-7 pairs of leaflets in opposite insertion with 5-6 pairs of second order leaflets alternately inserted, limb is asymmetrical ovoid, sometimes elliptical, with 1.5-3.5x1-2.5 cm emarginated or round apex, flat margin narrowly thickening; card form limb, glabrous, concolor, visible veins immersed in the limb in the superior face and salient in the inferior face. On the other hand, leaflets of S. polyphyllum shows higher number of pairs of leaflets (11-18, although less are present in leaflets close to the branch apex) in opposite insertion, also with higher number of pairs of second order leaflets (14-23) and insertion subopposite; limb is slightly asymmetrical, oblong (sometimes distal pairs are obovate and rarely proximal pairs are elliptical to oval), with 3-8x1.5-4 mm, mostly round apex but, sometimes, apex is obtuse, margin is revolute; card form limb, pubescent, subconcolor, darker superior face with invisible veins immersed in the limb and slightly visible in the inferior face [20-22]. S. rotundifolium has 6-13 pairs of leaflets in opposite insertion in distal pairs and subopposite in proximal pairs, 5-12 pairs of second order leaflets with alternate insertion (except distal pairs have opposite insertion), asymmetric to symmetric limb, generally orbicular, ovoid, elliptical or elliptical-ovoid (distal pairs are obovate) with 7-18x6-13 mm, asymmetrical apex generally retuse to emarginate, but sometimes round, sub-revolute margin, slightly thickening; card form limb, darker superior face with slightly visible immersed veins and central vein sometimes ridged, which is salient in the inferior face where the other veins are also slightly seen [20-22].
Inflorescence of these species are simple thyrse type. S. adstringens has snowy to yellowish inflorescences, rarely pinkish, geminate to ternate spikes, sometimes isolated, with 10-11 cm of length; S. polyphyllum has them in pink to reddish color, generally isolated spikes with 8-11 cm; while S. rotundifolium shows similar color of inflorescence as S. adstringens but 2-3 spikes of 9-18 cm of length . Flowers are hermaphrodite (but S. adstringens and S. rotundifolium can rarely show male and female flowers), calyx and corolla are campanulate. S. adstringens has snowy to yellowish flowers, corolla of 5 mm of length; S. polyphyllum has reddish flowers, corolla of 3-3.5 mm and, S. rotundifolium presents snowy, light green to yellowish flowers also with 3-3.5 mm corolla [20, 23]. They present seeds (8-10, 7-8 and 5-15, respectively in S. adstringens, S. polyphyllum, and S. rotundifolium) that are located in broad bean without salience [20, 23]. Nucoide legume of S. adstringensis straight, with rounded apex and base, S. polyphyllum and S. rotundifolium have it straight but rarely it is found slightly curved . There are no significant macro and microscopic differentiation among these species barks, which are commonly sold in free markets and therefore other assays could be done for identification, as tannin content [21, 24].
Attempts of conservation and domestication of these species in order to keep their chemical composition and biological properties include: germination [25-27], micropropagation [28, 29], callus culture [30, 31], and genetic studies [32, 33]. That is important since agricultural expansion eliminates native specimens and is an ecological concern that compels the sustainable management of these trees . Even more, barks are disordered extracted from the trees for medicinal purposes and the exploitation reduces regeneration process and the density of specimens, corroborating with the need of sustainable management, domestication, and conservation of the species [35-37].
5. Ethnopharmacological uses
Traditional medicine is an important source of medicinal information, and over time humans have learned from nature which plants, animals, and other elements could be used to help their survival. The wide biodiversity of flora in Brazil has provided an abundance of ethnopharmacologically important plants, and the use of “barbatimão” is constantly reported. It is noteworthy that the reports of the utilization of medicinal plants, including “barbatimão”, occurs mainly among adults with limited access to health care and is related to familiar traditional uses in addition to vendors in public markets or descendant of indigenous and maroon people [8, 24, 38-40].
Almost all collected papers about ethnopharmacological uses of “barbatimão” reported the treatment of wounds, followed by infection. Female genitourinary conditions and uterine disorders, and gastric ulcers were also frequently reported. Treatment of cancer was addressed in some ethnopharmacological surveys, as well as treatment of hemorrhage, diabetes, and pain. The most common preparations were infusions, macerations, and decoctions of the barks. S. adstringens and S. rotundifolium were the species most often observed. Cicatrizing, astringent, anti-inflammatory, and antimicrobial properties of the barks were the main attributes that characterized the folk choice of “barbatimão” and they were demonstrated scientifically [9, 41, 42]. Oral and topical were mentioned as the preferred routes of administration (Table 1).
Table 1. Overview of ethnopharmacological reports in literatureabout “barbatimão” uses.
One of the Brazilian policies related to the development of more economically accessible health treatments was to stimulate the phytotherapy in the primary healthcare system , and “barbatimão” was one of the ethnopharmacologically-used plants included in the list of medicinal plants in the system . Owing to this phytotherapeutic policy and the extensive ethnopharmacological use, the quality control, correct identification [54-56] and conservation of the species are essential requirements to ensure accurate treatment, to avoid toxicity or dose dilution with impurities . The Brazilian Pharmacopeia includes one monograph for correct identification of S. adstringens barks, purity and dose assays based in its high tannin content , which can vary throughout the year in the different species [57, 58]. Another ongoing concern is agricultural advance into habitat areas of these species .
Besides the stimulus for the national phytotherapeutic use of medicinal plants, ethnopharmacology has a cultural value and shelters an important source of molecules with biological activities and those are good reasons for more pharmacological studies and plant conservation practices.
6. Chemical composition 6.1. Metabolites identified in Stryphnodendron species The stem bark of “barbatimão” is the main utilized part of the plant and, therefore, its chemical composition was extensively studied focusing on its secondary metabolites, which led to the identification of high phenolic or tannic contents and elucidation of the main low- or high-weight tannins present in aqueous, hydroalcoholic, and acetone:water extracts [59-62]. Some extracts of “barbatimão” were also prepared using propylene glycol and water as solvent for use in pharmaceutical formulations. In those cases, a higher content of tannins was obtained with 80% propylene glycol .
Chromatographic methods are mainly used for the isolation and identification of the presence of a variety of polyphenolic compounds, especially hydrolysable and condensed (as the proanthocyanidins, prodelphinidins, prorobinetinidins, and profisetenidins) tannins in extracts and fractions of “barbatimão” . The compounds identified in the barks are presented in Table 2. The basic skeletal structure of hydrolysable tannins and proanthocyanidins are illustrated in Figure 2.
Table 2. Compounds identified in the stem bark of Stryphnodendron species known as “barbatimão”.