Review: African medicinal plants with wound healing properties

Author’s Accepted Manuscript Review: African medicinal plants with wound healing properties Christian Agyare, Yaw Duah Boakye, Emelia Oppong Bekoe, Andreas Hensel, Susana Oteng Dapaah, Theresa Appiah www.elsevier.com/locate/jep

PII: DOI: Reference:

S0378-8741(15)30209-9 http://dx.doi.org/10.1016/j.jep.2015.11.008 JEP9807

To appear in: Journal of Ethnopharmacology Received date: 29 June 2015 Revised date: 19 October 2015 Accepted date: 3 November 2015 Cite this article as: Christian Agyare, Yaw Duah Boakye, Emelia Oppong Bekoe, Andreas Hensel, Susana Oteng Dapaah and Theresa Appiah, Review: African medicinal plants with wound healing properties, Journal of Ethnopharmacology, http://dx.doi.org/10.1016/j.jep.2015.11.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Review: African medicinal plants with wound healing properties Christian Agyare1*, Yaw Duah Boakye1, Emelia Oppong Bekoe2, Andreas Hensel3, Susana Oteng Dapaah1, Theresa Appiah1 1

Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame

Nkrumah University of Science and Technology, Kumasi, Ghana 2

Department of Pharmaceutics and Microbiology, School of Pharmacy, College of Health

Sciences, University of Ghana, Legon, Accra, Ghana. 3

Institute for Pharmaceutical Biology and Phytochemistry, University of Münster, Corrensstraße

48, D-48149 Münster, Germany *

Corresponding author: Dr. C. Agyare, Tel: +233246369803; Email:

[email protected]; [email protected] Abstract Ethnopharmacological relevance: Wounds of various types including injuries, cuts, pressure, burns, diabetic, gastric and duodenal ulcers continue to have severe socio-economic impact on the cost of health care to patients, family and health care institutions in both developing and developed countries. However, most people in the developing countries, especially Africa, depend on herbal remedies for effective treatment of wounds. Various in vitro and in vivo parameters are used for the evaluation of the functional activity of medicinal plants by using extracts, fractions and isolated compounds. The aim of the review is to identify African medicinal plants with wound healing properties within the last two decades. Materials and methods: Electronic databases such as PubMed, Scifinder® and Google Scholar were used to search and filter for African medicinal plants with wound healing activity. The methods employed in the evaluation of wound healing activity of these African medicinal plants comprise both in vivo and in vitro models. In vivo wound models such as excision, incision, dead space and burn wound model are commonly employed in assessing the rate of wound closure (contraction), tensile strength or breaking strength determination, antioxidant and antimicrobial activities, hydroxyproline content assay and histological investigations including epithelialisation, collagen synthesis, and granulation tissue formation. In in vitro studies, single 1

cell systems are mostly used to study proliferation and differentiation of dermal fibroblasts and keratinocytes by monitoring typical differentiation markers like collagen and keratin. Results: In this study, 61 plants belonging to 36 families with scientifically demonstrated or reported wound healing properties were reviewed. Various plant parts including leaves, fruits, stem bark and root extracts of the plants are used in the evaluation of plants for wound healing activities. Conclusion: Although, a variety of medicinal plants for wound healing can be found in literature, there is a need for the isolation and characterization of the bioactive compounds responsible for the wound healing properties. Also, cytotoxicity studies should be performed on the promising agents or bioactive fractions or extracts. Keywords: African medicinal plants, wound models, antioxidant, antimicrobial, wound healing activity Abbreviations: Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC)

1. Introduction Wounds are physical, chemical or thermal injuries that result in an opening or breaking in the integrity of the skin or may also be defined as the disruption of anatomical and functional integrity of living tissue. According to the Wound Healing Society, wounds are physical injuries that result in an opening or break of the skin that causes disturbance in the normal skin anatomy and function. They result in the loss of continuity of epithelium with or without the loss of underlying connective tissue (Ramzi et al., 1994; Strodtbeck 2001). Wounds that exhibit impaired healing, including delayed acute wounds and chronic wounds, generally have failed to progress through the normal stages of healing. Such wounds frequently enter a state of pathologic inflammation due to a postponed, incomplete, or uncoordinated healing process. Most chronic wounds are ulcers that are associated with ischemia, diabetes mellitus, venous stasis disease, or pressure. Current estimates indicate that nearly 6 million people suffer from chronic wounds worldwide (Mathieu et al., 2006; Menke et al., 2007). Foot and leg ulcer is a common disorder, and approximately 1% of the European population suffer from such chronic and 2

recurrent ulceration (Nelzen et al., 1996). Non-healing or chronic wounds result in enormous health care expenditures, with the total cost estimated at more than $3 billion per year (Mathieu et al., 2006; Menke et al., 2007). Wounds such as injuries, cuts, pressure, diabetic, burns, gastric and duodenal ulcers continue to have severe impact on the cost of health care to patients as well as their families and health care institutions globally with increasing aging population. Wounds can be classified as open or closed wound depending on the underlying cause of wound creation and acute or chronic wound on the basis of physiology of wound healing. In open wounds, the skin is cracked open, leaving the underlying tissue exposed to the outside environment, which makes it more vulnerable to bleeding and infection. It is further classified as incised wound, laceration or tear wound, abrasions or superficial wounds, avulsions, puncture wounds, penetration wounds and gunshot wounds (Percival, 2002; Lazarus et al., 1998). However, in closed wounds, the skin is intact and the underlying tissue is not directly exposed to the outside world. Even with the skin intact, the damage can reach down to the underlying tissues, muscles, internal organs and bones. The blood escapes the circulatory system in some cases but remains in the body. It includes contusion or bruises, haematomas or blood tumor, crush injury etc. (Percival, 2002; Lazarus et al., 1998). Acute wound is a tissue injury that normally precedes through an orderly and timely reparative process that result in sustained restoration of anatomic and functional integrity. Acute wounds are usually caused by cuts or surgical incisions and complete the wound healing process within the expected time frame (Menke et al., 2007; Percival, 2002). Chronic wounds on the other hand are wounds that have failed to progress through the normal stages of healing and therefore enter a state of pathologic inflammation. Chronic wounds either require a prolonged time to heal or recur frequently or in most cases require extensive treatment to heal. Local infection, hypoxia, trauma, foreign bodies and systemic problems such as diabetes mellitus, malnutrition, immunodeficiency or medications are the most frequent causes of chronic wounds (Menke et al., 2007; Krishnan, 2006; Percival, 2002). The African continent is one of the continents endowed with the richest biodiversity in the world. This is mainly due to the geographical spread spanning a land mass of approximately 216, 634,000 hectares of closed forest areas. It is estimated to contain approximately 40,000 to 45,000 different plant species and out of which about 5,000 species are used medicinally in the 3

management of diverse diseases. This is not surprising since Africa is located within the tropical and subtropical climate regions of the world where most of these plants are found. It is a known fact that plants accumulate important secondary metabolites through evolution as a natural means of surviving in a hostile environment (Iwu, 1993; Gurib-Fakim, 2006; Manach et al., 2004). Nearly 80% of people living in the developing countries especially in Africa depend on herbal medicine for their health needs including wounds, infectious and metabolic diseases (Agyare et al., 2009). The main aim of the present review is to highlight the importance and potential of medicinal plants from the African biodiversity which have short- as well as long-term potential to be developed as future phytotherapeutic agents to treat and/or manage wounds and their associated complications. The review might also provide a starting point for future studies aimed at isolation, purification, and characterization of bioactive compounds present in these plants as well as exploring the underlying pharmacological mechanisms of action and potential niche market of these plants. 2.0 The wound healing process The acute wound healing process is a complex series of interrelated events that are mediated in its different phases by a wide range of chemically coordinated cellular processes, as well as hormonal influences. It is characterized by a sequence of independent and/or overlapping events (Diegelmann and Evans, 2004; Chan et al., 2008). The process can be broadly categorized into four stages: haemostasis (coagulating) phase, inflammatory phase, proliferative phase (formation of granulation tissue and collagen synthesis), and finally the remodelling phase, which ultimately determines the strength and appearance of the healed tissue. 2.1 Haemostasis (Coagulating) phase Under the influence of ADP (adenosine diphosphate) leaking from damaged tissues, the platelets adhere to the exposed type 1 collagen. They become activated and secrete adhesive glycoproteins, leading to platelet aggregation. They also secrete factors that interact with and stimulate the intrinsic clotting cascade through the production of thrombin, which in turn initiates the formation of fibrin from fibrinogen. The fibrin mesh strengthens the platelet aggregate into a stable hemostatic plug. The platelets secret growth factors like transforming growth factor beta 4

(TGF-β), platelet derived growth factor (PDGF), epidermal growth factor (EGF) and fibroblast growth factor (FGF) which play a vital role in the movement of monocytes and neutrophils to wound site to begin the inflammatory phase (Broughton et al., 2006; MacLeod, 1981). 2.2 Inflammatory phase The inflammatory response which begins 6 - 8 h after injury causes the blood vessels to become leaky, releasing plasma and neutrophils into the surrounding tissue. The neutrophils phagocytose debris and microorganisms and provide the first line of defense against infection. As they digest bacteria and debris, neutrophils die and release intracellular enzymes into the surrounding matrix, which further digest tissue. The neutrophils are replaced by macrophages which further digest and remove cell debris and other foreign bodies. Also, the macrophages facilitate the proliferation of endothelial cells and smooth muscle cells. Additionally, as fibrin is broken down as part of this clean-up, the degradation products attract the next cells involved such as fibroblasts and epithelial cells. They are aided by local mast cells (Li et al., 2007). 2.3 Proliferation phase The proliferation phase starts approximately 4 days after injury and usually lasts until day 21 in acute wounds, depending on the size of the wound and the health of the patient. Fibroblasts and endothelial cells which are the predominant key players facilitate angiogenesis, fibroblast proliferation (collagen deposition), granulation tissue formation, wound contraction and reepithelialisation which are controlled by FGF, TGF-β and VEGF. Hence, the proliferation phase is normally said to be characterized by angiogenesis, collagen deposition, granulation tissue formation, wound contraction and epithelialisation. Clinically, proliferation is observed by the presence of pebbled red tissue or collagen in the wound base and involves replacement of dermal tissues and sometimes sub-dermal tissues in deeper wounds, as well as contraction of the wound (Stadelmalmann, 1998; Madden and Peacock, 1968). 2.4 Remodelling/ Cellular differentiation phase In wound repair, the healing process involves remodelling and realignment of the collagen tissue to produce greater tensile strength comparable to that of normal skin. In addition, cell and capillary density decrease. The main cells involved in this process are the fibroblasts. Again, 5

epithelial tissues formed by strongly proliferating keratinocytes will be transformed will be transformed into the final barrier-forming system by terminal differentiation indicated by the typical protein markers such as cytokeratins K1 and K10, involucrin, loricrin etc. Remodelling can take up to 2 years after wounding (Diegelman and Evans, 2004; Iba et al., 2004; Kirsner and Eaglstein, 1993; Prockop et al., 1979).

Figure 1.0: Schematic representation of the wound healing process (Adapted and modified from Zatel and Hunt, 1993)

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3.0 Models for assessing wound healing activity Several models can be used in evaluating wound healing properties of active compounds. The wound healing models can be classified into two categories; in vitro and in vivo methods. The most relevant and commonly employed models are discussed below:

3.1 In vivo models for assessing wound healing activity In vivo models include both artificial and tissue models, however various models can be used depending on the parameters to be investigated. Artificial models include; subcutaneous chamber/sponges and subcutaneous tubes. Tissue models such as excision wounds, incision wounds, superficial wounds, dead space and burn wounds are usually used to determine the degree of re-epithelialisation, collagenation, neovascularization and tensile or breaking strength of wounds (Davidson, 1998; Dorsett-Martin and Wysocki, 2008; Gal et al., 2008). Models such as rabbit ear chamber, the hamster cheek pouch, the rabbit corneal pocket and the chick chorioallantoic membrane can also be employed to investigate the extent of re-epithelialisation, neovascularization and dermal reconstitution (Gottrup et al., 2000). 3.2 In vitro models for assessing wound healing activity In vitro models are generally simple, rapid and involve minimal ethical consideration compared to whole animal work and allow insight into the biochemical and physiological processes induced by the test agent/compound. Many pharmacological agents at different concentrations can be evaluated concurrently without intrinsic heterogenecity associated with in vivo models (Gottrup et al., 2000). As regenerative skin is characterised by connective as well as epithelial tissues, both cell types, dermal fibroblasts as well as human fibroblasts (either primary cells or cell lines) should be used for complete assessment of wound healing activity. In vitro models are relevant in study of cell-cell and cell-matrix interaction to mimic cell migration during wound healing. In vitro models can employ single cell systems, three dimensional systems, multicellular systems or organ cultures in assessing the wound healing properties of wound healing agents or compounds (Tarnuzzer and Schultz, 1996; Gottrup et al., 2000).

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4.0 Methods used for pinpointing herbal materials and natural products with wound healing activity from published literature Electronic databases including PubMed, Scifinder® and Google Scholar were searched for African medicinal plants evaluated for wound healing activity between 1990 and 2015. All filtered articles were appraised to determine whether they contain any validated in vitro or in vivo wound model. The search terms were “wound healing activity” or “African plants and wound healing activity” or “plant and wound healing activity” or “medicinal plants and wound healing activity”. Primary search results were independently screened by two investigators. Included articles were reviewed concerning plant botanical names, part of plants used in the respective study and studied type of plant extracts, active constituents or compounds and wound models used (in vivo or in vitro) or standardized clinical trials with clearly demonstrated wound healing activity in the models used. The authors looked for significant differences between test group and control group with respect to wound contraction, wound tensile strength, period of epithelialisation, neovascularization, collagenation, keratinization and fibrosis. In case of clinical studies, the respective design, number of patients, interventions, duration of treatment, and data related to the efficacy and tolerability of the patients to treatment were also monitored. Only, articles clearly presented or articulated in English were selected for the purpose of this review. Again, review articles, articles that studied mixture of the plant with agents other than herbs, experimental studies on the plants without significant biological wound healing activity, case reports and case control studies were excluded. References of finally included articles were reviewed for more relevant studies.

5.0 African Medicinal Plants with demonstrated wound healing properties The search resulted in a list of 61 African medicinal plant species belonging to 36 families with scientifically proven wound healing activity over the last 25 years (Table 1). 5.1 Acanthaceae Justicia flava (Forssk.) Vahl is found growing in disturbed habitat, on a wide range of soil types and in full sun or semi shady areas in tropical Africa. It is wide spread in tropical and southern 8

Africa. It is called “Afema” in local Asante-Twi language in Ghana. It is used in traditional medicine for the treatment of cough, paralysis, fever, epilepsy, convulsion and spasm, and skin infections and disorders. The roots are also used for diarrhea and dysentery (Agyare et al., 2009; Burkhill, 2000). The methanol leaf extract of J. flava (7.5% w/w) has been found to reduce wound size significantly (p<0.01) as compared to the untreated wounds in rats excision wound model. The extract also significantly (p<0.01) increased the tensile strength of wounds compared to the untreated wounds. Wound tissue form animals treated with the test extract showed improved angiogenesis, collagenation, and re-epithelialisation compared to the untreated wound tissues (Agyare et al., 2013). 5.2 Amaranthaceae Alternanthera sessilis (L.) R. Br. ex DC is a pan tropical plant which is traditionally used for the treatment of ulcers and cuts and wounds, fevers, ophthalmia, gonorrhoea, pruritis, burning sensations, diarrhea, skin diseases, dyspepsia, hemorrhoids, liver and spleen diseases (Hossain et al., 2014). The oral application of chloroform extract from the leaves of A. sessilis at a dose of 200 mg/kg body weight significantly reduced wound area (p<0.005) and increased reepithelialisation (p<0.0001). Furthermore, in excision wound model, scar area after complete epithelialisation was found to be 33.2±0.7 mm2 (p<0 .0008) with wound breaking strength of 3 88±5.85 g (p<0.0001) in incision wound model, granuloma dry weight of 47.7±2.29 g and granuloma breaking strength 247±10.2 g (p<0.022) in granuloma studies (Jalalpure et al., 2008). In addition to these functional activities, antibacterial and cytotoxicity studies of the leaves and aerial parts of A. sessilis have been demonstrated by Ullah et al. (2013). Antibacterial effect seems to be an essential property of an ideal wound healing agent (Houghton et al., 2005). Pupalia lappacea (L.) Juss is an annual or perennial herb found widespread in the tropics and sub-tropical regions in Africa and it used in folklore medicine for treatment of boils, chronic wounds and skin infections (Neeharika et al., 2013; Agyare et al., 2009). The leaf paste of P. lappacea with edible oil is used to treat bone fractures and inflammatory conditions (Ravi et al., 2012). Histological studies of wound tissues treated with extracts revealed appreciable collagenation, re-epithelialisation, granular tissue formation and angiogenesis for wounds treated with 2 and 10% v/w of ethanol leaf extract creams as well as 1% chloroform extract creams to untreated control wound tissues. The ethanol and chloroform extracts also exhibited high rate of 9

wound closure with 33.60% ± 2.29 to 67.23% ± 1.90 (p≤0.001) and 35.65% ± 2.30 to 67.68% ± 1.62 (p≤0.001), respectively from the 7th day post wounding to the 11th day as compared to the untreated wounds in excision wound model in rats (Apenteng et al., 2014). However, Udegbunam et al. (2014) also reported that higher concentrations (10 and 20% w/v ointment of methanol leaf extract of P. lappacea) significantly (p<0.05) accelerated wound healing, thereby the 20% ointment having the highest percentage wound contraction and rate of epithelialisation. Wound breaking strengths and weight of granuloma tissues formed in the extract treated groups were significantly (p<0.05) higher than those of the untreated control group. The methanol leaf extract also exhibited antimicrobial activity with the MIC of 3.0 to 9.0 mg/mL against Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and MBC of 7 to 10 mg/mL.

5.3 Anacardiaceae Lannea welwitschii (Hiern) Engl. is found growing in deciduous and secondary forests of Africa from Cote d’Ivoire to Cameroon and extending to Uganda and Angola. The plant is locally known in Asante-Twi language in Ghana as “kuntunkuri”. Decoction of the leaves is used traditionally for the treatment of diarrhea, dysentery, swellings, gout, gingivitis, topical infections, and wounds (Agyare et al., 2009). The roots are used for food poisoning, nasopharyngeal infections and as emetics. Methanol leaf extract of L. welwitschii (7.5% w/w) significantly (p<0.05) reduced wound size as compared to the untreated in excision wound model in rats. The extract also significantly (p<0.01) increased the tensile strength of wounds compared to the untreated wounds in rats. The extracts treated wound tissues showed improved angiogenesis, collagenation, and re-epithelialisation compared to the untreated wound tissues (Agyare et al., 2013). 5.4 Apiaceae Centella asiatica (L.) Urban (syn. Centella coriacea Nannfd., Hydrocotyle asiatica L., Hydrocotyle lunata Lam. and Trisanthus cochinchinensis Lour.) is a tropical medicinal plant native to Southeast Asian countries such as India, Sri Lanka, China, Indonesia, and Malaysia as well as South Africa and Madagascar (Jamil et al., 2007). Centella asiatica is effective in 10

treatment of wounds, even in infected wounds, as well as burns and postoperative hypertrophic scars (Bylka et al., 2013; Bylka et al., 2014). Asiaticoside, isolated from C. asiatica, has been studied in normal as well as delayed-type wound healing in guinea pigs. Topical applications of 0.2% solution of asiaticoside on wounds induced a 56% increase in hydroxyproline, 57% increment in tensile strength, increased collagen formation and improved re-epithelialisation. Also in streptozotocin-diabetic rats, where wound healing is typically delayed, topical application of 0.4% solution of asiaticoside over punch wounds increased hydroxyproline content, tensile strength, collagen content and epithelialisation thereby facilitating the healing. Asiaticoside was also found to be active by the oral route at a dose of 1 mg/kg in the guinea pig punch wound model. It promoted angiogenesis in the chick chorioallantoic membrane model at 40 μg/disk concentration (Shukla et al., 1999). Triterpene compounds such as asiatic acid, madecassic acid and madecassoside are the principal components of C. asiatica, responsible for wound healing. The action has been demonstrated both for the extracts as well as for the triterpene compounds in a large number of scientific reports involving in vitro and in vivo experiments (Bylka et al., 2013; Bylka et al., 2014). Cuminum cyminum L. is one of the oldest cultivated medicinal food herbs in Africa, Asia and Europe. This plant is well-known as Cumin and named Zireh-Sabz or Cravieh in Persian language. Its seeds have been commonly used for culinary and flavoring purposes and folklore therapy since antiquity in various countries (Rechinger, 1981; Mozaffarian, 1996; Gohari and Saeidnia, 2011). The alcoholic extract of seeds of C. cyminum and its petroleum ether fraction showed better re-epithelialisation (p<0.001), therefore promoted wound healing activity in excision, incision and granuloma wound models compared to the untreated wounds (Patil et al., 2009). 5.5 Apocyanaceae Catharanthus roseus L. also known as Vinca rosea, is native to the Caribbean Basin, Madagascar and has been found growing in tropical Africa. It has historically been used to treat a wide assortment of diseases. Extracts from the dried or wet flowers and leaves of plants are applied as a paste on wounds in some rural communities. The fresh juice from the flowers of C. roseus made into a tea has been used by Ayurvedic physicians in India for external use to treat 11

skin problems, dermatitis, eczema and acne. Ethanol flower extract of C. roseus significantly increased the wound breaking strength in the incision wound model compared to controls (p < 0.001). The extract-treated wounds were found to epithelialize faster, and the rate of wound contraction was significantly increased in comparison to control wounds (p<0.001), wet and dry granulation tissue weights, and hydroxyproline content in a dead space wound model increased significantly (p<0.05) (Nayak and Pinto-Periera, 2006). Strophanthus hispidus DC is found all over Africa and savannah forests in Ghana, Senegal, Sudan, Congo DR, Uganda, and Tanzania. It has many medicinal uses such as antidote to the poison of the black necked cobra, in treatment of syphilis ulcers, bony syphilis, and guinea worm sores and wounds (Krasner et al., 2007). The influence of the leaf and root extracts of S. hispidus on rate of wound closure was investigated using the excision wound model. It was revealed that, the extract (7.5% w/w) showed significant (p<0.05) wound contractions on day 11. Wound tissues treated with the extract showed improved collagenation, re-epithelialisation and rapid granulation formation compared with untreated wound tissues. The extracts were found to enhanced wound healing process (Agyare et al., 2013). Wrightia tinctoria R. Br. commonly known as Indrajauis a small deciduous tree distributed in Asia and some tropical countries in Africa such Ghana, Nigeria, Cameroun etc. It is used traditionally to treat various diseases (Joshi et al., 1980; Singh et al., 1980; Shah and Gopal, 1988). In vivo investigations revealed that ethanol stem bark extract of W. tinctoria exhibited significant wound healing activity. The extract improved breaking strength (p < 0.01), increased the percentage wound closure and decreased epithelialisation time (p<0.001) compared to the control. It also significantly increased (p<0.001) breaking strength and hydroxyproline content of ten day old granuloma of drug treated animals compared to control animals in dead space wound model. The pro-healing action seems to be due to the increased synthesis of collagen, it's crosslinking as well as better alignment and maturation (Veerapur et al., 2004). 5.6 Asclepiadaceae Calotropis gigantea R. Br. is a perennial undershrub found chiefly in wastelands throughout India, and also in African countries such as Angola, Gabon, DR Congo, Kenya, Sudan, Tanzania

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and Mozambique. It has been reported as a traditional folkloric medicine for a variety of ailments. The whole plant is used for treatment of skin diseases, boils and sores. C. gigantea is also used in some parts of India for wound healing in combination with other plants (Ahmed et al., 2005; Chitme et al., 2004; Argal and Pathak, 2005). C. gigantea whole plant extract in excision wound model increased the percentage of wound contraction, scar area and decreased re-epithelialisation time. Breaking strength of extract treated-wounds and hydroxyproline content increased compared to untreated (Deshmukh et al., 2009). Calotropis procera W. T. Aiton is a well-known plant in the Ayurvedic system of medicine. C. procera originated from the Afro-Asian monsoonal regions. It spreads on an arc expanding from north western Africa including Mauritania, Senegal, through the Arabian Peninsula and MiddleEast to the Indian subcontinent. It was introduced to subtropical America, the Mascarene Islands, drier parts of Australia and probably South-East Asia (Parsons and Cuthbertson, 2001). The latex of C. procera (1% w/v) significantly facilitated the wound healing process by increasing collagen, DNA and protein synthesis and epithelialisation leading to a marked reduction in wound area compared to the control in excision wound model (Rasik et al., 1999). 5.7 Asteraceae Ageratum conyzoides L. has long been known in herbal or folk medicine as a remedy for various ailments in Africa (Almagboul et al., 1985), Asia, and South America (Ekundayo et al., 1987; Borthakur and Baruah, 1987). The plant is used by the Fipa in South Africa as application to fresh wounds and in central Africa; the leaf is used to aid the healing of wound especially those caused by burns (Watt et al., 1962). The wound healing activities of petroleum ether, chloroform, methanol and aqueous extracts of A. conyzoides were evaluated using the excision, incision and dead space wound models. Methanol and aqueous leaf extracts of A. conyzoides showed faster rate of wound healing compared to other extracts under study. The chloroform extract of the selected plants also produced promising results but the effects are seen to be of lesser extent than the corresponding methanol and aqueous extracts (Oladejo et al., 2003). Chromolaena odorata L. is a perennial shrub that is native in Africa (De Rouw, 1995; Olaoye, 1986). Extracts from the leaves of C. odorata have been shown to be beneficial for treatment of

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wounds. The crude ethanol extract of the plant had been demonstrated to be a powerful antioxidant to protect fibroblasts and keratinocytes in vitro. Phenolic acids including protocatechuic, p-hydroxybenzoic, p-coumaric, ferulic and vanillic acids and complex mixtures of lipophilic flavonoid aglycones (flavanones, flavonols, flavones and chalcones) were antioxidants found to protect cultured skin cells against oxidative damage in colorimetric and lactate dehydrogenase release assay (Phan et al., 2001). Centaurea iberica Trev. ex Spreng also called Iberian star thistle is native to the Mediterranean region, southern Europe and northern Africa. Several Centaurea species are used in Turkish folk medicine to alleviate pain and inflammatory symptoms in rheumatoid arthritis, high fever, headache and wounds. Particularly, the aerial part of the plant has been practiced on wounds for improved healing. Histopathological evaluation of both ointment of aqueous and methanol extracts treated and untreated wound tissues from rats, supported the outcome of both incision and excision wound models. Moreover, the methanol extract exerted remarkable wound healing activity and also demonstrated a significant and dose-dependent anti-inflammatory activity (Koca et al., 2009). Sphaeranthus indicus L. is distributed throughout Africa, India, Sri Lanka and Australia. It is an important medicinal plant used for the treatment of styptic gastric disorders, skin diseases, anthelmintic, glandular swelling, and nervous depression. The decoction of the plant is used for the treatment of bronchitis, asthma, leucoderma, jaundice and scabies. The powdered bark along with whey is useful in the treatment of piles. Flowers have alterative, depurative and stimulant characters. The plant is also useful in preservation of food grains as it possess insecticidal property (Nadkarni, 2007; Chopra, 1956; Kirtikar and Basu, 1999). Extract of the aerial part of S. indicus significantly enhanced the rate of wound contraction and the period of epithelialisation comparable to neomycin in pigs (Sadaf et al., 2006). Tridax procumbens L. is commonly known as ‘coat buttons’ among English folks. The plant is native to tropical America and naturalized in tropical Africa, Asia, Australia and India. The influence of whole plant extract and aqueous extract of T. procumbens on lysyl oxidase activity, protein and nucleic acid contents as well as the tensile strength which are relevant to wound healing resulted in significant (p<0.01) increment in the above parameters in animals treated with 14

whole plant aqueous extract and aqueous extract fractions compared to the untreated in dead space wound healing model. Butanol and petroleum ether fractions treated albino rats showed a decrease in all these parameters except tensile strength. In these two groups, the hexosamine levels were increased (p<0.001). Whole plant extract were more active as compared to the other extracts in dead space wound model (Udupa et al., 1995). Yaduvanshi et al. (2011) revealed that, excision wounds treated with extract of the juice of T. procumbens (1 mg/g) and VEGF (1 μg/mL) exhibited a significant (p<0.05) increase of 38.81 and 47%, respectively in collagen biosynthesis compared to the vehicle-treated wounds. Histopathological investigations also showed increased infiltration of inflammatory cells, fibroblast proliferation and reepithelialisation with moderate vascularity in dermal wounds treated with extract of the juice of T. procumbens. However, dermal wounds treated with extract of the juice of T. procumbens at a dose of 4 mg/g induced inflammation, oedematous tissue and decreased vascularity. Again, Talekar et al. (2012) showed that ethanolic and aqueous extract T. procumbens significantly (p<0.05) increase in wound tensile strength. In the excision model, biochemical markers such as hydroxyproline, collagen and hexosamine increased significantly (p<0.05) compared to the untreated control group. 5.8 Bignoniaceae Kigelia africana (Lam.) Beneth. is found widespread across Africa including Ghana, Sierra Leone, Gambia, Sudan, and Nigeria and also found growing in wet savannah and near river bodies where it occurs in abundance (Irvine, 1961). It is used to treat skin ailments including fungal infections, boils, psoriasis and eczema, leprosy, syphilis, and cancer. The roots, wood, and leaves have been found to contain kigelinone, vernolic acid, kigelin, iridoids, luteolin, and 6hydroxyluteolin (Houghton, 2002). The iridoids have antibacterial effect (Picerno, 2005). The methanol stem bark extract of K. africana (7.5% w/w aqueous cream) in rat excision wound model, showed significant (p < 0.05) wound contraction on day 7 with 72% of wound closure compared to the untreated control group. Wound tissues treated with the extracts showed improved collagenation, re-epitheliazition and rapid granulation formation compared to untreated wound tissues (Agyare et al., 2013).

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Spathodea campanulata P. Beauv. is a plant species used in folkloric medicine in Ghana and several African countries to treat various forms of wounds. Among the Ashanti ethnic group in Ghana, S. campanulata stem bark is applied to wounds by traditional healers in form of a paste (Mensah et al., 2003; Houghton et al., 2005). Excision wounds treated with 20 % w/w Spathodea cream and Cicatrin® cream showed a rapid and comparable decrease (p<0.05) in wound size in rats. In uninfected wounds, both 20% w/w Spathodea cream and Cicatrin® cream application resulted in 95% wound closure seen on day 20, and a complete closure seen on day 24. In infected wounds, both 20 % w/w Spathodea cream and Cicatrin® cream administration led to approximately 91 % wound closure on day 24 and a complete wound contraction on day 28 (Ofori-Kwakye et al., 2011). 5.9 Boraginaceae Heliotropium indicum L. has a pantropical African distribution, but is probably native of tropical America. It is widespread and common throughout Africa. Throughout tropical Africa it is used as an analgesic (rheumatism), diuretic and for numerous skin problems (e.g. yaws, urticaria, scabies, ulcers, eczema, impetigo and wounds) (Iwu, 1993; Sofowora, 1993; Burkhill, 1985). According to Dash and Murthy (2011), H. indicum extracts (petroleum ether, chloroform, methanol, and aqueous) promoted wound healing activity. The highest activity was observed with the methanol fraction. Significant increase in the granulation tissue weight, increased hydroxyproline content, and increased activity of superoxide dismutase and catalase level with the animals treated with methanol extract in dead space wound model further augmented the wound healing potential of H. indicum. 5.10 Cactaceae Opuntia ficus-indica (L.) is commonly known as cactus or prickly pear. O. ficus-indica is a tropical and subtropical plant that grows in arid and semi-arid climates with a geographical distribution encompassing Mexico, Latin America, South Africa and Mediterranean countries (Butera et al., 2002; Hassan et al., 2011). It has been used in traditional folk medicine because of its role in treating a number of diseases including inhibition of stomach ulceration (Galati et al., 2003). The methanol stems extract of O. ficus-indica and its hexane, ethyl acetate, n-butanol and

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aqueous fractions were evaluated for their wound healing activity in rats. The extract and less polar fractions showed significant (p>0.05) wound healing effects compared to the untreated wounds (Park and Chun, 2001). The wound-healing potential of two lyophilized polysaccharide extracts obtained from O. ficus-indica (L.) cladodes applied on large full-thickness wounds in the rat have been reported. When topically applied for 6 days, polysaccharides with a molecular weight >10(4) Da accelerated the re-epithelialisation and remodelling phases, also by affecting cell-matrix interactions and by modulating laminin deposition. However, the wound-healing activity is high for polysaccharides with a MW ranging between 10(4)-10(6) Da than for those with molecular weight >10(6) Da (Trombetta et al., 2006). 5.11 Caricaceae Carica papaya L. is commonly known as pawpaw. The edible part of C. papaya is widely used all over the world and is cultivated in most tropical countries. The leaves are used traditionally as a dressing component for wounds (Burkill, 2000). The aqueous extract of C. papaya leaves were investigated for wound healing potential in rats. Wounds treated with 5 and 10% w/v extract in vaseline and solcoseryl jelly accelerated wound healing compared to the wounds treated with blank vaseline (Mahmood et al., 2005). In streptozotocin-induced diabetic rats using excision and dead space wound models, the aqueous extract of C. papaya exhibited 77% reduction in the wound area when compared to controls which was 59%. The wet and dry granulation tissue weight and hydroxyproline content increased significantly when compared to controls (Nayak et al., 2007a). Carbopol gel containing 1.0 and 2.5% of dried papaya latex have been found to accelerate wound closure, increase hydroxyproline content and stimulate epithelialisation compared to the control in burn wound model (Gurung and Škalko-Basnet, 2009). 5.12 Cecropiaceae Myrianthus arboreus P. Beauv is a dioecious shrub or tree which grows up to 20 m tall. It is found growing in forest zones of tropical Africa including Ghana, Sierra Leone, Sudan, Ethiopia, southern part of DR Congo, Tanzania and Angola. It called ‘nyankama’ in Asante-Twi language in Ghana. Extracts of the leaves and leafy shoots of M. arboreus are used in the treatment of dysentery, diarrhoea, wounds, boils, dysmenorrhoea and incipient hernia and vomiting. The study revealed that 5% w/w methanol leaf extracts of M. aboreus cream has potent wound 17

healing capacity with better wound closure (p<0.05) on day 1 and day 9 (p<0.001) compared with untreated wounds in excision wound model. Histological investigations showed enhanced wound tissue proliferation, fibrosis and re-epithelialisation compared with the untreated wound tissues (Agyare et al., 2014). 5.13 Combretaceae Terminalia arjuna (Roxb. Ex DC) Wight and Arn. is native to India and Sri Lanka but it has been planted and naturalized in many African countries. In Mauritius, it is traditionally used in the management of dysentery and rheumatism. The effect of topical application of fractions (fraction I, II and III) obtained from a hydroalcoholic extract of the stem bark were assessed on the healing of rat dermal wounds. The fractions significantly increased the tensile strength of the incision wounds and degree of re-epithelialisation of excision wounds compared to control animals (p<0.05). However, topical treatment with fraction I, consisting mainly of tannins, was found to demonstrate a comparatively high increase in the tensile strength of incision wounds and exhibited the fastest rate of epithelialisation and also increased hexosamine content (Chaudhari and Mengi, 2006). Combretum mucronatum Schum. & Thonn. occurs in West Africa in countries such as Ghana Senegal, DR Congo and Gabon. The leaves are traditionally used for wound healing in Western Africa. Aqueous leaf extract of C. mucronatum has been shown to stimulate viability of human keratinocytes and dermal fibroblasts. In vitro studies were performed using HaCaT keratinocyte cell line, primary keratinocytes and primary skin fibroblasts with determination of viability (MTT assay), cell proliferation (BrdU incorporation ELISA), cell toxicity (LDH release) and keratinocyte differentiation, using involucrin and keratin K10 as differentiation marker (confocal laser scanning microscopy, Western blot). The extract stimulated cellular differentiation of primary keratinocytes significantly at 1 and 10 μg/mL. The isolate, procyanidin B2 at 1 and 10 µM was shown to be responsible for the induction of this cellular differentiation, while epicatechin and procyanidins B5, C1 and D1 also isolated from the extract were inactive (Kisseih et al., 2015).

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5.14 Curcubitaceae Momordica charantia L. also known as bitter gourd or bitter lemon belongs to the family Curcubitaceae. In Ghana, among the Asante Twi community it is called “Nyanya”. In Ghana it is used in the management of wounds, peptic ulcer, fever, piles and skin infections and parasitic infections (Burkhill, 1994; Agyare et al., 2009). Preparations made from stems and leaves are used to treat yaws (Burkhill, 1994). In excision wound model, the methanol leaf extract of M. charantia showed significant (p<0.05) wound closure and histological investigation of the wound tissues revealed high fibrosis and collagenation compared to the untreated wound tissues in rats (Agyare et al., 2014). 5.15 Cyperaceae Cyperus rotundus L. is indigenous to India, but now it is found in tropical, subtropical and temperate regions from Asia, Africa and South America (Gordon-Gray, 1995). C. rotundus is used in folkloric medicine for the treatment of dyspepsia, fever, pruritis, wounds and pains (Chopra et al., 1956; Chopra et al., 1969). An alcoholic extract of tuber parts of C. rotundus ointments showed an increase in wound contracting ability, tensile strength and a decrease in wound closure time (Puratchikody et al., 2006). 5.16 Euphorbiaceace Alchornea cordifolia (Schum. &Thonn.) Muell. Arg. is an evergreen dioecious shrub which grows up to 8 m tall and it grows in the eastern part of Senegal to Kenya and Tanzania and throughout Central Africa to Angola. It is also cultivated in DR Congo for its medicinal purposes (Mavar-Mangar, 2007). A. cordifolia is known in Asante-Twi dialect in Ghana as ‘agyama’. The poultice of the leaves is used for the treatment of wounds. The leaves and root bark of A. cordifolia are externally applied to treat leprosy and as antidote to snake venom (Burkill, 1997; Agyare et al., 2009). The study showed that 10% w/w aqueous leaf extracts of A. cordifolia cream in excision wound model, exhibited potent wound healing capacity with better wound closure (p<0.05) at day 1 and day 9 (p<0.001) compared with untreated wounds. Histological

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investigations showed enhanced wound tissue proliferation, fibrosis and re-epithelialisation compared with the untreated wound tissues (Agyare et al., 2014). Jatropha curcas L. also called physic nut is a perennial poisonous shrub which grows up to 5 m high. The plant originated from Central America but has spread to other tropical and subtropical countries and mainly grows in Asia and Africa. The seeds have also been employed in biodiesel production. The plant has been employed in the management of many ailments including ulcer, sores etc in some parts of Africa (Igoli et al., 2005; Gonasekera, et al., 1995). The study indicated that leaf and stem bark of J. curcas accelerates the healing process by increasing the skin breaking strength, granulation tissue breaking strength, wound contraction, dry granulation tissue weight and hydroxyproline levels. A marked decrease in epithelialisation period was also observed. The histopathological examination of granulation tissue also showed the presence of more collagen, which has organized to form bundles indicative of advance wound healing (Shetty et al., 2006). Arabinogalactan protein JC from Jatropha curcas seed endosperm (mean molecular weight 140 kDa) was isolated by cold water extraction and characterized concerning sugar and amino acid composition. At 10 and 100 µg/mL JC stimulated mitochondrial activity (MTT assay) of human skin cells (HaCaT keratinocytes and dermal fibroblasts) and the ATP status of primary keratinocytes. JC did not influence the cellular proliferation, while primary keratinocytes were triggered into differentiation status. Investigations on a potential mode of action of JC were performed on complex organotypic skin equivalents. JC induced HGF, KGF and TGFβ expression, with TGFβ being the main inductor for the differentiation-inducing effect of JC. Also the expression of GM-CSF was stimulated strongly by JC. This in vitro activity profile indicated JC to be a potent inductor of cellular differentiation via stimulation of growth hormones and TGF-β-induced cell signaling (Zippel et al., 2010). Mallotus oppositifolius (Geiseler) Müll. Arg. is called ‘Nyanyafurowa’ among the Asante-Twi community in Ghana and ‘Ukpo’ in South-Eastern part of Nigeria. A leaf or stem bark infusion is used to expel tapeworms and to treat diarrhoea. The crushed or chewed fresh leaves, sometimes mixed with butter, are applied to cuts and sores as haemostatic and antibacterial agents, and on skin eruptions and rashes for fast healing. They are also applied to burns to calm pain. A steam bath with the leaves is taken to treat headache, epilepsy or mental illness. Leaf sap 20

is used as nose drops or eye drops and the head is massaged with the pulped leaves to treat headache. The crushed leaves or leaf sap are applied to aching teeth and inflamed eyes (Iwu, 1993; Burkhill, 1994; Kabran et al., 2012). Methanol leaf extract of M. oppositifolius showed significant (p<0.05) wound closure, fibrosis and collagenation in excision wound model (Agyare et al., 2014). 5.17 Fabaceae Mimosa pudica L. originated in tropical Central and South America and naturalized throughout the tropics including Africa. Its wound healing properties were studied in three different wound model in rats (excision, incision and estimation of biochemical parameter) using both aqueous and methanol root bark extract of M. pudica. Treatment of wounds with ointment containing 2% w/w of methanol and aqueous extract exhibited significant (p<0.001) wound healing activity by increasing rate of wound contraction, tensile strength and hydroxyproline content compared to the control. The period for re-epithelialisation was reduced compared to the control (Kokane et al., 2009).

5.18 Gentianaceae Anthocleista nobilis G. Don is used in local medicine in Ghana and other parts of West Africa for curing fever, stomach ache, diarrhoea, gonorrhoea and also as poultice for sores (Irvine, 1961; Dokosi, 1992). Methanol extract of A. nobilis at concentration of 33.3% w/w significantly (p<0.02) enhanced wound closure and hydroxyproline production compared to the control in the excision wound model in rats. In the incision wound model, the extract significantly increased tensile strength of A. nobilis treated-wounds compared to the control. However, the methanol extract of A. nobilis had no significant effect on the proliferation of human dermal fibroblast at concentrations as high 50 µg/mL. Doses over 50 µg/mL showed cytotoxic effects on the human dermal fibroblasts (Annan and Dickson, 2008). 5.19 Hypericaceae Hypericum patulum Thumb is a perennial plant distributed in Southern Africa, Asia and North America. It is used traditionally to treat dog bites and bee sting (Baruah et al., 2001). The study investigated the wound healing potential of leaf methanol extract of H. patulum using the 21

excision and incision model of wounds in rats. The methanol extract of leaves (HPM), in the form of an ointment with two different concentrations (5% and 10% w/w ointment of leaf extract) showed enhanced wound contraction rate, re-epithelialisation, tissue granulation and increased tensile strength when compared with the control group (Mukherjee et al., 2000). Hypericum perforatum L. is commonly called St John Worts, klamath weed, tipton weed, goat weed, and enola weed (Muenscher, 1946). H. perforatum is a perennial flowering herb native to Europe, but has spread to temperate locations in Asia, Africa, Australia, Europe and North and South America (Gleason and Cronquist, 1991). Olive oil extract of the flowering aerial parts of H. perforatum is a popular folk remedy for the treatment of wounds in Europe. Aerial parts of H. perforatum have been found to possess remarkable wound healing activities. Flavonoids including hyperoside, isoquercitrin, rutin and (−)-epicatechin, and naphthoquinones especially hypericins were found as the active components of H. perforatum (Suntar et al., 2010). The total extract of H. perforatum in in vivo experimental wound models of linear incision, circular excision and thermal burn showed that topical treatment with extract for 21 days improve wound contraction rate and period of re-epithelialisation. The results demonstrated that the tested novel ointment has significant wound healing effect in skin injuries and appears to be safe for use (Prisăcaru et al., 2013). A plant-derived wound dressing containing a mixture of hypericum oil (Hypericum perforatum L.) and neem oil (Azadirachta indica A. Juss.), in scalp wounds with exposed bone (Laeuchli et al., 2014) and paediatric burn wounds (Mainetti and Carnevali, 2013) was observed to promote healing by enhancing granulation tissues formation and reepithelialisation. 5.20 Lamiaceae Occimum sanctum L. occurs naturally in tropical America, Africa and Asia. It is used traditionally in the treatment of diverse ailments like infections and skin diseases (Godhwani et al., 1988). The wound healing parameters were evaluated by using incision, excision and dead space wound models in rats. The alcoholic (400 and 800 mg/kg) and aqueous extract (400 and 800 mg/kg) of O. sanctum significantly (p<0.05) increased wound contraction rate, wound breaking strength, hydroxyproline, hexuronic acid, hexosamines, superoxide dismutase, catalase and reduced glutathione levels. Lipid peroxidation was significantly (p<0.05) reduced when 22

compared with the control group (Shetty et al., 2008). Goel et al. (2010) also reported that 10% O. sanctum aqueous leaf extract in petroleum jelly increased rate of wound contraction and reepithelialisation compared to the control in excision model of wound repair in Wistar albino rats. Occimum gratissimum L. is an aromatic medicinal plant found in tropical Africa including Ghana, Nigeria and Kenya among others. The leaves are rubbed between the palms and sniffed as a treatment for blocked nostrils. Leaf extract of O. gratissimum promote wound healing by significant wound contraction (p<0.05) on day 10 in the experimental group compared with the control group. Histology of the healed scar showed non-significant (p>0.05) decrease in the mean fibroblast count for the experimental group (83.80 +/- 5.70) relative to fibroblast count of 90.20 +/- 17.90 in the control group (Osuagwu et al., 2004). Chah et al. (2006) also reported similar wound healing properties of O. gratissimum. Hoslundia opposita Vahl is used in ethnomedicine to treat sore throats, colds, sores, veneral diseases, herpes and other skin diseases (Abbiw, 1990); malaria, microbial infections, epilepsy, fever and inflammation (Olajide et al., 1998;

Moshi

et al., 2005). H. opposite

methanol extract at concentration of 33.3% w/w significantly (p<0.01) increased wound contraction and hydroxyproline content compared to the control in the excision wound model in rats. In the incision wound model, the extract significantly improved tensile strength of wounds compared to the control. The extract had no significant effect on the growth of human dermal fibroblast up to concentrations of 50 µg/ml. Doses of extracts above 50 µg/mL rather had toxic effects on the cells (Annan and Dickson, 2008). Hyptis suaveolens (Poit), commonly called bush tea, is a native to tropical America, but it is also widespread in tropical Africa, Asia and Australia. It grows under a wide variety of soil and climates, mainly in warm area. H. suaveolens is used in traditional medicine for treatment of various diseases and the essential oil has been found to possess insecticidal and larvicidal properties (Peerzada, 1997). Ethanol leaf extract of H. suaveolens (400 and 800 mg/kg) increased skin breaking strength, granuloma breaking strength, wound contraction, hydroxyproline content and dry granuloma weight and decreased the re-epithelialisation period. A supportive study made on granuloma tissue to estimate the levels of catalase and superoxide dismutase recorded a significant (p<0.05) increase in the level of these antioxidant enzymes which may result in better 23

collagenation (Shirwaikar et al., 2003). Shenoy et al. (2009) also showed the effect of petroleum ether, alcohol, and aqueous extract from the leaves of H. suaveolens on excision, incision and dead space wound models using Albino Wistar rats. All three extracts at a dose of 500 mg/kg enhanced wound healing by accelerating wound closure and period for re-epithelialisation compared to the control. Tensile strength, dry weight granulation tissue, breaking strength of granulation tissue and hydroxyproline content were also increased compared to the control. However, wound healing activity was highest for the petroleum ether fraction. Leucas hirta of the genus Leucas comprises of about 80 species (Hedge, 1990). The highest species diversity has been found in East Africa (Ryding, 1998), and about 43 species are available in India (Mukerjee, 1940). Decoctions of dry and fresh herbs of L. hirta are used for skin diseases and as gargle for the treatment of thrush respectively. Roots are also used for snake bites (Williamson, 2002). A leaf poultice is used on swelling and boils. The latex of L. hirta is applied on lower eyelids to cure eye sores. The wound healing effect of aqueous and methanol leaf extracts of L. hirta at a dose of 35 mg/kg was evaluated in excision, incision and dead space wound models. The methanol and aqueous leaf extracts were found to possess significant wound healing activity which was evidenced by decrease in the period of re-epithelialisation, increase in the rate of wound contraction, skin breaking strength, granulation tissue dry weight, hydroxyproline content and breaking strength of granulation tissue. Histopathological study of the granulation tissue showed increased collagenation when compared to the respective control group of animals (Manjunatha et al., 2006). 5.21 Lythraceae Lawsonia inermis L. is widely distributed throughout Africa. It also occurs in the Middle East. Ethanol leaf extract of L. inermis (200 mg/kg/day) demonstrated high rate of wound contraction (p<0.001), a decrease in the period of epithelialisation (p<0.001), high skin breaking strength (p<0.001), a significant increase in the granulation tissue weight (p<0.001) and hydroxyproline content (p<0.05). The extract-treated animals showed 71% reduction in the wound area when compared with controls which was 58%. Enhanced wound contraction, increased skin breaking strength, hydroxyproline and histological findings suggest the use of L. inermis in the management of wound healing (Nayak et al., 2007b). 24

Punica granatum L. commonly called pomegranate, originates from Persia including Iran. It is widely distributed in Mediterranean, Europe, Africa and Asia. Leaf extract of P. granatum possess wound healing activity at concentrations of 2.5 and 5% w/w in rats . The amount of hydroxyproline increased by twofold in the group treated with 5.0% gel. The extract was found to contain gallic acid and catechin as major components (Chidambara et al., 2004). 5.22 Malvaceae Hibiscus rosa sinensis L. is native in the tropics and sub tropics (Kumar and Singh, 2012). It has been used traditionally for the treatment of a variety of diseases as well as to promote wound healing. Ethanol leaf extract (120 mg/kg/day) exhibited an 86% reduction in the wound area compared with controls, which exhibited a 75% reduction in rats. The extract-treated animals showed a significant epithelialisation (p<0.002) and have shown significantly higher skinbreaking strength than controls (p<0.002). The dry and wet weight of granulation tissue and hydroxyproline content were also increased significantly when compared with controls (Nayak et al., 2007c). Bhaskar and Nithya (2012) also reported the influence of ethanolic extract of the flowers of H. rosa sinensis (5 and 10% w/w) on Wistar albino rats using excision, incision and dead space wound model. The extract increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in DNA, total protein and total collagen content of granulation tissues. The extract was observed to significantly (p<0.001) promote wound healing which was indicated by improved rates of epithelialisation and wound contraction as well as increased wound tensile strength and wet and dry granulation tissue weights compared to the control. 5.23 Meliaceae Carapa guianensis Aublet is found in Guiana and Africa. The leaves of C. guianensis have been used to treat ulcers, skin parasites, and skin problems. The ethanol leaf extract of C. guianensis exhibited 100% reduction in the wound area when compared to controls (95%) with significant decrease in the epithelialisation period. Skin breaking strength (p<0.001), wet (p<0.002) and dry (p<0.02) granulation tissue and hydroxyproline content (p<0.03) were significantly higher in extract treated animals. The increased rate of wound contraction, skin breaking strength and

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hydroxyproline content may support application of C. guianensis for treatment of wounds (Nayak et al., 2011). Azadirachta indica A. Juss (Neem tree) is a native of Asia but has now naturalized in West Africa. In excision wound model, aqueous leaf extract of A. indica significantly increased (p<0.05) rate of wound closure in experimental group compared to control group (Osunwoke et al., 2013). The 5% w/w methanol extract of the leaves of A. indica ointment has also been reported to significantly (p<0.05) promote the wound healing activity in both excision and incision wound models (Barua et al., 2010). Pandey et al. (2012) reported that A. indica oil increases wound tensile strength and wound closure rate. 5.24 Moringaceae Moringa oleifera Lam. is commonly known as drumstick. It is widely distributed in India, Arabia and cultivated in tropical Africa, tropical America, Sri Lanka, India, Mexico and Malaysia (Kirtika and Basu, 1980). The whole plant is used in the treatment of psychosis, eye diseases, fever and as an aphrodisiac and leaf extract is used in the management of wounds (Chopra, 1993). Qualitative phytochemical investigation confirmed the presence of phytosterols, glycosides, tannins, and amino acids in the various leaf extracts of M. oleifera whereas its seed extracts showed the presence of phytosterols, glycosides, phenolic compounds, carbohydrates and amino acids. The ethanolic and ethyl acetate extracts of the seeds showed significant antipyretic activity in rats, whereas ethyl acetate leaf extract exhibited significant wound healing activity (10% extracts in the form of ointment) on excision, incision and dead space (granuloma) wound models in rats (Hukkeri et al., 2006). 5.25 Musaceae Musa sapientum L. originated from native South-Western Pacific home and spread to India and to the Islands of the Pacific, then to the West Coast of Africa as early as 200-300 BC (Rahman, 2003). It has been shown to possess ulcer healing activity (Goel and Kumar, 2002). Aqueous and methanol extracts (100 mg/kg) have been found to increase wound breaking strength and levels of hydroxyproline, hexuronic acid, hexosamine, superoxide dismutase, reduced glutathione in the granulation tissue and decreased percentage of wound area, scar area and lipid

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peroxidation when compared with the control group. The wound healing effect of M. sapientum may be due to its antioxidant effect and on various wound healing biochemical parameters (Agarwal et al., 2009). 5.26 Myrsinaceae Embelia ribes Burm. is one of the important medicinal plants of India. These climbers are found in the hilly parts of India in places up to the height of 1500 m, and ranges from India to Southern China, south to Indonesia and East Africa (Lal and Mishra 2013). Traditionally the seeds are employed as a remedy for toothache, headache and snakebite. The seeds are mainly used for maintaining healthy skin and to support the digestive function (Chopra et al., 1996). It is also effective in the treatment of fever, abdominal disorders, lung diseases, constipation, fungus infections, mouth ulcer, sore throat, pneumonia, heart disease and obesity (Lal and Mishra 2013). Ethanol leaf extract E. ribes and its isolated quinone compound, embelin, were screened for wound healing activity. In embelin treated group (4 mg/mL in a 0.2% w/v sodium alginate gel), re-epithelialisation of the incision wound was faster with a high rate of wound contraction. The tensile strength of the incision wound was significantly increased than the ethanol extract. In dead space wound model also the weight of the granulation was increased indicating increase in collagenation. The histological examination of the granulation tissue of embelin treated group showed increased cross-linking of collagen fibers and absence of monocytes (Kumara et al., 2007). 5.27 Pedaliaceae Sesamum indicum L. is used in native medicine in Africa and Asia for a variety of diseases. Mucilaginous leaves or leaf sap are used to treat fever, as a remedy for cough and sore eyes, dysentery and gonorrhoea. In eastern and southern Africa the leaves are used for the treatment of ulcers. The seeds of S. indicum are used traditionally in the folklore for the treatment of various kinds of wounds. Seeds and oil treatment (2.5 and 5% w/w) exhibited significant decrease in the period of epithelialisation and wound contraction (50%) increased the breaking strength of wound tissues compared to the control. Also, the seeds and oil treatment (250 and 500 mg/kg; po) in dead space wound model, produced a significant increase in the breaking strength, dry

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weight and hydroxyproline content of the granulation tissue which suggest that the extract and its oil exhibited wound healing property (Kiran and Asad, 2008). 5.28 Piperaceae Piper betel L. is extensively grown in India, Srilanka, Malaysia, Indonesia, Philippines and East African countries (Parmer et al., 1997). Ointment of white soft paraffin containing 1% of dried residue of aqueous extract of P. betel was found to possess wound healing activity (Santhanam and Nagarajan, 1990). 5.29 Potulacaceae Portulaca oleracea L. is a cosmopolitan weed occurring especially in warm areas; it occurs throughout tropical Africa. It is eaten in many African countries, e.g. Côte d’Ivoire, Benin, Cameroon, Kenya, Uganda, Angola and South Africa. It is especially popular in Sudan and Egypt, where it is known in Arabic as ‘rigla’. It is used for external treatment of ulcers, eczema and dermatitis (Rubatzky and Yamaguchi, 1997; Phillips, 2002). Fresh homogenized crude aerial parts of P. oleracea accelerated the wound healing process in mice (strain JVI-1) by decreasing the surface area of the wound and increased the tensile strength. The highest rate of contraction was found at dose of 50 mg, followed by 25 mg treatment (Rashed et al., 2003). 5.30 Phyllanthaceae Bridelia ferruginea Benth is a common savannah specie. Its common names are Kirni, Kizni (Hausa), Marehi (Fulani), Iralodan (Yoruba) and Ola (Igbo) (Kolawale et al., 2007; Rashid et al., 2000). Ethnomedicines prepared from the bark, leaves and fruits are used for the treatment of bruises, boils, burns, wounds and skin disease (Sofowora, 1993). Ethanol stem bark extract of B. ferruginea on wound contraction and epithelization in rats significantly enhanced wound contraction and epithelialisation (Udegbunam et al., 2011) and the extract (1 to 30 μg/mL) has been reported to influence the proliferation of dermal fibroblasts significantly (p<0.05) (Adetutu et al. 2011). 5.31 Rubiaceae

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Morinda citrifolia L. is one of the most important traditional Polynesian medicinal plants. The primary indigenous use of this plant appears to be of the leaves, as a topical treatment for wound healing. The ethanol extract of noni leaves (150 mg/kg/day) was used to evaluate the wound healing activity in rats, using excision and dead space wound models. The extract exhibited 71% reduction in the wound area when compared with controls which exhibited 57%. The granulation tissue weight and hydroxyproline content in the dead space wounds were also increased significantly in noni-treated animals compared with controls (p<0.002). Enhanced wound contraction, decreased epithelialisation time, increased hydroxyproline content and histological characteristics may indicate that noni leaf extract may be beneficial in wound healing (Nayak et al., 2009). Pentas lanceolata Pentas Benth originated from East Africa, and is commonly called the “Red Egyptian star”. The ethanol flowers extract of the of P. lanceolata given by oral route to rats at dose of 150 mg/kg per day for 10 days, was evaluated on its effect on wound healing, using excision wound mode. There was significant (p<0.05) increment in granulation tissue weight, tensile strength, hydroxyproline and glycosaminoglycan content. There was marked increment in the wound contraction in extract treated group as compared to that of controls and these effects may be due to increased collagen deposition as well as better alignment and maturation (Nayak et al., 2005). Rubia cordifolia L. is popular all over the world for its medicinal uses in skin diseases like eczema, dermatitis and skin ulcers. R. cordifolia has an extremely large area of distribution, ranging from Africa to tropical Asia, China, Japan and Australia. In Africa, it is found from Sudan and Ethiopia to South Africa. Hydrogel of the alcoholic extract has been found to improve wound contracting ability, wound closure, decrease in surface area of wound, tissue regeneration at the wound site significantly (p<0.01) in treated mice (Karodi et al., 2009). 5.32 Sapotaceae Mimusops elengi L. is native to India, Sri Lanka, the Andaman Islands, Myanmar and IndoChina, but is commonly planted as an ornamental tree throughout the tropics, also in Africa, where it has been growing in Ghana, Tanzania, Mozambique, Réunion Island and Mauritius. In 29

Asia the leaves are used medicinally to treat headache, toothache, wounds and sore eyes, and are smoked to cure infections of the nose and mouth. A decoction of the bark, sometimes mixed with the flowers, has been used treatment of fever, diarrhoea, inflammation of the gums, toothache, gonorrhea and wounds. The flowers have been used for the management of diarrhoea (Lemmens, 2005; Pennington, 1991; Shah et al., 2003). Methanol extract of bark of M. elengi (5% w/w) exhibited significant (p<0.05) influence on the rate of wound closure, tensile strength and dry granuloma weight. Histological investigation of the wound tissues revealed similar effects consistent with its in vivo wound healing properties (Gupta and Jain, 2011). 5.33 Solanaceae Datura metel L. is found growing in most tropical countries in Africa and it is used for the treatment of haemorrhoids, boils, sores and skin diseases (Ratsch, 1998; Avery, 1959). The ethanol leaf extract increased cellular proliferation and collagen synthesis at the wound site, as evidenced by increase in synthesis of DNA, total protein and total collagen content of granulation tissues. The extract treated wounds were found to heal much faster as indicated by improved rates of epithelialisation and wound contraction and these were confirmed by histological examinations of the wound tissues. The leaf extract of D. metel significantly (p<0.001) increased the wound breaking strength compared to the controls. The extract-treated wounds were found to epithelialize faster, and the rate of wound contraction was significantly (p<0.001) increased in comparison to control wounds. Wet and dry granulation tissue weights increased significantly (p<0.001). There was a significant increase in wound closure rate, tensile strength, dry granuloma weight, wet granuloma weight and a decrease in epithelialisation period in D. metel extract treated group when compared to control and commercial drug treated groups (Nithya, 2011). Solanum xanthocarpum Schrad and Wendl is known as Indian night shade or yellow berried night shade plant. It is more commonly used for the management of diseases like bronchial asthma, cough, worms etc. The fruits facilitate the seminal ejaculation, alleviate worms, itching, and fever and reduce fats (Burkill, 2007). Ethanol leaf extract of S. xanthocarpum significantly (p<0.01) improved wound healing via increaseed re-epithelialisation, tensile strength and hydroxyproline content which may be due to the presence of secondary metabolites such as 30

alkaloids, glycosides, saponins, carbohydrates, tannins, phenolic compounds, proteins and fats (Dewangan et al., 2012). 5.34 Verbenaceae Clerodendron splendens G. Don is a climbing shrub, mostly found growing on cultivated lands between food crops in Ghana and other West African countries. The plant is used ethnomedicinally in Ghana for the treatment of vaginal thrush, bruises, wounds and various skin infections (Irvine, 1961). The methanolic extract of the aerial parts of C. splendens improved wound closure and hydroxyproline biosynthesis compared to the control group in the excision wound model in rats. The methanol extract also increased the tensile strength of wounds compared to the control group (Gbedema et al., 2010). Lantana camara L. occurs widely in the Asia-Pacific region, Australia, New Zealand, Central and South America, West Indies and Africa. It is used in herbal medicine for the treatment of skin itches, as an antiseptic for wounds, and externally for leprosy and scabies (Lyons and Miller 1999). Treatment of the wounds in animals with leaf extract of L. camara enhanced the rate of wound contraction (98%), synthesis of collagen and decreased mean wound healing time. (Nayak et al., 2009).

5.35 Zingiberaceae Curcuma aromatica Salisb. is a medicinal plant cultivated most extensively in India, Bangladesh, China, Thailand, Cambodia, Malaysia, Indonesia, and Philippines. It has been grown in most tropical regions in Africa, America, and Pacific Ocean Islands. Rhizomes of C. aromatica are used as a stomachic, carminative and emmenogogue remedies for skin diseases (Kojima et al., 1998) and also for snakebites (Chopra et al., 1941). Report by Santhanam and Nagarajan (1990) has shown that ointment of white soft paraffin containing 1% of powdered C. aromatic rhizome promotes wound contraction and epithelialisation. Kumar et al. (2009) also reported that the dried rhizome of C. aromatic ethanol extract significantly (p<0.001) improved wound contraction in rat excision wound model.

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5.36 Zygophyllaceae Balanites aegyptiaca L. Diel is widely distributed in tropical regions of Africa. The plant is used in folk medicine for circumcision wounds, worm

infestation and as abortifacient and

contraceptive; to treat abdominal and chest pains (Liu and Nakanishi, 1982; Kamel et al., 1999). Methanol extract of B. aegyptiaca at concentration of 33.3% w/w significantly (p<0.001) improved wound closure and hydroxyproline production compared to the control in the excision wound model in rats. The methanol extract significantly increased tensile strength of compared to the control. The extract had no significant effect on the growth of human dermal fibroblast up to concentrations of 50 µg/ml. Doses of extracts above 50 µg/mL rather had toxic effects on the cells (Annan and Dickson, 2008). Fagonia schweinfurthii Hadidi is traditionally used in Asia and Africa for treatment of inflammation, open wounds, boils, skin eruptions, allergies etc. Ethanol extract of F. schweinfurthii formulated gel (10 and 20%) promote wound closure time in excision wound model in rats (Alqasoumi et al., 2011). 6.0 Conclusion Overall, wound healing activities of several traditional African medicinal herbs have been proven by modern scientific studies. Considering the paucity of clinical studies on the efficacy of the mentioned medicinal plants despite numerous in vitro and in vivo evidences, advanced clinical trials are recommended for confirming efficacy and safety of these herbal remedies. 7.0 Acknowledgements We are grateful to Dr. Paul Poku Sampene Ossei, Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi, Ghana for the proof reading of the manuscript and graduate students of Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana for their assistance in the preparation and review of the manuscript.

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Review: African medicinal plants with wound healing properties

Leaves

In vitro wound models

Root barks

Stem barks

Promote wound healing activity

African traditional medicinal plants

Flowers In vivo wound models Seeds

Table 1: African medicinal plants with wound healing properties No. Plant species Family

References

1

Ageratum conyzoides L.

Asteraceae

Oladejo et al., 2003

2

Alchornea cordifolia (Schum. &Thonn.)

Euphorbiaceace

Agyare et al., 2014

Muell. Arg. 3

Alternanthera sessilis (L.) R. Br. ex DC

Amaranthaceae

Jalalpure et al., 2008

4

Anthocleista nobilis G. Don

Gentianaceae

Annan and Dickson, 2008

5

Azadirachta indica A. Juss.

Meliaceae

Barua et al., 2010 Pandey et al., 2012 Osunwoke et al., 2013

6

Balanites aegyptiaca L. Diel

Zygophyllaceae

Annan and Dickson, 2008

7

Bridelia ferruginea Benth.

Phyllanthaceae

Udegbunam et al., 2011 Adetutu et al. 2011

8

Calotropis gigantea R. Br.

Asclepediaceae

Deshmukh et al., 2009

9

Calotropis procera W. T. Aiton

Asclepiadaceae

Rasik et al., 1999

10

Carapa guianensis Aublet

Meliaceae

Nayak et al., 2011

11

Carica papaya L.

Caricaceae

Mahmood et al., 2005 Nayak et al., 2007a Gurung and ŠkalkoBasnet, 2009

12

Catharanthus roseus L.

Apocyanaceae

(Vinca rosea)

Nayak and PintoPeriera, 2006

13

Centaurea iberica Trev. ex Spreng

Asteraceae

Koca et al., 2009

14

Centella asiatica (L.) Urban

Apiaceae

Bylka et al., 2013; Bylka et al., 2014

15

Chromolaena odorata L.

Asteraceae

Phan et al., 2001

16

Clerodendron splendens G. Don

Verbanaceae

Gbedema et al., 2010

17

Combretum mucronatum Schum. & Thonn.

Combretaceae

Kisseih et al., 2015

18

Cuminum cyminum L.

Apiaceae

Patil et al., 2009

1

19

Curcuma aromatica Salisb.

Zingiberaceae

Santhanam and Nagarajan, 1990

20

Cyperus rotundus L.

Cyperaceae

Puratchikody et al., 2006

21

Datura metel L.

Solanaceae

Nithya, 2011

22

Embelia ribes Burm.

Myrsinaceae

Kumara et al., 2007

23

Fagonia schweinfurthii Hadidi.

Zygophyllaceae

Alqasoumi et al., 2011

24

Heliotropium indicum L.

Boraginaceae

Dash and Murthy, 2011

25

Hibiscus rosa sinensis L.

Malvaceae

Nayak et al., 2007c Bhaskar and Nithya (2012

26

Hoslundia opposita Vahl

Lamiaceae

Annan and Dickson, 2008

27

Hypericum patulum Thumb

Hyperacaceae

Mukherjee et al., 2000

28

Hypericum perforatum L.

Hyperacaceae

Prisăcaru et al., 2013 Mainetti and Carnevali, 2013 Laeuchli et al., 2014

29

Hyptis suaveolens (Poit),

Lamiaceae

Shirwaikar et al., 2003 Shenoy et al., 2009

30

Jatropha curcas L.

Euphorbiaceace

Shetty et al., 2006 Zippel et al., 2010

31

Justicia flava (Forssk.) Vahl

Acanthaceae

Agyare et al., 2013

32

Kigelia africana (Lam.) Beneth.

Bignoniaceae

Agyare et al., 2013

33

Lannea welwitschii (Hiern) Engl.

Anacardiaceae

Agyare et al., 2013

34

Lantana camara L.

Verbenaceae

Nayak et al., 2009

35

Lawsonia inermis L.

Lythraceae

Nayak et al., 2007b

36

Leucas hirta (Heyne ex Roth) Spreng

Lamiaceae

Manjunatha et al., 2006

37

Mallotus oppositifolius (Geiseler) Müll. Arg.

Euphorbiaceace

Agyare et al., 2014

38

Mimosa pudica L.

Fabaceae

Kokane et al., 2009

39

Mimusops elengi L.

Sapotaceae

Gupta and Jain, 2011

2

40

Momordica charantia L.

Curcubitaceae

Agyare et al., 2014

41

Morinda citrifolia L.

Rubiaceae

Nayak et al., 2009

42

Moringa oleifera Lam.

Moringaceae

Hukkeri et al., 2006

43

Musa sapientum L.

Musaceae

Goel and Kumar, 2002 Agarwal et al., 2009

44

Myrianthus arboreus P. Beauv

Cecropiaceae

Agyare et al., 2014

45

Occimum gratissimum L.

Lamiaceae

Osuagwu et al., 2004 Chah et al. (2006

46

Occimum sanctum L.

Lamiaceae

Shetty et al., 2008 Goel et al. (2010

47

Opuntia ficus-indica (L.)

Cactaceae

Trombetta et al., 2006

48

Pentas lanceolata Pentas Benth.

Rubiaceae

Nayak et al., 2005

49

Piper betel L.

Piperaceae

Santhanam and Nagarajan, 1990

50

Portulaca oleracea L.

Potulacaceae

Rashed et al., 2003

51

Punica granatum L.

Lythraceae

Chidambara et al., 2004

52

Pupalia lappacea (L.) Juss.

Amaranthaceae

Apenteng et al., 2014; Udegbunam et al., 2014

53

Rubia cordifolia L.

Rubiaceae

Karodi et al., 2009

54

Sesamum indicum L.

Pedaliaceae

Kiran and Asad, 2008

55

Solanum xanthocarpum Schrad. and Wendl.

Solanaceae

Dewangan et al., 2012

56

Spathodea campanulata P. Beauv.

Bignoniaceae

Ofori-Kwakye et al., 2011

57

Sphaeranthus indicus L.

Asteraceae

Sadaf et al., 2006

58

Strophanthus hispidus DC

Apocyanaceae

Agyare et al., 2013

59

Terminalia arjuna (Roxb. Ex DC.) Wight and

Combretaceae

Chaudhari and Mengi,

Arn. 60

2006

Tridax procumbens L.

Asteraceae

Udupa et al., 1995 Yaduvanshi et al., 2011 Talekar et al., 2012

61

Wrightia tinctoria R. Br.

Apocyanaceae 3

Veerapur et al., 2004