2016 Jun 5;185:182-201. doi: 10.1016/j.jep.2016.02.053. Epub 2016 Mar 2.

Luz DA¹, Pinheiro AM², Silva ML², Monteiro MC¹, Prediger RD³, Ferraz Maia CS⁴, Fontes-Júnior EA¹.

Author information

¹Faculdade de Farmácia, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém 66075-900, Pará, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pará, Belém 66075-900, Pará, Brazil.
²Faculdade de Farmácia, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém 66075-900, Pará, Brazil.
³Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis 88049-900, Santa Catarina, Brazil.
⁴Faculdade de Farmácia, Instituto de Ciências da Saúde, Universidade Federal do Pará, Belém 66075-900, Pará, Brazil; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pará, Belém 66075-900, Pará, Brazil. Electronic address: crismaia@ufpa.br.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Petiveria alliacea L. commonly grows in the tropical regions of the Americas such as the Amazon forest, Central America, Caribbean islands and Mexico, as well as specific regions of Africa. Popularly known by several different names including 'mucuracaá', 'guiné' and 'pipi', P. alliacea has been used in traditional medicine for the treatment of various central nervous system (CNS) disorders, such as anxiety, pain, memory deficits and seizures, as well as for its anaesthetic and sedative properties. Furthermore, the use of this species for religious ceremonies has been reported since the era of slavery in the Americas. Therefore, the present review aims to provide a critical and comprehensive overview of the ethnobotany, phytochemistry and pharmacological properties of P. alliacea, focusing on CNS pharmacological effects, in order to identify scientific lacunae and to open new perspectives for future research.

MATERIALS AND METHODS:

A literature search was performed on P. alliacea using ethnobotanical textbooks, published articles in peer-reviewed journals, unpublished materials, government survey reports and scientific databases such as PubMed, Scopus, Web of Science, Science Direct and Google Scholar. The Plant List, International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names.

RESULTS AND DISCUSSION:

Crude extracts, fractions and phytochemical constituents isolated from various parts of P. alliacea show a wide spectrum of neuropharmacological activities including anxiolytic, antidepressant, antinociceptive and anti-seizure, and as cognitive enhancers. Phytochemistry studies of P. alliacea indicate that this plant contains a diversity of biologically active compounds, with qualitative and quantitative variations of the major compounds depending on the region of collection and the harvest season, such as essential oil (Petiverina), saponinic glycosides, isoarborinol-triterpene, isoarborinol-acetate, isoarborinol-cinnamate, steroids, alkaloids, flavonoids and tannins. Root chemical analyses have revealed coumarins, benzyl-hydroxy-ethyl-trisulphide, benzaldehyde, benzoic acid, dibenzyl trisulphide, potassium nitrate, b-sitosterol, isoarborinol, isoarborinol-acetate, isoarborinol-cinnamate, polyphenols, trithiolaniacine, glucose and glycine.

CONCLUSIONS:

Many traditional uses of P. alliacea have now been validated by modern pharmacology research. The available data reviewed here support the emergence of P. alliacea as a potential source for the treatment of different CNS disorders including anxiety, depression, pain, epilepsy and memory impairments. However, further studies are certainly required to improve the knowledge about the mechanisms of action, toxicity and efficacy of the plant as well as about its bioactive compounds before it can be approved in terms of its safety for therapeutic applications.

KEYWORDS:

Astilbin (PubChem CID 119258); Benzyl trisulphide (PubChem CID 122842); CTK5A6491 (PubChem CID 57351065); Central nervous system; Ethnobotany; Isoarborinol (PubChem CID 12305182); Isoarborinol acetate (PubChem CID 91746815); Leridal chalcone (PubChem CID 15298277); Leridol (PubChem CID 10495449); Myricetin (PubChem CID 5281672); Petiveria alliacea; Petiveriin (PubChem CID 46926327); Pharmacology; Phytochemical constituents; Trans-stilbene (PubChem CID 638088)

PMID:

26944236

DOI:

10.1016/j.jep.2016.02.053

Journal of Ethnopharmacology

Volume 185, 5 June 2016, Pages 182–201

Review

Ethnobotany, phytochemistry and neuropharmacological effects of Petiveria alliacea L. (Phytolaccaceae): A review

Diandra Araújo Luz ^a^,^b,
Alana Miranda Pinheiro ^a,
Mallone Lopes Silva ^a,
Marta Chagas Monteiro ^a^,^b,
Rui Daniel Prediger ^c,
Cristiane Socorro Ferraz Maia ^a^,^b^,^,^,,
Enéas Andrade Fontes-Júnior ^a^,^b

http://dx.doi.org/10.1016/j.jep.2016.02.053

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Abstract

Ethnopharmacological relevance

Petiveria alliacea L. commonly grows in the tropical regions of the Americas such as the Amazon forest, Central America, Caribbean islands and Mexico, as well as specific regions of Africa. Popularly known by several different names including ‘mucuracaá’, ‘guiné’ and ‘pipi’, P. alliacea has been used in traditional medicine for the treatment of various central nervous system (CNS) disorders, such as anxiety, pain, memory deficits and seizures, as well as for its anaesthetic and sedative properties. Furthermore, the use of this species for religious ceremonies has been reported since the era of slavery in the Americas. Therefore, the present review aims to provide a critical and comprehensive overview of the ethnobotany, phytochemistry and pharmacological properties of P. alliacea, focusing on CNS pharmacological effects, in order to identify scientific lacunae and to open new perspectives for future research.

Materials and methods

A literature search was performed on P. alliacea using ethnobotanical textbooks, published articles in peer-reviewed journals, unpublished materials, government survey reports and scientific databases such as PubMed, Scopus, Web of Science, Science Direct and Google Scholar. The Plant List, International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names.

Results and discussion

Crude extracts, fractions and phytochemical constituents isolated from various parts of P. alliacea show a wide spectrum of neuropharmacological activities including anxiolytic, antidepressant, antinociceptive and anti-seizure, and as cognitive enhancers. Phytochemistry studies of P. alliacea indicate that this plant contains a diversity of biologically active compounds, with qualitative and quantitative variations of the major compounds depending on the region of collection and the harvest season, such as essential oil (Petiverina), saponinic glycosides, isoarborinol-triterpene, isoarborinol-acetate, isoarborinol-cinnamate, steroids, alkaloids, flavonoids and tannins. Root chemical analyses have revealed coumarins, benzyl-hydroxy-ethyl-trisulphide, benzaldehyde, benzoic acid, dibenzyl trisulphide, potassium nitrate, b-sitosterol, isoarborinol, isoarborinol-acetate, isoarborinol-cinnamate, polyphenols, trithiolaniacine, glucose and glycine.

Conclusions

Many traditional uses of P. alliacea have now been validated by modern pharmacology research. The available data reviewed here support the emergence of P. alliacea as a potential source for the treatment of different CNS disorders including anxiety, depression, pain, epilepsy and memory impairments. However, further studies are certainly required to improve the knowledge about the mechanisms of action, toxicity and efficacy of the plant as well as about its bioactive compounds before it can be approved in terms of its safety for therapeutic applications.

Graphical abstract

: Figure options

Abbreviations

CNS, central nervous system;
KNO₃, potassium nitrate;
EAF, acetate fraction;
FH, hexanic fraction;
FHA, hydroalcoholic fraction;
FHAppt, precipitated hydroalcoholic fraction;
EPM, elevated plus maze;
WP, whole plant;
AP, aerial parts;
R, roots;
FST, forced swimming test;
OFT, open field test;
ETM, elevated T-maze;
MWM, Morris water maze;
SCE, sister chromatid exchanges;
PaLHE, P. alliacea leaf hydroalcoholic extract;
IC₅₀, half-maximal inhibitory concentration;
OECD, Organisation of economic co-operation and development;
DTS, dibenzyl trisulphide;
TLC, thin-layer chromatography;
MeOH, methanol;
HCl, hydrochloric acid;
NH₄OH, ammonium hydroxide;
HPLC, high-performance liquid chromatography;
MAPK, mitogen-activated protein kinase;
RSK, ribosomal S6 kinase;
NFTs, neurofibrillary tangles;
BSA, bovine serum albumin;
RBCs, red blood cells;
PKC, protein kinase C;
NO, nitric oxide;
NFκB, nuclear factor kappa B;
TNF-α, tumour necrosis factor alpha;
IL-1β, interleukin 1β;
COX-2, cyclooxygenase-2;
CG/MS, gas chromatography coupled to mass spectrometry

Chemical compounds studied in this article

Astilbin (PubChem CID 119258);
Benzyl trisulphide (PubChem CID 122842);
CTK5A6491 (PubChem CID 57351065);
Isoarborinol (PubChem CID 12305182);
Isoarborinol acetate (PubChem CID 91746815);
Leridol (PubChem CID 10495449);
Leridal chalcone (PubChem CID 15298277);
Myricetin (PubChem CID 5281672);
Petiveriin (PubChem CID 46926327);
Trans-stilbene (PubChem CID 638088)

Keywords

Petiveria alliacea;
Ethnobotany;
Phytochemical constituents;
Pharmacology;
Central nervous system

1. Introduction

The Petiveria belongs to the Phytolaccaceae, the most archaic family of the Caryophyllales, comprising about 17 genera and 120 pantropical species widely distributed throughout the American continent ( Duarte and Lopes, 2005). Among the species of Petiveria, the most popular is Petiveria alliacea L. It is a perennial shrub with a rigid and straight stem, reaching a height of up to 5–150 cm (Almanza, 2012; Duarte and Lopes, 2005; Rzedowski and de Rzedowski, 2000). The alternating and elliptical leaves, small bisexual flowers (white, whitish-pink or green) and achene-type fruits are typical of this plant ( Andrade, 2011 and Andrade et al., 2012; Duarte and Lopes, 2005 and Rzedowski and de Rzedowski, 2000; Soares et al., 2013). This plant is native in tropical regions such as the Amazon rainforest, Central and South America, the Caribbean islands and sub-Saharan Africa (Rzedowski and de Rzedowski, 2000). The medicinal use of P. alliacea occurs in several regions of the world, mainly in American continent. In the folk medicine, it has curative and mystical purposes, which illustrates the importance to local tradition and culture.

For example, in Brazil, this plant has been used in religious ceremonies in Brazil at least since the slavery era. Slaves used P. alliacea for its toxic and sedative effects. Thus, the plant is also popularly known as ‘Remedy to tame the Master’, which refers to its sedative property and potential to alter the mind and brain function ( Bastide, 1971, Caminhoá, 1884, Camargo, 2007, Gomes et al., 2005, Gomes et al., 2008, Peckolt and Peckolt, 1900 and Ramos, 1988; Rodrigues et al., 2003; Santos Filho, 1947).

According to indigenous medicine, the root, powder and leaf of P. alliacea have been associated with several therapeutic properties, such as diuretic, antispasmodic, emmenagogic, analgesic, anti-inflammatory, antileukaemic, antirheumatic, antihelminthic, antimicrobial and depurative properties ( Duarte and Lopes, 2005; Lima et al., 1991). In addition, different preparations of P. alliacea are utilized for its activities on the central nervous system (CNS) such as anticonvulsant, anxiolytic, mnemonic, anaesthetic and sedative ( Gomes et al., 2005 and Lima et al., 1991).

Over the last two decades, different research groups have validated many traditional uses of P. alliacea through the use of laboratory animals and a range of neurobehavioural paradigms and pharmacological approaches. Moreover, phytochemical research has expanded the knowledge about the metabolites present in the plant (i.e. sulphur derivatives, flavonoids, alkaloids and many others), revealing their potential to interact with biological systems, including many targets in the CNS ( Benevides et al., 2001; De Sousa et al., 1990; Monache and Suarez, 1992 and Williams et al., 2007). However, the P. alliacea mechanisms of action remain mostly unknown as well as the compounds involved in such activities.

On the other hand, despite its beneficial pharmacological properties, P. alliacea is also known to exert toxic effects on the CNS ( Lima et al., 1991). Remarkably, deaths after one year of chronic exposure to this plant have been reported (Peckolt and Peckolt, 1900). Therefore, the toxicological profile of this species has been addressed in recent studies.

The purpose of this review is to provide comprehensive information on the botany, traditional uses, phytochemistry, neuropharmacology and toxicological research of P. alliacea in order to explore its therapeutic potential focused on neuropharmacological properties, highlight the lacunae in the current knowledge and evaluate future research opportunities. The available information on P. alliacea was collected via electronic search (using PubMed, Scopus, Web of Science, Science Direct, Google Scholar) and a library search for articles published in peer-reviewed journals, unpublished materials, theses and ethnobotanical textbooks. The Plant List (www.theplantlist.org), International Plant Name Index and Kew Botanical Garden Plant name databases were used to validate the scientific names. This review thus may provide the scientific basis for future research work on the central effects of P. alliacea. Besides, this data compilation highlights the security in traditional medicine, religious rituals and ceremonies.

2. Ethnobotany

2.1. Taxonomy and botanical aspects

The taxonomic rating of P. alliacea shows some diversions, probably because earlier studies were performed using more archaic analytical techniques. Including, the plant has some scientific, registered and valid synonyms of P. alliacea include: Petiveria foetida Salisb., P. alliacea var. grandifolia Moq., P. alliacea var. octandra (L.) Moq., P. foetida Salisb., P. hexandria Sessé& Moc., P. ochroleuca Moq., P. octandra L. and P. paraguayensis D. Parodi ( Tropicos.org, 2015). It is probably that the diversions on taxonomy occurs because earlier studies were performed using more archaic analytical techniques. Consequently, the accurate morphology of some structures (the seed, for example) could not be identified and a genus was included in the wrong family (Neves and Bauermann, 2006). For instance, this species was classified as a member of the Rivinoideae subfamily ( Nowicke, 1968 and Rohwer, 1993). Other authors classified P. alliacea as a member of the Petiveriaceae, which is a subgroup of the Phytolaccaceae ( Brown and Varadarajan, 1985, Culham, 2007 and Judd et al., 2002). The species of the Petiveriaceae have four tepals, a minimum of four stamens, a gynoecium with one carpel and a drupe or achene with indehiscent-type fruit, with a slightly lenticular seed and embryonic distinctions (Almanza, 2012; APG III, 2003; Brown and Varadarajan, 1985, Culham, 2007 and Cronquist, 1981; Engler and Prantl, 1894; Judd et al., 2002 and Neves and Bauermann, 2006).

On the other hand, according to the majority of the botanical studies on P. alliacea, the plant belongs to the order of Caryophyllales, also known as Centrospermae, and a member of Phytolaccaceae, which is a more accurate taxonomic classification ( Almanza, 2012, APG III, 2009 and Cronquist, 1981). The Phytolaccaceae comprises 17 genera, and 70–125 pantropical species have been reported. The members of this family are better adapted to shaded and subhumid places (Almanza, 2012; Duarte and Lopes, 2005; Gomes, 2006 and Ke et al., 2003; Marchioretto, 1989; Soares et al., 2013; Steinmann, 2010; Stevens, 2010).

Robert Brown first described the Phytolaccaceae. It is primarily composed of perennial herbs, but shrubs, trees and vines have also been reported. Members of this family have a straight stem as well as alternating, petiolate leaves in the majority of cases. The flowers are actinomorphic in shape, are more frequently hermaphroditic and are organized into inflorescences, which may be of auxiliary, terminal, racemose, cymose, panicle or spike types. A minimum of three stamens constitute the androecium, which are not distributed ordinately but are associated with the tepals and inserted in a hypogynous disc. The ovaries are often superolateral, and the indehiscent fruits can be fleshy or dry with one unique wilt seed per locule (Almanza, 2012; Rzedowski and de Rzedowski, 2000; Shang et al., 2003; Steinmann, 2010 and Stevens, 2010). The plants of this family show variable pollen morphology, with birds and wind spreading the seeds, and insects promoting pollination (Lorenzi, 1992; Neves and Bauermann, 2006).

The complete botanical description of P. alliacea is presented in Table 1. The Petiveria represents a group of herbaceous or shrub plants and perennial herbs. It is characterized by an erect, branched and cylindrical main structure or stem. The chemical components of the plant produce a strong odour, usually associated with garlic ( Almanza, 2012; Rzedowski and de Rzedowski, 2000). This feature justifies its species name alliacea ( Alonso, 1998). This genus is characterized by alternating leaves. As depicted in Fig. 1, the leaves also exhibit small stipules, and are petiolate, membranous and glabrous (Almanza, 2012; Rzedowski and de Rzedowski, 2000).

Table 1. Botanical characteristics of Petiveria alliacea L.

Petiveria alliaceaL.
Representatives and structures	Description	Dimension	Reference
Representatives	Perennial herbaceous or shrubby plant.	5cm to 1.5m	Almanza, 2012; Duarte and Lopes, 2005; Rzedowski and de Rzedowski, 2000.
Stem	It is a straight and rigid structure. It is commonly contains a slender branch with longitudinal stripes.	Variable length	Almanza, 2012; Andrade, 2011; Joly, 1979; Gomes, 2006; Rzedowski and de Rzedowski, 2000.
Roots	Fusiform roots with irregular branches and fine longitudinal stripes. The external surface presents a light greyish-brown or yellowish-brown colour.	Variable length	Gomes, 2006.
Leaves	It is an acuminate leaf with oblong or elliptical anatomy. The leaves are alternately distributed and membranous with herbaceous consistency, short petiole of pinnate camptodromous (brachidodromous) venation type. The length of the petioles and stipules vary between 0.6 and 1cm and 2mm, respectively.	5–10cm in length;2–6cm wide	Almanza, 2012; Di Stasi and Hiruma-Lima, 2002; Duarte and Lopes, 2005; Gomes, 2006; Rocha et al., 2006; Rzedowski and de Rzedowski, 2000; Soares et al., 2013.
Peduncle	Simple free peduncle, characterized by its narrow shape and flexibility.	0.5–2.5cm in length	Rzedowski and de Rzedowski, 2000.
Flowers	Flowers white, sessile and bisexual, with actinomorphic symmetry, whitish-pink or green to pale brown in colour. It has three main longitudinal ribs, oblong linear petals and a tetramerous perigonium. The flowers are composed of spikes or inflorescences.	4–6mm long and about 1 MM wide (the petals)	Almanza, 2012; Andrade, 2011; Di Stasi and Hiruma-Lima, 2002; Gomes, 2008; Rzedowski and de Rzedowski, 2000; Soares et al., 2013; Udulutsch et al., 2007.
Inflorescence	The inflorescences are racemose and present two possible localizations, terminal or axial.	10–15cm in length	Di Stasi and Hiruma-Lima, 2002; Gomes, 2008.
Filaments	There are fine filaments uneven in length, more or less persistent.	3–5mm in length	Rzedowski and de Rzedowski, 2000.
Androecium	The androecium presents four to eight irregular stamens shorter than tepals. The androecium is localized in a fleshy structure and contains free filiform fillets.	–	Soares et al., 2013; Udulutsch et al., 2007
Gynoecium	The gynoecium is a unicarpellate, subulate, deflexed and laterally flattened organ. This structure is tomentose, and the stigma is sessile and penicillate.	–	Di Stasi and Hiruma-Lima et al., 2002; Soares et al., 2013; Udulutsch et al., 2007
Fruit	Cylindrical achene-type fruit, with longitudinal stripes and similar seed dimensions. It is flattened and rounded and linear, with adherent pericarp and membranous forehead situated close to the rachis. It may be wrapped by rigid petals.	6–8mm in length;1–2mm in width	Di Stasi and Hiruma-Lima, 2002; Rzedowski and de Rzedowski, 2000; Soares et al., 2013; Udulutsch et al., 2007
Anthers	Frequently, the anthers are prematurely obsolete, sagittal or cylindrical, localized near the oblong, long linear slit at both ends.	1.5–2mm in length	Soares et al., 2013; Udulutsch et al., 2007
Ovary	The ovary is cylindrical or flattened.	–	Rzedowski and de Rzedowski, 2000.
Stigma	It is sessile or pedicle, localized laterally.	–	Rzedowski and de Rzedowski, 2000; Soares et al., 2013; Udulutsch et al., 2007
Pollen	Pollen grains are of the stephanopontoperculate type. It is tiny, circular and radially symmetrical with a high concentration of sexine in the pores.	24–27.1µm	Bath and Barbosa, 1972; Neves and Bauermann, 2006

Adapted from Almanza (2012).

Table options

: Fig. 1.
Principal anatomic structures of Petiveria alliacea L. Adapted from Almanza (2012).; Figure options

The flowers are small, actinomorphic, hermaphroditic, and white, green or pink in colour. The inflorescences are composed of long curls, which may be axillary or terminal. The curls are composed of 8–30 flowers with bracts and bracteoles as well. The perianth consists of four free petals, which are intimately associated with the fruit. The androecium is filiform in nature, with the number of stamen filaments ranging from four to nine. The anthers are fixed, and the fruit is an achene with two lobules and four to six spines on the dorsal area (3–5 mm in length) (Almanza, 2012; Rzedowski and de Rzedowski, 2000).

In this genus, the seed and embryo are straight and membranous in the superior region. The ovary is unicarpelar and unilocular in nature, and is localized on the apocarps (top region) presenting a single egg. The stigma may be sessile or subsessile, and is connected by a lateral gap (Almanza, 2012; Rzedowski and de Rzedowski, 2000). The South American samples were found to be of stephanopontoperculate pollen morphology. This pollen morphology could only be characterized through electron microscopy analysis (Neves and Bauermann, 2006). Thus, earlier studies on the pollen morphology of this genus, which used only optic microscopy, reported a pantoporate morphology (Barth and Barbosa, 1972, Bortenschlager, 1973 and Erdtman, 1952).

In P. alliacea samples from the Amazon, flowering was the highest in the months of September and November, for an average of 20–21 days. The lowest flowering average was recorded in February and July, for nine and seven days, respectively. Fruiting was not observed in March, June, July and November. The highest fruiting average was 21 days in the months of April and May. The lowest fruiting average was six days in the month of December ( Assis et al., 2013).

For the samples collected from the southern region of Brazil, flowering was the highest from the months of November to March (Neves and Bauermann, 2006). Flowering and fruiting were also reported from December until April (Hatschbach and Guimarães, 1973). The different periods of flowering and fruiting reported in various studies can be primarily attributed to the different climate conditions of the regions from which the samples were collected. These variations may influence other plant traits, such as phytochemical composition (see the following sections).

2.2. Distribution and traditional uses

Different theories have been proposed for the original geographic distribution of P. alliacea. This species was first described in Jamaica in the 18th century ( Linnaeus, 1753), which supports the theory of slaves bringing P. alliacea L. from Africa to Brazil in South America (Gomes, 2008; Kubec and Musah, 2001).

According to studies conducted by Germosén-Robineau (1995), this plant is native to Central America (Rocha et al., 2006), whereas Di Stasi and Hiruma-Lima (2002) indicated that South America was the first area where this plant occurred. Moreover, recent studies have noted a higher incidence of this species in a wild and subspontaneous state throughout South America (Andrade, 2011; Marchioretto, 2010; Soares et al., 2013).

Based on these data, P. alliacea is found to be common in tropical regions of the Americas such as the Amazon forest, Central America, Caribbean islands and Mexico, as well as specific regions of Africa. This species is endemic to these regions ( Almanza, 2012 and Gupta, 1995; García-González et al., 2006; Rzedowski and de Rzedowski, 2000). It adapts to humid, warm and shaded environments (Marchioretto, 1989; Soares et al., 2013). In addition, as summarized in Table 2, P. alliacea is known by various popular names according to their geographic localization.

Table 2. Popular names of Petiveria alliacea L. According to geographic localization.

Popular name	Geographic localization	References
Ajillo	Colombia	Gupta, 1995.
Amansa-senhor (Tame-master)	Brazil: Amazonas and Bahia	Braga, 1992; Camargo, 2007; Gupta, 1995; Di Stasi and Hiruma-Lima, 2002; Gomes et al., 2005; Ximenes, 2008.
Amanu	Cuba	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Anamú	Colombia; Cuba; Panama; Peru; Dominican republic; Venezuela; USA	Braga, 1992; Gomes, 2006; Gupta, 1995; Rodríguez et al., 2004.
Apacin	Brazil: amazonas, Pará and Roraima; Guatemala	Braga, 1992; Gomes, 2006; Gupta, 1995; Rodríguez et al., 2004.
Apasote de zorro	Guatemala	Rodríguez et al., 2004.
Apurito	Colombia	Braga, 1992; Gomes, 2006; Gupta, 1995.
Ave	Haiti	Rodríguez et al. (2004).
Caá	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Chambira	Peru	Braga, 1992; Gomes, 2006; Gupta, 1995.
Da-hua-ta	Colombia: Mikuna	Braga, 1992; Gomes, 2006; Gupta, 1995.
Erva de alho	Brazil: Amazonas, Pará and Roraima	Braga, 1992; Gomes, 2006; Gupta, 1995.
Erva-guiné	Brazil	Hoehne, 1939; Pio Correa, 1969.
Erva-pipi	Brazil: Pernambuco and São Paulo	Di Stasi and Hiruma-Lima, 2002.
Erva-de-tipi	Brazil	Lima et al., 1991.
Gambá-tipi	Brazil: Mato Grosso	DI Stasi and Hiruma-Lima, 2002.
Gorarema	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Gorazema	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Guiné	Brazil: Pernambuco and São Paulo	Braga, 1992; Gupta, 1995; Hoehne, 1939; Lima et al., 1991; Pio Correa, 1969; Ximenes, 2008.
Guinea hen	Colombia: San Andrés and Providencia	Rodríguez et al., 2004.
Guinea hen weed	Jamaica, Panamá and USA	Braga, 1992; Gupta, 1995; Rodríguez et al., 2004; Ximenes, 2008; Yukes and Balick, 2010.
Herbe aux poules	France	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Hierba del Zorrillo	Mexico	Fletes-Arjona et al., 2013.
Ipacina	Honduras and Nicaragua	Rodríguez et al., 2004.
Ipicina	Nicaragua	Braga, 1992; Gupta, 1995; Ximenes, 2008; Yukes and Balick, 2010.
Iratacaca	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Koujourouck	Dominican Republic	Rodríguez et al., 2004.
Lanceilla	Colombia	Braga, 1992; Gomes, 2006; Gupta, 1995.
Macur	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Mapurita	Colombia	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Mapurite	Venezuela	Braga, 1992; Gupta, 1995; Rodríguez et al., 2004; Ximenes, 2008.
Micura	Peru	Braga, 1992; Gomes, 2006; Gupta, 1995.
Mucura	Colombia, Peru	Braga, 1992; Gomes, 2006; Gupta, 1995; Rodríguez et al., 2004.
Mucuracaá or Mucura-caá	Amazon Region (Brazil): Amazonas, Pará and Roraima	Braga, 1992; DI Stasi and Hiruma-Lima, 2002; Gomes, 2006; Gupta, 1995; Hoehne, 1939; Pio Correa, 1969; Rocha, 2004; Ximenes, 2008.
Mapuro	Colombia	Braga, 1992; Gomes, 2006; Gupta, 1995.
Ocoembro	Brazil: Rio de Janeiro	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Ojúùsàjú	Africa	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Paraacaca	Brazil: Rio de Janeiro	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Paracoca	Brazil: Rio de Janeiro	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Patscang ay (skunk leaf)	Mexico: Isthmus of Tehuantepe (Zoque-Popoluca)	Leonti et al., 2003.
Pats ujts (Skunk herb)	Mexico: Isthmus of Tehuantepe (lowland Mixe)	Leonti et al., 2003.
Pipi	Brazil: Rio de Janeiro; Colombia; Venezuela	Braga, 1992; Gomes, 2006; Gupta, 1995; Di Stasi and Hiruma-Lima, 2002; Hoehne, 1939; Lima et al., 1991; Pio Correa, 1969; Ximenes, 2008.
Pipí	Argentina	Rodríguez et al. (2004).
Puante	France	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Raiz-de-conconha	Brazil: Pernambuco and São Paulo	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Raiz-de-guiné	Brazil: Pernambuco and São Paulo	Braga, 1992; Di Stasi and Hiruma-Lima, 2002; Gupta, 1995; Ximenes, 2008.
Raiz de pipi	Colombia	Braga, 1992; Gomes, 2006; Gupta, 1995.
Timbó	Brazil: Amazonas	Braga, 1992; Gupta, 1995; Ximenes, 2008.
Tipi	Brazil: Amazonas, Ceará and Bahia	Bezerra, 2006; Braga, 1992; DI Stasi and Hiruma-Lima, 2002; Gomes, 2006; Gupta, 1995; Hoehne, 1939; Lima et al., 1991; Pio Correa, 1969; Rodríguez et al., 2004; Ximenes, 2008.
Tipi verdadeiro	Brazil: Ceará and Bahia	Braga, 1992; Di Stasi and Hiruma-Lima, 2002; Gomes, 2006; Gupta, 1995.
Zorrillo	Colombia; Mexico	Gupta, 1995; Rodríguez et al., 2004.

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Due to its diverse medicinal uses, this plant was exported to other continents. Nowadays, P. alliacea is available in North America (southern USA and Mexico), Central America (El Salvador, Guatemala, Panama, Nicaragua and Honduras), the Caribbean (Cuba, Haiti, Jamaica and Martinique), South America (Brazil, Argentina, Colombia, Peru, Venezuela and Paraguay), Africa and India ( Almanza, 2012; Rzedowski and de Rzedowski, 2000) (see Fig. 2).

: Fig. 2.
Geographical distribution of Petiveria alliacea L.; Figure options

P. alliacea was employed ethnomedically primarily in the American continent, but nowadays it is widely used in traditional medicine in different regions of the world ( Almanza, 2012 and Camargo, 2007). In general, the consumption of 9 g of the dried plant with 600 ml of boiled water is recommended three times daily ( Ferraz et al., 1991a and Ferraz et al., 1991b). Other traditional preparations include a decoction or infusion prepared with 30 g of dried anamu whole herb in a litre of water. For this treatment, dosages from a quarter to half a cup must be consumed three times daily or used topically ( Taylor, 2005). Additional uses of P. alliacea in folk medicine are presented in detail in Table 3 and Table 4.

Table 3. Indications and forms of traditional use of Petiveria alliacea L.

Indication	Forms of use
Buccal anti-inflammatory and analgesic	Tea of roots and leaves: 10g in 1L of water, four times a day.
Cancer	Decoction of leaves: 40g in 1L of water, three times a day.
Cancer	Plant juice (juice): 25–30 fresh leaves (green), filtered with 1L of cold water, pure. This filtered juice should be consumed three times a day (morning, afternoon and night).
Cystitis	Decoction of leaves or roots: 30g/L.
Headache	Compress of macerated leaves.
Rheumatic pains, neuralgia, polyneuritis (beriberi), paralysis	Tincture to friction: 350g from roots in 40% alcohol.
Stimulant, diaphoretic and diuretic	Decoction from leaves or roots: 30g in 1L of water to be taken in tablespoons during the day.
Paralysis	Baths: 500g of roots in each bath.

Source: Adapted from Gomes (2006).

Table options

Table 4. Traditional uses of Petiveria alliacea L. worldwide.

Plant part	Location	Administration	Medicinal use	References
Aerial parts1	Bolivia	Oral	Colds	1Desmarchelier et al., 1997; 2Barrett, 1994; 3Desmarchelier et al., 1996a; 4Coe and Anderson, 1996a; 5Desmarchelier et al., 1996b.
Entire plant2	Nicaragua	Not stated
Leaf3	Argentina	Infusion oral
Leaf4	Nicaragua	Decoction oral
Leaf5	Peru	Leaves oral
Stem and root1	Guatemala	Powder inhalation	Sinusitis	1Girón et al., 1991.
Root1	Paraguay	Decoction oral	Sinusitis	1Girón et al., 1991.
Entire plant1	Nicaragua	Not stated	Other respiratory tract disorders	1Coe and Anderson, 1996a; 2Perez and Anesini, 1994; 3Ruffa et al., 2002; 4Leonti et al., 2003.
Leaf2	Argentina	Decoction oral
Leaves and stem 3	Argentina	Not stated
Not stated 4	Mexico	Not stated
Aerial parts1	Colombia	Infusion external	Snakebite	1Otero et al., 2000; 2Barrett, 1994.
Entire plant2	Nicaragua	Plant external	Snakebite	1Otero et al., 2000; 2Barrett, 1994.
Aerial parts1	Colombia	Oral	Childbirth	1Garcia-Barriga, 1974; 2Cosminsky, 1982; 3Hodge and Taylor, 1957.
Entire plant2	Mexico	Infusion oral
Entire plant3	Dominican Republic	Oral
Aerial parts1	Paraguay	External	Insecticide	1Schmeda-Hirschmann and Rojas de Arias, 1992; 2Medeiros et al., 2013; 3Schmeda-Hirschmann and Rojas de Arias, 1990.
Not stated2	Brazil	Not stated
Leaf3	Brazil	Leaves not stated
Entire plant1	Brazil	Oral	Abortive	1Dragendorff, 1898; 2Milliken, 1997; 3Schmeda-Hirschmann and Rojas de Arias, 1990; 4Lores and Pujol, 1990; 5Mihalik, 1978; 6Roig and Mesa, 1945; 7Amadeo, 1888; 8Burlage, 1968.
Roots2,3	Brazil	Infusion or decoction
Entire plant4	Cuba	Decoction oral
Entire plant5	Guyana	Decoction oral
Entire plant6	Mexico	Oral
Root7,8	Puerto Rico and USA	Oral
Entire plant1	Brazil	Oral	Diuretic	1Dragendorff, 1898; 2Milliken, 1997; 3Schmeda-Hirschmann and Rojas de Arias, 1990; 4Silva, 2002; 5Medeiros et al., 2013; 6Bandoni et al., 1976.
Roots2,3	Brazil	Infusion or decoction
Not stated4	Brazil	Not stated
Leaf5	Brazil	Tea
Not stated6	Argentina	Oral
Leaf1	Argentina	Decoction oral	Urinary tract infections	1Perez and Anesini, 1994.
Aerial parts1	Brazil	Oral	Toothache or caries	1Van Den Berg, 1984; 2Medeiros et al., 2013; 3Silva, 2002; 4Barrett, 1994; 5Filipov, 1994; 6Martínez, 2010; 7Weniger et al., 1986.
Not stated2	Brazil	Not stated
Root or leaves3	Brazil	Mash roots and apply on tooth
Entire plant4	Nicaragua	Oral
Roots5	Argentina	Root periodontal or smoke inhalation
Entire plant6	Argentina	Infusion or decoction
Leaf7	Haiti	Macerated leaves
Entire plant1	Brazil	Infusion or decoction oral	Headache	1Elisabetsky and Castilhos, 1990; 2Oliveira et al., 2010; 3Schmeda-Hirschmann and Rojas de Arias, 1990; 4Branch and Silva (1983); 5Comerford, 1996; 6Weniger et al., 1986; 7Filipov, 1994; 8Oakes and Morris, 1958.
Leaf2	Brazil	Pomade and tincture
Leaf3	Brazil	Poultice and wash
Leaf and root4	Brazil	Tea
Leaf5	Guatemala	Leaves external
Leaf6	Haiti	Leaves inhalation
Root7	Argentina	Smoke inhalation
Root8	Virgin Islands	Oral
Entire plant1 and leaf2	Nicaragua	Decoction oral OR infusion external	Analgesic (other types of pains)	1Coe and Anderson, 1996a; 2Coe and Anderson, 1996b; 3Girón et al., 1991; 4Oliveira et al., 2010; 5Garcia et al., 2010; 6Ruffa et al., 2002.
Entire plant1 and leaf2	Paraguay	Decoction external
Root3	Brazil	Decoction
Leaf4	Brazil	Pomade and tincture
Leaf5	Brazil	Pomade and tincture
Leaves and stem6	Argentina	Not stated
Entire plant1	Cuba	Decoction	Diabetes	1Lores and Pujol, 1990.
Entire plant1	Cuba	Decoction oral	Anti-inflammatory	1Lores and Pujol, 1990; 2Germano et al. (1993); 3Medeiros et al., 2013; 4Quílez et al., 2004; 5Ruffa et al., 2002.
Root2	Brazil	Infusion oral
Not stated3	Brazil	Not stated
Not stated4	Dominican Republic	Not stated
Leaf and stem5	Argentina	Not stated
Entire plant1	Mexico	Plant external	Pimples	1Zamora-Martinez and Pola, 1992; 2Caceres et al., 1987.
Leaf2	Guatemala	Infusion external	Pimples	1Zamora-Martinez and Pola, 1992; 2Caceres et al., 1987.
Entire plant1	Mexico	Oral	Emmenagogue	1Roig and Mesa, 1945; 2Bandoni et al., 1976; 3Moreno, 1975; 4Gonzalez and Silva, 1987; 5Heckel, 1897; 6Amadeo, 1888; 7Burlage, 1968.
Not stated2	Argentina	Oral
Not stated3	Paraguay	Not stated
Not stated4	Venezuela	Oral
Root5,6,7	French Guiana, Puerto Rico and USA	Oral
Leaf1	Guatemala	Decoction external	Fever	1Comerford, 1996; 2Loustalot and Pagan, 1949; 3Milliken, 1997; 4David and Pasa, 2013; 5Girón et al., 1991; 6Bandoni et al., 1976.
Leaf and Stem2	Puerto Rico	Oral
Root3	Brazil	Infusion oral or tea
Leaf4	Brazil	Decoction oral
Root5	Paraguay	Oral
Not stated6	Argentina	Oral
Leaf1	Guatemala	Infusion external	Skin diseases	1Caceres et al., 1987; 2Girón et al., 1991; 3Martinez, 1984; 4Medeiros et al., 2013; 5Yukes and Balick, 2010.
Root2	Paraguay	Decoction external
Leaf3	Mexico	Leaves external
Not stated4	Brazil	Not stated
Leaf5	Dominican republic	External (topically)
Leaf and root1	Puerto Rico	Oral	Cholera	1Amadeo, 1888.
Entire plant1	Guatemala	Oral	Diarrhoea	1Logan, 1973; 2Perez and Anesini, 1994.
Leaf2	Argentina	Decoction oral	Diarrhoea	1Logan, 1973; 2Perez and Anesini, 1994.
Entire plant1	Guatemala	Oral	Digestive disorders	1Logan, 1973; 2Girón et al., 1991; 3Comerford, 1996; 4Branch and Silva, 1983.
Root2	Paraguay	Decoction oral
Leaf3	Guatemala	Decoction oral
Leaf and root4	Brazil	Tea
Leaf1	Guatemala	Oral	Ringworm	1Caceres et al., 1990; 2Germano et al., 1993.
Root2	Brazil	Infusion oral	Ringworm	1Caceres et al., 1990; 2Germano et al., 1993.
Not stated1	Brazil	Not stated	Malaria	1Moreno, 1975; 2Milliken, 1997; 3Carabalo et al., 2004; 4Vigneron et al., 2005; 5Ruffa et al., 2002.
Root2	Brazil	Infusion oral
Entire plant3	Brazil	Decoction
Leaf4	French Guiana	Not stated
Leaf and stem5	Argentina	Not stated
Entire plant1	Nicaragua	Not stated	Heart diseases	1Barrett, 1994; 2Silva et al., 2009.
Leaf2	Brazil	Not stated	Heart diseases	1Barrett, 1994; 2Silva et al., 2009.
Leaf1	Guatemala	Leaves oral	Blood disorders	1Villar et al., 1997.
Entire plant1	Nicaragua	Not stated	Liver disorders	1Barrett, 1994.
Entire plant1	Trinidad and Tobago	Not stated	Kidney disorders	1Barrett, 1994; 2Lans, 2006; 3Souza et al., 2014.
Leaf2	Trinidad and Tobago	Not stated
Leaf3	Brazil	Green leaf OR dry leaf
Not stated1	Brazil	Not stated	Allergy	1Medeiros et al., 2013; 2Oliveira et al., 2010.
Leaf2	Brazil	Not stated	Allergy	1Medeiros et al., 2013; 2Oliveira et al., 2010.
Root1,2	Brazil	Tea and baths	Osteoporosis	1Alves et al., 2007; 2Ferraz et al., 1991b.
Not stated1	Brazil	Not stated	Arthrosis	1Medeiros et al., 2013; 2Oliveira et al., 2010.
Leaf2	Brazil	Pomade and tincture	Arthrosis	1Medeiros et al., 2013; 2Oliveira et al., 2010.
Not stated1	Brazil	Not stated	Rheumatism	1Medeiros et al., 2013; 2Oliveira et al., 2010; 3Silva, 2002; 4Ferraz et al., 1991a; 5Bandoni et al., 1976.
Leaf2	Brazil	Pomade and tincture
Leaf3	Brazil	Bath associated with other plants
Entire plant4	Brazil	Bath associated with other plants
Not stated5	Argentina	Infusion oral
Not stated5	Argentina	Oral
Roots1	Dominican Republic	Alcoholic tincture oral	Arthritis	1Yukes and Balick, 2010.
Roots1	Dominican Republic	Infusion oral	Gynaecological disorders	1Ososki et al., 2002; 2Yukes and Balick, 2010.
Leaf and/or roots2	Dominican Republic	Infusion oral	Gynaecological disorders	1Ososki et al., 2002; 2Yukes and Balick, 2010.
Leaf1	Cuba	Not stated	Cancer	1Green Reinoso et al., 2014; 2Ruffa et al., 2002; 3Lores and Pujol, 1990; 4Rossi et al., 1990.
Leaf and stem2	Cuba	Not stated
Entire plant3	Cuba	Decoction
Leaf 4	Brazil	Oral
Leaf1	Brazil	Ointment	Worms	1Branch and Silva, 1983.
Leaf1	Guatemala	Decoction external	Fevers	1Comerford, 1996; 2Loustalot and Pagan, 1949; 3Cifuentes et al., 2001; 4Girón et al., 1991.
Leaf and stem2	Puerto Rico	Oral
Roots3	Brazil	Infusion oral
Roots4	Paraguay	Decoction oral
Leaf and stem1	Guatemala	Powder inhalation	Sinusitis	1Girón et al., 1991.
Roots1	Paraguay	Decoction oral	Sinusitis	1Girón et al., 1991.

Table options

Ethnobotanical studies have shown that leaf infusions or decoctions from P. alliacea were used in sacred rituals in Nicaragua, Panamá, Guatemala and Brazil ( Camargo, 2007; Coe and Anderson, 1996b; Girón et al., 1991, Joly et al., 1987, Leitão et al., 2009, Schardong and Cervi, 2000 and Souza and Neto, 2010). Reports describe P. alliacea associated with other plants for diverse purposes. For example, the healers and indigenous communities of the Amazon forest used P. alliacea in herbal baths to protect against witchcraft. These ceremonies were a means of driving away ‘bad spirits’ and producing visions or hallucinations ( Taylor, 1998; Maciel and Neto, 2006).

In Populaca culture (a Macro-Mayan ethnic group from Mexico), P. alliacea was used to ward off black magic ( Leonti et al., 2003). Moreover, P. alliacea, combined with many other additives, was used to prepare the ritual drink of ayahuasca ( Camargo, 2007 and Hoehne, 1939). This preparation is utilized to treat illnesses of a magical origin or that are intractable by medicine. The ayahuasca drink is employed in religious ceremonies for inducing visions and increasing spiritual abilities ( Rivier and Lindgren, 1972). Reports of the plant’s hallucinogenic effects are indicative of its ability to act on the CNS. Furthermore, voodoo practitioners in Haiti used P. alliacea as a ‘zombie poison’ to induce a prolonged psychotic state, with subjects falling into a deathlike stupor ( Albuquerque et al., 2012).

The Ticuna, an indigenous people of the Amazon, used roots of P. alliacea along with other plants to prepare curare, applied as poison to their arrows. This poison induces neuromuscular blockade, lethargy and death by asphyxia. The effects of these different preparations may not be exclusively related to P. alliacea, because the association of plants possibly produces synergistic or antagonistic effects ( Rodrigues and Carlini, 2004 and Rodrigues et al., 2008). The leaves and roots of this plant were used as stimulants in various regions across Brazil (Negri and Rodrigues, 2010). Trinidadian hunters bathed their dogs with a preparation of P. alliacea roots for increased alertness, as well as dabbing it on the dogs' noses to improve their scent-tracking ability ( Lans et al., 2001 and Muñoz et al., 2000).

In contrast, P. alliacea is also consumed in Latin America for its sedative effects in the form of infusions and aqueous preparations of roots at high temperature ( Germano et al., 1993). In the Dominican Republic, the root infusion is orally consumed to alleviate anxiety ( Ososki et al., 2002 and Mañon Rossi, 1983). The island communities of Brazil mash the leaves in alcohol and use this preparation to treat convulsions in children (Branch and Silva, 1983). In addition, migrants living in the remnants of the South-East Atlantic Forest (Brazil) treat cases of anxiety by the inhalation of the aerial parts (APs) of the plant (Garcia et al., 2010). Traditional populations of Mexico and some areas of Latin America use a leaf infusion to alleviate epilepsy crises, anxiety and paralysis (Martinez, 1984; Zamora-Martinez and Pola, 1992; Taylor, 1998). Indeed, weak infusion of the leaves or roots have been used in several parts of the world to boost memory (Mors et al., 2000).

During the era of slavery, female slaves used preparations of P. alliacea to seduce their masters or to protect themselves from being harassed by their employers. Thus, the plant was popularly known as amansa-senhor (‘Tame-Sir’ or ‘Tame-Master’ in English) ( Camargo, 2007, Schardong and Cervi, 2000 and Souza and Neto, 2010). Moreover, the surviving members of the quilombola communities have reported the use of this plant for its mind-altering effects ( Rodrigues and Carlini, 2004 and Rodrigues and Carlini, 2006). Quilombola communities prepare a cigarette known as tira-capeta (‘removing-the-devil’ in English). The tira-capeta is recommended for improving the learning abilities of adolescents and children, in cases of nervous breakdown due to overwork and for relieving sleep disturbances. Nine plants belonging to the tonics for the brain category are used in the preparation of this cigarette, including P. alliacea ( Rodrigues et al., 2008). It is also indicated to reduce cannabis use and other non-CNS uses (i.e. sinusitis, cold, etc.) ( Negri and Rodrigues, 2010).

Prolonged use of P. alliacea has been known to cause insanity. For instance, the acute consumption of high doses of this plant induces insomnia, hyperarousal and hallucinations, whereas chronic exposure leads to paradoxical symptoms including seizures, weakness and mental retardation. There are reports of deaths within one year of chronic use of P. alliacea ( Peckolt and Peckolt, 1900).

3. Phytochemistry

Many compounds have been isolated from P. alliacea, and some of them are patent protected ( Ferrer, 2007 and Taylor, 1998). The main chemical components include sulphur compounds, flavonoids, lipids and triterpenes, among others ( Benevides et al., 2001 and Cuervo, 2011).

3.1. Sulphur compounds

Unique to P. alliacea, these compounds are mainly localized in the roots, and are known as azufre derivatives (Fig. 3). The presence of cis-3,5-diphenyl-1,2,4 trithiolane (1) and elevated amounts of elementary sulphur was first identified by Adesogan (1974). When submitted to column chromatography, the petrol root extracts of P. alliacea afforded dibenzyl trisulphide (DTS) (2), isolated as a viscous and pungent-smelling oil ( De Sousa et al., 1990). This finding revealed DTS as a natural product, which has thus far been described as a synthetic product. It is a significant representative of sulphur.

: Fig. 3.
Sulphur compounds from Petiveria alliacea: cis-3,5-diphenyl-1,2,4 trithiolane (1), dibenzyl trisulphide (2), dibenzyl sulphide (3), dibenzyl disulphide (4), dibenzyl tetrasulphide (5), benzylhydroxymethyl sulphide (6), di(benzyltrithio) methane (7), di-n-propyl disulphide (8), (RsSc)-S-benzyl-L-cysteine sulphoxide (petiveriin A, 9), (SsRc)-S-benzyl-L-cysteine sulphoxide (petiveriin B, 10), (R)-S-(2-hydroxyethyl) cysteine (11), 6-hydroxyethiin A (12), 6-hydroxyethiin B (13), S-(2-hydroxyethyl) (2-hydroxyethane)-thiosulphinate (14), S-(2-hydroxyethyl) phenylmethane-thiosulphinate (15), S-benzyl (2-hydroxyethane)-thiosulphinate (16), S-benzyl phenylmethane-thiosulphinate (17), (Z)-thiobenzaldehyde S-oxide (18), (S_C2R_C7)-c-glutamyl-S-benzylcysteine (19), γ-L-glutamyl-petiveriin A (20) and γ-L-glutamyl-petiveriin B (21). Adapted from Bezerra, 2006 and Kubec and Musah, 2001, Kubec et al. (2002), Kubec and Musah (2005) and PubChem Compound Database (2015).; Figure options

Benevides et al. (2001) evaluated the antifungal activity of methanolic extracts of P. alliacea, reporting the highest activity with the root extracts. Thus, they submitted this extract to successive liquid/liquid partitioning in different solvents. The resultant residues were concentrated and posteriorly subjected to a new step of fractionation. This procedure resulted in six bioactive fractions, which afforded five new polysulphides. Thus, yellow and colourless oily substances called dibenzyl sulphide (3) and benzyl hydroxymethyl sulphide (4), respectively, were identified.

Other compounds included the yellow amorphous solid dibenzyl disulphide (5), as well as dibenzyl tetrasulphide (6) and di(benzyltrithio) methane (7), both being identified as orange amorphous solids. Finally, Benevides et al. (2001) described two sulphur compounds that were already registered: di-n-propyl disulphide (8), a colourless volatile oil with a strong odour of garlic, and DTS (2), described as a yellow amorphous solid.

Additionally, Kubec and Musah (2001) reported on the isolation and identification of non-volatile phytochemicals. Disruption of the P. alliacea tissue may have produced these compounds, because most of these elements are not present in the fresh tissue. These non-volatile constituents may serve as precursors of the phenyl/benzyl-containing compounds mentioned previously. In this study, fresh roots were extracted in boiling methanol (MeOH). The sequential addition of 3% hydrochloric acid (HCl) promoted the precipitation of the same material. This precipitate was filtered and subjected to cation exchange to separate the amino acid fraction. This fraction was eluted in ammonium hydroxide (NH₄OH), concentrated and subjected to high-performance liquid chromatography (HPLC). From this process, two diastereoisomers of the sulphoxide of S-benzylcysteine were obtained (Kubec and Musah, 2001); one appeared as small white plates and the other resembled long tiny white needles. According to the absolute configuration of the isolated amino acid, they were designated as (RsSc)-S-benzil-L-cysteine sulphoxide (petiveriin A) (9) and (SsRc)-S-benzyl-L-cysteine sulphoxide (petiveriin B) (10), respectively.

Subsequently, three additional amino acids, S-methyl-, S-ethyl- and S-propylcysteine derivatives, were detected in the roots of P. alliacea ( Kubec et al., 2002). The method used in the previous study was modified to achieve these amino acids (Kubec et al., 2001). Thus, this work identified three white solid compounds as S-substituted cysteine, named (R)-S-(2-hydroxyethyl) cysteine (11), 6-hydroxyethiin A (12) and 6-hydroxyethiin B (13) (Fig. 3). Furthermore, Kubec and Musah (2002) isolated four thiosulphinates: S-(2-hydroxyethyl) (2-hydroxyethane)-thiosulphinate (14), a yellow oil, as well as S-(2-hydroxyethyl) phenylmethane (15), S-benzyl (2-hydroxyethane) (16) and S-benzyl phenylmethane (17) thiosulphinates, which were white solids. The authors indicated these compounds to be products of the enzymatic breakdown of S-substituted cysteine derivatives (Kubec et al., 2002).

Sensory observations during experiments on P. alliacea led Kubec et al. (2003) to investigate these properties. On conducting the analysis, the disrupted tissue emitted a strong garlic odour, irritating the nasal and ocular mucosae, leading to a serious nasal discharge and lachrymation, respectively. A fresh homogenate from P. alliacea roots was submitted to chromatographic methods. This process isolated (Z)-thiobenzaldehyde S-oxide (18), a yellow sulphine pungent oil. This sulphine gave off an intense alliaceous odour, typically when the plant was bruised or cut. By contrast, none of the previously isolated thiosulphinates showed strong odour or lachrymatory effects. Therefore, the authors implicated this metabolite in determining these features of the plant.

The presence of γ-glutamyl dipeptides, which possibly act as a reserve of nitrogen and sulphur, was reported. Among other functions, these elements serve as intermediates in the biosynthesis of S-alk(en)ylcysteine sulphoxides (Kubec and Musah, 2005). (S_C2R_C7)-c-glutamyl-S-benzylcysteine (19) and two diastereomeric sulphoxides were termed (S_C2R_C7R_S)-c-glutamyl-S-benzylcysteine S-oxides or γ-L-glutamyl-petiveriins A (20) and B (21), respectively (Kubec and Musah, 2005) (Fig. 3), all three of which were white hygroscopic solids.

Finally, sulphur compounds have been detected in P. alliacea roots, at elevated concentrations and diversity. Thus, most studies on these compounds focus on the roots of the plant. It is worth noting that DTS (5) and DTS (2) were recently identified in the stem and leaves of P. alliacea ( Hernández et al., 2014). Moreover, organosulphur compounds were detected in the hydroalcoholic extracts of leaves by thin-layer chromatography (TLC) (Silva et al., 2015). Taken together, these data are indicative of the presence of these compounds in other plant parts.

3.2. Flavonoids and derivatives

Flavonoids and derivatives have been detected in the APs of P. alliacea, particularly in the leaves ( Monache et al., 1996, Di Stasi and Hiruma-Lima, 2002, Blainski et al., 2010 and Audi et al., 2001). The flavanones 6-formyl-8-methyl-7-0-methylpinocembrin (22), 6-hydroxymethyl-7-0-methylpinocembrin (leridol) (23) and 5-O-methyl ether (5-O-methylleridol) (24) were identified in the chloroform fraction of the leaf extract (Monache and Suarez, 1992). Moreover, the ethyl acetate fraction of the same extract was found to contain the flavonoids engeletin (25) and astilbin (26), as well as the flavonol myricitrin (27) (Fig. 4).

: Fig. 4.
Flavonoids and derivates from Petiveria alliacea: 6-formyl-8-methyl-7-0-methylpinocembrin (22), 6-hydroxymethyl-7-0-methylpinocembrin (leridol, 23), 5-O-methyl ether (5-O-methylleridol, 24), engeletin (25), astilbin (26), myricitrin (27), dihydro-kempleferol (28), dihydroquercetin (29), myricetin (30), leridal chalcone (31), petiveral (32) and petiveral 4-ethyl (33). Adapted from Bezerra, 2006 and PubChem Compound Database, 2015.; Figure options

The acid hydrolyses of the leaf extract afforded dihydro-kempleferol (28), dihydroquercetin (29) and myricetin (30) (Monache and Suarez, 1992). Previous research identified the AP extracts of P. alliacea as the source of the flavonoid leridal chalcone (31), as well as the flavanones petiveral (32) and o-petiveral-4-ethyl (33) ( Monache et al., 1996) (Fig. 4). Recently, the ethyl acetate fraction of P. alliacea obtained from leaves and stems was found to contain leridol, myricetin, petiveral and petiveral-4-ethyl ( Hernández et al., 2014).

3.3. Other compounds

Some phytochemical screenings were performed to identify secondary metabolites in P. alliacea. As expected, different fractions collected from different regions exhibited different phytochemical profiles. For example, in a TLC analysis of P. alliacea roots, a significant amount of coumarins, but not alkaloids, was detected ( Rocha and Silva, 1969). However, in a study investigating medicinal plants collected in Argentina, alkaloids were detected in the leaves and roots of P. alliacea ( Bandoni et al., 1976).

Fontoura et al. (2005) performed a phytochemical prospection of the ethanolic extract of P. alliacea leaves. The aqueous and chloroformic fractions of this extract were also studied. A colourimetric reaction was used to identify these compounds in the ethanolic extract. The results expressed the intensity of the reaction presented by each metabolite. A TLC analysis helped to identify the metabolite classes in the fractions. Thus, the ethanolic extract and the aqueous fraction showed a strongly positive reaction for steroids and coumarins, but not for tannins. The chloroformic fraction was found to present coumarins and tannins, but in lower concentrations.

Oliveira (2012) conducted a phytochemical prospection using a similar methodology to that used by Fontoura et al. (2005). This work evaluated the variation in the chemical composition of the powder and hydroalcoholic extracts of the APs and roots of P. alliacea. The plant material was collected in two different seasons (dry and rainy). The powder and AP extract were found to contain spumidic saponins in equal proportions in both periods. In the root samples, only the extract showed a major proportion of these saponins independently of the season of collection.

The intensity of the alkaloids' reactions varied with the detection technique used. The roots extract prepared from material collected during the rainy season showed a strong reaction in the Dragendorff test. Other preparations under study showed a similar profile of alkaloids to that in APs. Sugar reduction was observed in the roots and APs. Only the roots were found to contain sesquiterpene lactones, depsides and depsidones, but in low concentrations in both periods (Oliveira, 2012).

In their study, De Sousa et al. (1990) investigated the chemical constituents of P. alliacea. The plant material was collected, air-dried and separated into roots, stems, leaves and inflorescences. These parts of the plant were ground first with petrol and then with ethanol. The known chemical constituents were detected through standard physical and spectrometric methods and compared with authentic samples, whereas unknown compounds were identified based on their microanalysis and spectral data.

Thus, the inflorescence extract included the carbohydrate pinitol (34), as well as other unknown plant compounds, such as the steroid β-sitosterol (35), which is isolated from the roots and stem (Fig. 5). Potassium nitrate (KNO₃) was precipitated from the extracts of roots, stem and leaves. An elevated amount of nitrate was found to induce methaemoglobinaemia in cattle (Trheebilcock et al., 1978). This effect had already been identified in experimental murine models (Andrade, 2011 and Andrade et al., 2012), and it may be toxic to humans (De Sousa et al., 1990).

: Fig. 5.
Structures of other chemical constituents found in Petiveria alliacea: pinitol (34), β-sitosterol (35), trans-N-metil-4-methoxyproline (36), allantoin (37), α-friedelinol (38), isoarborinol (39), isoarborinol-acetate (40), babinervic acid (41) and 3-epiilexgenin A (42). Adapted from Bezerra, 2006 and PubChem Compound Database, 2015.; Figure options

In the same study, De Sousa et al. (1990) described two alkaloids from P. alliacea: an unpublished highly polar alkaloid isolated from the stem and termed trans-N-metil-4-methoxyproline (36), and allantoin (37), which is found in the stem and leaves. Some lipids and the triterpene α-friedelinol (38) were also detected in the leaves. Segelman and Segelman (1975) isolated the triterpenes isoarborinol (39) and isoarborinol-acetate (40) from the leaves of P. alliacea. Two other triterpenes were obtained from the AP extracts of the plant, babinervic acid (41) and 3-epiilexgenin A (42) ( Monache et al., 1996) (Fig. 5).

3.4. Essential oil

The essential oil can be obtained from the leaves, stem, roots and inflorescences of P. alliacea, which is yellow in colour, with a strong and unpleasant odour due to allyl sulphide ( Domínguez, 1928). P. alliacea also contains a powdery amorphous component known as petiverine, which is odourless, bitter, spicy and soluble in alcohol and ether. It is slightly soluble in acidic water solutions at 100 °C ( Matta, 1913 and Peckolt and Peckolt, 1900).

Bezerra (2006) conducted a comparative study of the volatile constituents of P. alliacea roots from two cities in the north-east of Brazil (Maranguape and Apuiarés) with gas chromatography coupled to mass spectrometry (CG/MS). The root essential oil from Manguarape was found to contain benzaldehyde (61.5%) (43), dibenzyl disulphide (18.1%) (5), trans-stilbene (14.1%) (44) and cinnamaldehyde (6.5%) (45), corresponding to 100% of the peaks obtained on the chromatogram. However, only benzaldehyde (53.8%), dibenzyl disulphide (29.7%) and trans-stilbene (3.3%) varied in the quantity of metabolites between the two distinct origins ( Bezerra, 2006) (Fig. 6).

: Fig. 6.
Components found in the essential oil of Petiveria alliacea: benzaldehyde (43), trans-stilbene (44), cinnamaldehyde (45), benzoic acid (46), benzyl thiol (47), benzyl alcohol (48), carvacrol (49), (Z)-3-hexenyl benzoate (50), p-vinyl-guaiacol (51), pentodecane (52), spathulenol (53), heneicosanone (54), undecane (55), toluenethiol (56) and phytol (57). Adapted from Bezerra, 2006 and PubChem Compound Database, 2015.; Figure options

In 1998, Ayedoun et al. investigated the volatile compounds in the essential oil of P. alliacea roots from Benin (West Africa). They obtained the oil by boiling the roots in deionized water using pentane as a liquid extractor, and the phytochemicals were detected by chromatographic methods. The analysis identified 13 compounds, which represent 97% of the oil composition. As illustrated in Fig. 5 and Fig. 6, the most abundant components were benzaldehyde (48.3%) (43), dibenzyl disulphide (23.3%) (5), DTS (9.4%) (2) and trans-stilbene (6.8%) (44) (Ayedoun et al., 1998). The chloroformic extracts of P. alliacea roots were found to contain organic compounds such as benzaldehyde (43), trans-stilbene (44) and benzoic acid (45) ( Adesogan, 1974).

Previously, Zoghbi et al. (2002) studied the composition of the inflorescence (3.3 g) essential oil from Belém and Ananindeua (northern Brazil). The oil was subjected to simultaneous distillation–extraction. The drying process was sequentially carried out in anhydrous sodium sulphate, yielding 0.05% w/w. The mass spectra and chromatographic analysis led to the detection of 11 substances (97.9%). The main compounds found were benzaldehyde (54.8%) (43), benzyl thiol (20.3%) (46) and dibenzyl disulphide (18.0%) (2) (Fig. 5 and Fig. 6). In their study, Neves et al. (2011) investigated the phytochemical composition of the essential oil from the leaves, stem, roots and inflorescence of P. alliacea from Pernambuco (a north-eastern state of Brazil). They followed a similar method of extraction and chemical characterization to that used by Zoghbi et al. (2002).

A better yield (0.12%) of the essential oil was obtained from the inflorescence than from other plant parts (<0.1%). The root oil contained the majority of compounds such as benzyl alcohol (46.6%) (47), dibenzyl disulphide (19.1%) (5), trans-stilbene (6.2%) (44) and DTS (5.6%) (2). The essential oil from the stem and leaves primarily consisted of carvacrol (stem: 48.3%; leaves: 50.9%) (48), (Z)-3-hexenyl benzoate (stem: 9.5%; leaves: 18.6%) (49), dibenzyl disulphide (stem: 23.1%; leaves: 17.6%) and additional benzyl thiol in the stem (9.0%) (46). Inflorescences present (Z)-3-hexenyl benzoate (30.5%) (49), carvacrol (29.7%) (48), dibenzyl disulphide (15.7%) (5) (2) and also DTS (5.8%) (2) ( Fig. 6).

Further studies have identified benzaldehyde in the essential oils of P. alliacea leaves (12.8%), roots (55.1%) and inflorescences (32.5%) from Rio de Janeiro (south-eastern state of Brazil) ( Castellar et al., 2014). Leaves were found to contain p-vinyl-guaiacol (24.3%) (50) and/or benzyl thiol (or benzenemethanethiol, 14.5%) (46). The roots presented a lower concentration of pentadecane (7.6%) (51), spathulenol (5%) (52) and heneicosane (4.4%) (53) as well as a small concentration of undecane (14.7%) (54) in the inflorescence (Fig. 6).

Recently, researchers evaluated the volatile components of P. alliacea APs from seven distinct regions of Martinique (French West Indies), collected during the dry and rainy seasons ( Kerudo et al., 2015). The most abundant among the 51 (89.1–98.1%) components found in the oil of different origins were toluenethiol (2.3–23.0%) (55), phytol (6.4–41.2%) (56), dibenzyl disulphide (13.2–35.3%) (5) and benzaldehyde (0.8–57.1%) (43) ( Fig. 5 and Fig. 6). Forty of these substances have been identified in previous studies. Kerudo et al. (2015) also noted that the differences in the concentration of major constituents depend on the region of collection and the harvest season. Moreover, some compounds detected in some studies were not reported in others, which highlights the differences between origin and phytochemical compositions.

4. Neuropharmacological activities

As described before, P. alliacea has been widely used in folk medicine to treat CNS disorders ( Branch and Silva, 1983 and Lima et al., 1991). The following sections of the present review will address the available data obtained in experimental studies using laboratory animals to highlight the promising neuropharmacological effects of P. alliacea as well as its isolated fractions and compounds.

4.1. Antinociceptive activity

P. alliacea is used across Latin America to relieve several types of pain, such as toothache and headache ( Lima et al., 1991) as well as ‘pain in the legs’ (Albuquerque et al., 2012). In this regard, Gomes et al. (2005) investigated the antinociceptive effects of acute administration of acetate (FA), hexanic (FH), hydroalcoholic (FHA) and precipitated hydroalcoholic fractions (FHAppt) of extracts from P. alliacea roots on female Swiss mice and the putative involvement of CNS mechanisms. The intraperitoneal (i.p.) administration of all tested fractions of P. alliacea (at doses of 100 and 200 mg/kg) attenuated neurogenic pain induced by the chemical stimuli with acetic acid (0.6%, 10 ml/kg, i.p.) (Gomes et al., 2005).

The antinociceptive effects of the P. alliacea fractions were also observed in the formalin test (formalin 1%, 20 µl, i.p.). FHA (100 and 200 mg/kg) induced a significant inhibition of pain responses in both the first (51.4% and 55.4%) and second (57.9% and 97.9%) phases of the test (Gomes et al., 2005). In addition, FH (200 mg/kg) and FHAppt (200 mg/kg) elicited antinociception selectively in the second phase of the formalin test, similarly to that observed for morphine (10 mg/kg, 89.6% inhibition), used as the positive control (Gomes et al., 2005).

Interestingly, the subcutaneous (s.c.) administration of the opioid receptor antagonist naloxone (2 mg/kg) prior to the formalin test was unable to prevent the antinociceptive effects of FH (200 mg/kg in both phases), FHA (200 mg/kg in the first phase) and FHAppt (200 mg/kg in the second phase) (Gomes et al., 2005). These results suggest a non-opioidergic mechanism mediating the antinociceptive effects of acute administration of different fractions of extracts from P. alliacea roots in mice. However, it must be emphasized that the methodological tools used by the authors to assess the antinociceptive effects (writhing and formalin test) are not adequate to identify a specific mechanism of action (Silva et al., 2013; Trevisan et al., 2012 and Trevisan et al., 2014).

As the two phases of the formalin test are sensitive to centrally acting drugs, these results may suggest that some substances presented in the fractions of P. alliacea root extracts might induce antinociception via other CNS mechanisms. Nevertheless, peripheral mechanisms may also account for the diverse antinociceptive effects exerted by different fractions of P. alliacea ( Le Bars et al., 2001).

In accordance with this view, during the hot-plate test, mice previously treated with P. alliacea fractions (100 and 200 mg/kg, i.p.) did not display increased latency in response to the thermal stimulus in comparison to animals treated with morphine (10 mg/kg, i.p). As the behaviours (hindpaw licking and jumping) assessed in the hot-plate test are primarily mediated supraspinally (Le Bars et al., 2001), these findings suggest peripheral mechanisms as underlying the antinociceptive effects of the various fractions of P. alliacea root extracts.

Additionally, myricitrin is a flavonoid glycoside also found in P. alliacea that was reported to have antioxidant, analgesic, anti-inflammatory and antinociceptive properties ( Meotti et al., 2006, Schwanke et al., 2013 and Domitrović et al., 2015). In recent years, several studies have reported the antinociceptive effects of this flavonoid, which are associated, at least in part, with the following mechanisms: i) inhibition of the protein kinase C (PKC) and PI-3 kinase activities, ii) decrease in the nitric oxide (NO) production and activation of nuclear factor kappa B (NFκB), iii) activation of the protein Gi/0 pathway, iv) increase in the K⁺ efflux, v) and decrease in intracellular Ca²⁺ influx ( Gamet-Payrastre et al., 1999, Meotti et al., 2006 and Meotti et al., 2007). Therefore, myricitrin may represent one of many active compounds found in P. alliacea that can be responsible for pain relief in both humans and laboratory animals.

4.2. Anxiogenic/anxiolytic activity

As mentioned previously, P. alliacea has been used in traditional medicine to treat anxiety ( Garcia et al., 2010). Thus, some studies were conducted to assess the validity of this popular use scientifically. Gomes et al. (2008) investigated the acute effects of root extract fractions of P. alliacea (FA, FH, FHA and FHAppt) at doses of 100 and 200 mg/kg (i.p.) on the anxiety-related behaviours of female Swiss mice evaluated in the elevated plus maze (EPM) test, a well-validated paradigm for the screening of anxiolytic/anxiogenic compounds. FA (100 and 200 mg/kg, p.o.) reduced the number of entries and the time spent in the open arms of the EPM indicative of an anxiogenic profile. In contrast, FA, FH and FHA (100 and 200 mg/kg, i.p.), as well as FHAppt (200 mg/kg, i.p.), significantly reduced the open arms time. Overall, these results indicate that, contrary to popular belief, P. alliacea (at least the roots) does not exert anxiolytic effects ( Gomes et al. 2008).

In addition, Blainski et al. (2010) addressed anxiety-related effects of the whole plant (WP), AP and root (R) lyophilized crude extracts of P. alliacea. They observed that acute oral administration of WP (300 and 600 mg/kg), AP (600 and 900 mg/kg) and R (300, 600 and 900 mg/kg) did not reduce the anxiety-like behaviour of male Swiss mice subjected to the EPM test. In addition, AP (300 mg/kg) significantly decreased both the number of entries and time spent in the open arms of the EPM, once again indicating an anxiogenic-like profile.

On the other hand, Blainski et al. (2010) reported anxiolytic-like effects of WP of P. alliacea (300 and 900 mg/kg, p.o.) on male mice subjected to EPM. Corroborating these findings, also demonstrated that the WP extract of P. alliacea (900 mg/kg, p.o.) induced anxiolytic-like effects in female Wistar rats assessed in the open field test. In this study, the WP extract of P. alliacea was able to increase the total number of crossings and central quadrants crossed, indicative of an anxiolytic-like effect.

Audi et al. (2001) also evaluated the putative anxiolytic activity of a lyophilized hydroalcoholic extract of P. alliacea APs. Male Wistar rats were acutely administered with EBG (200, 400 and 600 mg/kg, p.o.) and were evaluated using the EPM test. EBG (600 mg/kg) significantly increased the percentage of entries in the open arms of the apparatus. However, it did not alter the percentage of time spent in the open arms or the number of entries in the enclosed arms of the EPM. Overall, these data indicated that EBG exerted a selective anxiolytic effect, with no effects on the spontaneous locomotor activity of the animals.

Taken together, evidence from animal models indicates that our comprehension of the P. alliacea effects on anxiety is still far from complete. Further studies combining data from different fractions and compounds isolated from P. alliacea in a range of behavioural paradigms of anxiety will enable a more conclusive view.

4.3. Antidepressant activity

There is no clear description in literature about the antidepressant use of P. alliacea in folk medicine. However, the leaves and roots of P. alliacea are used as stimulants in various regions across Brazil and Trinidad ( Lans et al., 2001, Muñoz et al., 2000 and Negri and Rodrigues, 2010). Depressive disorders have a set of symptoms, such as depressed mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, disturbed sleep or appetite, and poor concentration (WHO, 2015). Thus, the use of P. alliacea as a stimulant could be a palliative treatment for depressive symptoms, since stimulant drugs frequently act in monoamine neurotransmission (noradrenaline, serotonin and dopamine), which is also the main pharmacological target of classic antidepressants ( Ayflegül Yildiz et al., 2002).

The antidepressant effect of P. alliacea was initially investigated by Gomes et al. (2008). In this study, the authors investigated the effects of FA, FH, FHA and FHAppt of P. alliacea (when administered acutely, 100 or 200 mg/kg, p.o. and i.p.) on female Swiss mice evaluated with the forced swimming test (FST). Surprisingly, all fractions (100 and 200 mg/kg) produced depressant-like effects when given p.o. as well as i.p., as indicated by the significant increase in the immobility time of the animals subjected to the FST (Gomes et al., 2008).

On the other hand, observed antidepressant-like effects of the WP extract of P. alliacea (900 mg/kg, p.o.) on female Wistar rats evaluated in the FTS. They observed that the extract caused a significant reduction in the immobility time of the rats, thereby suggesting a possible antidepressant activity. The authors speculate that these antidepressant-like effects of WP extract of P. alliacea might be associated with the presence of coumarins, which are known to act via serotonergic and noradrenergic transmissions to modulate mood behaviour ( Ariza et al., 2007). These discrepant findings on depressive-like behaviours of the P. alliacea could be attributed to methodological differences including the part of the plant and doses administered, as well as the animal’s species.

Overall, from these limited results in this field it appears that P. alliacea might be particularly useful for the treatment of depression, despite the lack of clear popular indications for the treatment of depression. Therefore, further studies are welcome in order to confirm the antidepressant properties of P. alliacea, as well as to investigate the underlying mechanisms of action.

4.4. General CNS depressant activity

In traditional medicine, P. alliacea is known to act as a general CNS depressant, thereby earning the title ‘Remedy to tame the Master’ ( Camargo, 2007). Moreover, preparations of P. alliacea are popular for their sedative activities ( Germano et al., 1993). Lima et al. (1991) described for the first time that the acute administration of an aqueous crude extract of P. alliacea roots (500, 1000 and 2000 mg/kg, p.o.) reduced the spontaneous locomotor activity of male Swiss mice in the OFT. Although the high dose utilized by Lima and colleagues, this work was the first report to support the evidence of the popular use by slaves.

In addition, it seems that this effect requires lower doses (100 and 200 mg/kg, i.p. and orally) when using root extract fractions, as shown by Gomes et al. (2008). In this study, the effects of P. alliacea fractions on autonomic behaviours, such as locomotor activity, rearing and grooming, in female Swiss mice subjected to the OFT were evaluated. All fractions reduced locomotor activity, but only rearing and grooming parameters were reduced in a similar way to diazepam (2 mg/kg, i.p.). Furthermore, they also demonstrated the potential hypnotic effect of this extract, with the aforementioned fractions increasing the sleep time induced by pentobarbital, thereby supporting the role of P. alliacea as a general CNS depressant.

Rodrigues et al. (2008) evaluated the CNS depressant effects of the cigarette ‘tira-capeta’ in mice. Initially, the extract induced a stimulant response followed by a general depressant state, thereby characterizing a biphasic effect. The animals displayed a reduced latency for sleeping and an increased sleeping time (50, 100 and 500 mg/kg) in the pentobarbital-induced sleeping test. However, no significant motor incoordination was observed in the rotarod test (doses up to 200 mg/kg). The ‘tira-capeta’ extract (500 mg/kg) also elicited a cataleptic state after 10 and 50 min. As previously mentioned, nine plants comprise the ‘tira-capeta’ preparation. For this reason, it is difficult to establish the degree of influence of P. alliacea on the results shown.

Contrasting with these findings, Blainski et al. (2010) described an increase in locomotor activity in male Swiss mice subjected to the OFT when acutely treated with 900 mg/kg of P. alliacea root extract. Interestingly, the variability in dose range, extract fractioning and plant part used to prepare the extract may contribute to the very controversial effects of P. alliacea. For instance, Cifuentes et al. (2001) observed that root extracts (1250 mg/kg) caused a slight decrease in spontaneous motor activity in mice, whereas leaf extracts induced hyperexcitability at the same dose. Furthermore, both the AP and WP extracts of P. alliacea (300 and 900 mg/kg) have been shown to increase locomotor activity ( Andrade, 2011, Andrade et al., 2012 and Blainski et al., 2010).

Therefore, the CNS depressant activity of P. alliacea remains controversial. The conflicting effects described in literature may be associated with differences on the part of the plant, as well as the dose administered. However, it is important to emphasize that both stimulant and depressant effects of P. alliacea support the ethnopharmacological use of this plant by slavers and in religious ceremonies.

4.5. Anticonvulsant activity

Lima et al. (1991) were the first to evaluate the possible anticonvulsant activity of P. alliacea. Male Swiss mice were acutely treated with an aqueous crude extract of the roots of this plant (500, 1000 and 2000 mg/kg, p.o.), with either pentylenetetrazol (75 mg/kg, i.p.) or maximal transcorneal electroshock (rectangular pulses of 50 mA) being used to induce convulsive behaviour. Animals pretreated with the high extract doses (1000 and 2000 mg/kg) showed a significant increase in convulsive thresholds and a decrease in the duration of convulsion when compared with the control group. These findings support the use of P. alliacea for both the prevention and cessation of convulsive episodes. However, these results could not be relevant in the pharmacological practice, since high doses were employed in this study to elicited anticonvulsant effects.

Nevertheless, similar to depressor activity, lower doses of roots fractions also promote anticonvulsant effects. For example, Gomes et al. (2008) reported putative anticonvulsant activity of P. alliacea roots fractions (100 and 200 mg/kg, i.p. and p.o.) on pentylenetetrazol-induced seizure model. The authors also observed the anticonvulsant effects of these fractions, in line with the finding of Lima et al. (1991). Although the available scientific evidence supports the use of P. alliacea root-derived extracts, the traditional medicine of Latin American communities uses the leaves instead of the roots. Nevertheless, the leaf-based extracts of P. alliacea need to be investigated for their anticonvulsant activity ( Branch and Silva, 1983 and Zamora-Martinez and Pola, 1992).

4.6. Cognitive enhancer activity

As mentioned previously, leaves from P. alliacea and other species included in the ‘tonic for the brain’ category have been used as memory/cognition enhancers ( Negri and Rodrigues, 2010 and Rodrigues et al., 2008). In folk medicine, preparations containing leaves and roots of P. alliacea have been used to improve memory (Mors, 2002). were the first to report the effects of P. alliacea extract on the learning and memory processes in laboratory animals. In their study, evaluated learning and memory in female Wistar rats acutely treated with a WP extract (900 mg/kg, p.o.) using an elevated T-maze (ETM) paradigm. Saline (0.9%, 10 ml/kg, p.o.) and caffeine (10 mg/kg) were used as the negative and positive controls, respectively. On analysing the data, they found that WP extract-treated rats showed improvement in long-term memory, but not in short-term memory.

Attributed this effect to the possible presence of dibenzyl trisulphide (DTS) in the WP extract of P. alliacea. This chemical component increases the hyperphosphorylation of growth factor-induced mitogen-activated protein kinase (MAPK) (ERK1 and ERK2), which is a critical mechanism associated with long-term memory improvement and neuronal growth ( Williams et al., 2007).

In view of the traditional use of the plant (leaves and roots) for memory improvement, Silva et al. (2015) designed a study to investigate the possible effects of P. alliacea leaf hydroalcoholic extract (PaLHE) on the learning and memory of male and female Wistar rats. The animals were acutely treated with PaLHE (900 mg/kg, p.o.), caffeine (10 mg/kg, i.p.) or saline (0.9%, 10 ml/kg, p.o.) and subjected to the step-down inhibitory avoidance and Morris water maze (MWM) tests. The results obtained from both tests confirmed the positive effects of PaLHE on long-term memory. These effects were attributed to the chemical constituents of the extract such as flavonoids, steroids, triterpenes, organosulphur compounds (DTS), thiosulphates and polysulphides. These results also identify substances known to have a positive effect on cognitive function ( Kubec and Musah, 2001, Williams et al., 2007 and Kennedy and Wightman, 2011).

Although research is at a very early stage, the findings reviewed above further highlight the cognitive-enhancing properties of P. alliacea evaluated in different behavioural paradigms in laboratory animals, thereby supporting the traditional use of this plant by quilombola adolescents and children to improve cognitive function. Therefore, the investigation of the putative effects of P. alliacea in experimental models of learning/memory dysfunction such as Alzheimer’s disease and attention deficit hyperactivity disorder (ADHD) represents a very interesting field.

5. Toxicity studies

The toxicity of different extracts obtained from P. alliacea remains to be elucidated. In an overview, the acute toxicity of this plant in animal models (up to 14 days) was found to be low. However, in chronic and subchronic exposure, P. alliacea was able to induce moderate to high toxicity, including mutagenicity and genotoxicity. In addition, most studies confirmed the diverse acute effects of P. alliacea on the CNS, including anxiety, restlessness, confusion, ataxia, tremors and seizures, as mentioned previously. Thus, several studies on animal and human models of the toxicity of this species are described below.

In animal models of acute toxicity, mice exposed once to high levels of crude aqueous extract of P. alliacea roots (800–8000 mg/kg) showed reduced locomotor activity during the behavioural tests. Furthermore, mice treated with a dose of 8000 mg/kg presented ptosis and ataxia, although none of the animals died, thereby demonstrating the low toxicity of this extract (Lima et al., 1991). In another study, a hippocratic test was conducted to evaluate the response of female Swiss mice to the acute toxicity of the hydroalcoholic extract of P. alliacea roots at an i.p. dose ranging from 500 to 3000 mg/kg; in particular, the oral administration of 100–400 mg/kg of the P. alliacea root extract showed low acute toxicity ( Gomes, 2006).

Other researchers have also reported the low toxicity of P. alliacea extract. For instance, Audi et al. (2001) showed that the AP hydroalcoholic extract (up to 3000 mg/kg) did not induce any sign of toxicity in mice. However, these authors also showed that a dose fivefold that of the tested P. alliacea extract was necessary for eliciting an anxiolytic effect and reducing gastric ulcers. In fact, Oliveira (2012) evaluated the oral acute toxicity of P. alliacea roots and APs collected during different seasons (dry and rainy) on mice. The animals were orally administered a single dose of 5000 mg/kg and monitored for 14 days. They were analysed for manifestation of signs of toxicity, food consumption and weight change. Later, the mice presented no change in behaviour and food consumption. Only the root extract collected during the dry season led to a reduction in the body weight gain.

Fontoura et al. (2005) reported that the hydroalcoholic extract of P. alliacea leaves (500, 1000, 5000 and 10,000 mg/kg) did not cause behavioural or histopathological changes in the liver, kidney, lung and heart. However, 1000 mg/kg of the extract did not result in the same decrease in secretion and intestinal motility as with lower doses (250 and 500 mg/kg). Similarly, a single dose (4000 mg/kg) of the dry crude extract of P. alliacea leaves administered to albino rats did not cause mortality or any signs of toxicity after 14 days. However, this dose did alter the leucocyte count, eosinophil differentials, the mean corpuscular volume, mean corpuscular haemoglobin values and haematocrit. In addition, the biochemical results were indicative of hepatic overload ( Ximenes, 2008).

In the WP hydroalcoholic extract, the acute toxic effects of the 2000 and 5000 mg/kg doses caused lethargy and drowsiness in mice, but not death (Andrade, 2011 and Andrade et al., 2012). Morón (1990) demonstrated the toxicity of a P. alliacea decoction at higher oral doses (10,000 mg/kg) in mice without death or signs of toxicity even when administered for seven consecutive days. Germano et al. (1993and 1995) evaluated the toxic effects of the hydroalcoholic root extract administered topically and orally at a dose of 1 mg/kg (equivalent to 7.7 mg of dry root) for 15 days, reporting no sign of local irritation in the gastric mucosa.

García-González et al. (2006) showed that acute (18 days) and subchronic (70 days) doses of the aqueous extract (1000 and 2000 mg/kg) of P. alliacea leaves did not result in the death of mice. Nevertheless, 1000 mg/kg of the extract led to an increase in the blood glucose concentration and a decrease in the haematocrit. For some animal species, high doses of P. alliacea may cause intoxication. In this context, Núñez et al. (1983) reported that sheep that consumed this plant daily (3000 or 6000 mg/kg of P. alliacea, up to 46 days) presented with initial symptoms of salivation, lachrymation, bradycardia, polyuria, diarrhoea, ataxia and marked inhibition of blood cholinesterase, along with lateral decubitus opisthotonos and atrophy of muscle mass, as well as lesions in the nervous and muscular system. The necropsy presented renal lesions and muscle atrophy with fragmentation and hyalinization of muscle fibres. Other studies reported a lethal dose 50 (DL₅₀) of 360 mg/kg for oral administration of P. alliacea leaf extracts in rats and i.p. administration at 1700 mg/kg in mice (Estevez et al., 1976; Delaveau et al., 1980). Moreover, Wistar rats subjected to chronic intoxication (90 days) with an aqueous extract of P. alliacea dried leaves at doses of 12.36, 61.8 and 309 mg/kg did not show any signs of toxicity. An increase in urea nitrogen and alanine transaminase is the only indication of a toxic effect (Ximenes, 2008).

In the aerial pathway, histological analyses of the respiratory tract of female Wistar rats showed morphological modifications after the animals were exposed to the steam of P. alliacea root (150 g) for a short duration (3 min). After exposure, the animals were sacrificed and aerial pathways were observed for 5–30 min. In the 5–15 min after exposure, significant alterations in the bronchioles, trachea and lungs were noted. Some of the tracheal manifestations included epithelium hyperplasia, signs of increased goblet cell secretion, muscle congestion, mononuclear infiltrate and the absence of epithelium and cilia in some areas. The bronchioles revealed activation of Clara cells, the absence of the epithelium in some areas and the presence of mononuclear cells. In the lungs, thickening of the alveolar septa, an increase in collagen fibres, congestion, extravasation and intra-alveolar exudates were reported (Fletes-Arjona et al., 2013).

These results indicate that the steam of P. alliacea roots contains components with an aggressive mechanism of action. Petiverine and coumarin may be attributed to the manifestations observed, based on the increased secretion and induction of vascular congestion associated with the mononuclear infiltration capacity of petiverine and coumarin, respectively. It is important to note that even after 30 min of exposure, anormal bronchiolar features were found with no reversion of the lung damage reported for the shorter durations of steam exposure (Fletes-Arjona et al., 2013).

On conducting in vitro assays, some authors reported that the extract of P. alliacea leaves showed low cytotoxicity with a half-maximal inhibitory concentration (IC₅₀) of 1709.77 μg/mL (Oliveira et al., 2013), whereas the P. alliacea fraction derived from leaves and stems in normal fibroblasts and peripheral blood mononuclear cells showed an IC₅₀ of 440 and 151 µg/mL, respectively (Urueña et al., 2008). In addition, mutagenic and carcinogenic effects have also been reported, with Hoyos et al. (1992) demonstrating the dose-dependent mutagenic and carcinogenic effect of P. alliacea extract. They reported DNA damage with the formation of sister chromatid exchanges (SCEs) in human lymphocytes in vitro and in mouse bone marrow cells in vivo, especially at higher concentrations of 100 and 1000 µg/ml (in vitro) and 204 mg/kg (in vivo). Our group recently demonstrated the genotoxic effect of P. alliacea extract (data not published yet).

According to the Organisation for Economic Co-operation and Development (OECD, 2001), a substance is categorized under level five of acute toxicity (low toxicity) when a few behavioural alterations, but not death, are reported in animals. Based on this categorization and the results of a study on the toxicity of several extracts from P. alliacea, the species is known to cause low toxicity; however, at very high doses and prolonged exposure, the plant can exert toxic effects. Moreover, the plant part, season and region of collection may interfere with this toxic effect ( Oliveira, 2012).

In humans, acute intoxication was found to cause insomnia, hyperarousal and hallucinations, whereas prolonged use (such as one year of chronic exposure) elicits opposite symptoms such as seizures, weakness, mental retardation and even death, depending on the dose (Peckolt and Peckolt, 1900). Although several studies have reported the low toxicity of the plant, ethnopharmacological reports have indicated death after consumption of high doses (not well established by Peckolt and Peckolt (1900)) for a prolonged period. Moreover, the amount consumed daily in some regions is higher than the dose used in toxicity studies (Ferraz et al., 1991b). Therefore, the toxicity of P. alliacea must be investigated further to establish the accurate dose and duration for treatment.

6. Conclusion and perspectives

Popularly known by several different names including ‘mucuracaá’, ‘guiné’ and ‘pipi’, P. alliacea is a valuable botanical source because of its many uses and wide range of pharmacological biological activities. Crude extracts, fractions and phytochemical constituents isolated from various parts of P. alliacea show a wide spectrum of neuropharmacological activities including anxiolytic, antidepressant, antinociceptive and anti-seizure, and as cognitive enhancers. Phytochemistry studies of P. alliacea indicate that this plant contains a diversity of biologically active compounds, with qualitative and quantitative variations of the major compounds depending on the region of collection and the harvest season. Although significant advances have been made in the phytochemistry and pharmacology of P. alliacea, information on health effects and clinical value is insufficient. A large number of bioactive compounds have been previously isolated but not tested; therefore, these compounds must be evaluated biologically in more detail. Further in vitro and in vivo genotoxic tests of P. alliacea are also important in order to assess ethnomedical claims. Therefore, in future, detailed and extensive studies are certainly required to improve the knowledge about the mechanisms of action, toxicity and efficacy of the plant as well as about its bioactive compounds before it can be approved in terms of its safety for therapeutic applications.

Acknowledgments

Diandra Araújo Luz, Alana Miranda Pinheiro and Mallone Lopes da Silva were supported by a Brazilian government fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Rui Daniel Prediger is supported by a research fellowship from Conselho Nacional de Desenvolvimento Científico e Profissional (CNPq-Brazil). We would like to thank Universidade Federal do Pará (UFPA) for providing financial support. The authors have no financial or personal conflicts of interest related to this work.

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Thursday, 19 January 2017