Ethnoveterinary medicine in Turkey: a comprehensive review

* Correspondence: s_kultur@istanbul.edu.tr

includes more than 10,000 species of vascular plants with a nearly 31% endemism rate [8]. As is the case elsewhere in the world, the majority of Turkish people living in rural areas use plants for medicinal purposes. Since these practices are orally transmitted from generation to generation, they face the danger of extinction and thus this valuable heritage needs to be documented. The beginning of ethnobotanical studies in Turkey dates back to the early 19th century. In recent years, the extensive knowledge on traditional medicine has drawn the attention of many researchers in our country as well. According to the literature, it can be said that ethnobotanical studies in our country have mostly been conducted in the Central Anatolia Region and that the lowest number of studies have been performed in the Southeast Anatolia Region. Some of these studies include medicinal plants used in animal diseases [3,6,9].
Ethnoveterinary knowledge is the practice of local people in a given area to maintain the health and ensure the wellbeing of their domestic animals, and treat livestock ailments with their traditions, customs, and beliefs. Ethnoveterinary research focuses on systematic investigation and application of folk veterinary knowledge, theory, and practice [10,11]. Although historical records show that the relations of people with animals have existed for over 14,000 years, the recognition of traditional medicine for animals is a very recent one in scientific circles. Early studies in the field of folk veterinary beliefs and practices as the subject of scientific research began to emerge in the mid-1970s and gained momentum from the early 1980s. The term "ethnoveterinary" was introduced after the mid-1980s. Over the past 35 years, professionals from various fields have researched, evaluated, and documented the potential effectiveness of traditional animal health practices throughout the world. Traditional Turkish culture and history based on ancient Anatolian civilizations such as Hittite, Persian, Roman, Byzantine, Selçuk, and Ottoman are the foundations of Turkish folk medicine and ethnoveterinary medicine. Resources reveal that people's association with animals started around 6000 BC with cattle in Anatolia. Much ethnoveterinary information on domestic animals is available from the past. For instance, De Materia Medica, the work of Dioscorides, is assumed to be one of the most important pharmaceutical books of antiquity and the first well-documented study on medicinal plants in Anatolia. Materia Medica, considered to be the oldest comprehensive document on Anatolian folk medicine, mentions 8 drugs (7 herbal) for veterinary purposes. Although the usage of medicinal plants in animal diseases is widespread, records are inadequate in many countries [12][13][14]. An increasing number of ethnoveterinary studies have very recently focused on the documentation of traditional ethnoveterinary knowledge in Turkey. Many of these studies have been conducted in the last decade [15][16][17][18][19][20][21]. Furthermore, ethnobotanical studies containing traditional knowledge of plants used in animal diseases provide information on the ethnoveterinary practices in Turkey .
Medicinal plants included in ethnobotanical and ethnoveterinary studies have become increasingly recognized as valuable sources for pharmacological studies. However, the most important problems encountered in herbal remedies are the lack of standardization of the active substance in the herbal preparations in terms of concentration and purity and the inability to control their side effects. More recently, the scientific evaluation of ethnobotanical knowledge has become much more common, particularly as a number of drug discovery studies have begun the regular screening of traditional herbal remedies [3,6,9].
Considering Turkey's floral richness and abundance of traditional medicinal knowledge from the past, ethnoveterinary and ethnobotanical studies based on these features need to be compiled. It is of utmost importance to maintain traditional knowledge that is likely to be lost if it is not given enough importance. Documentation of the traditional practices through ethnobiological studies is also crucial for the conservation and utilization of biological resources. The main purpose of this study is to compile medicinal plants used in ethnoveterinary medicine in Turkey with detailed usage information. Also included is an overview undertaken on the pharmacology, phytochemistry, and toxicity of plants to evaluate ethnobotanical claims and to identify gaps required to be filled by future studies, which could lead to new pharmaceuticals.

Methodology 2.1. Literature search
Ethnobotanical and ethnoveterinary studies carried out in different regions of Turkey from 1990 to 2018 were reviewed and medicinal plants used to treat animal diseases were determined. Relevant studies were searched in detail and were collected from books, doctorate dissertations and master's theses, and scientific literature databases (PubMed, Scopus, Google Scholar, Web of Science, SciFinder, Springer, and Elsevier). Key words such as "ethnoveterinary", "ethnobotany", and "medicinal plants + animal diseases" for ethnoveterinary research and "Helleborus orientalis", "Allium sativum", "Juniperus oxycedrus", "Sambucus ebulus", "Pinus brutia var. brutia", "Berberis crataegina", "Cydonia oblonga", and "Olea europaea" for pharmacological discussion were used to facilitate access to the related information. The scientific names of plants and plant families were verified using the International Plant Names Index (https://www.ipni.org/).

Data analyses
Specific information about medicinal plants such as botanical, family, and local names; used parts; preparation methods; administration/dosage and duration of the treatment; and ailments treated/therapeutic effects are presented in Table 1. Moreover, the most cited plant families, the most cited medicinal plants, and the most common animal diseases are presented in graphics (Figures 1-3).

Results and discussion
From the literature search, 7 ethnoveterinary and 59 ethnobotanical articles were obtained. A total of 37 pharmacology papers were referred to in order to evaluate the effectiveness of traditional usage of the most cited plants.

Pharmacological studies 3.2.1. Helleborus orientalis Lam. (Ranunculaceae)
People benefit from leaves, roots, and rhizome for medicinal purposes. However, the preparation method of the plant has not been reported in many studies. Roots are the most frequently used part of the plant. Crushed roots of H. orientalis are added to fodder as an immunostimulant and inserted into the ears or tails of animal to treat colds [31,66]. Cut roots are inserted into the ear to cure animal weaknesses [78]. Roots are also used externally for the treatment of mastitis, keratitis, and edema [28,45]. Roots are prepared by decoction to treat malaria [28]. While leaves are used externally as an antipyretic and analgesic [22] and for the treatment of joint ailments [31], they are used internally for the treatment of diarrhea and colds [29][30][31]. Rhizomes are also used for the treatment of diarrhea and colds, but the preparation and administration methods were not mentioned in the literature [30]. According to other records, rhizomes are inserted into a cow's ear to treat colds [29] and they are added to fodder to treat diarrhea [29]. Moreover, they are administered externally against sunstroke [23]. There are few studies supporting the traditional use of the plant. It was reported that ethanol extracts of H. orientalis roots showed antiinflammatory activity in mice (carrageenan-induced hind paw edema model) and antinociceptive activity was observed using the p-benzoquinone-induced abdominal constriction test [80]. Moreover, leaf and flower extracts of H. orientalis showed potent antioxidant activity [81].

Allium sativum L. (Amaryllidaceae)
People use bulbs of A. sativum in the treatment of various animal diseases. Crushed bulbs are mixed with yogurt and applied to treat sunstroke and sunburn, ringworm, mange, interdigital dermatitis, constipation, and distemper                 [16,19]. Pressed bulbs with milk are used internally to relieve flatulence [32]. For ruminants, crushed bulbs are applied externally to treat mange and bulbs in pills are applied internally in the treatment of babesiosis. Moreover, bulbs are used internally for poisoning and externally for hip lameness, abscess, sunstroke, poisoning, trichophytosis, babesiosis, mange, and leeches. However, the preparation method for bulbs was not recorded [18,20,26,31]. Methanol extract of the bulbs of A. sativum was evaluated for its in vitro anthelmintic activity against Haemonchus contortus and positive results were obtained [82]. Also, an earlier report was published supporting the anthelmintic activity of this plant [83]. The ethanol extract of A. sativum showed various inhibition levels against Staphylococcus aureus and Salmonella enteritidis [84]. The chemical content of allicin is particularly responsible for the antibacterial effect [85]. An aqueous extract of A.
sativum has been shown to possess antimicrobial activity by inhibition of bacteria, yeasts, fungi, and rotavirus strains [86]. In vitro virucidal activities of allicin and other thiosulfinates were also found [87]. Bozin et al. [88] investigated the antioxidant potential of A. sativum by testing the extract of the whole plant with various methods and concluded that the phenolic and flavonoid contents are thought to be responsible for the antioxidant activity. Another study revealed that extracts of bulbs of A. sativum confirmed their ethnoveterinary usage by demonstrating antioxidant, antimicrobial, and insecticidal activity [89]. Venugopal and Venugopal [90] showed the antidermatophytic activity of the aqueous extract of A. sativum. According to Stoll and Seebeck [91], this plant has antibacterial, anthelmintic, and antiprotozoal activities, besides its diuretic and carminative effects. A. sativum oil exhibited an inhibitory effect on trypsin and      [16,18,21]. It is also used internally to treat ticks, colds, babesiosis, gastrointestinal parasites, and fasciolosis [21,39,49]. While infusion of branches is used internally against gastrointestinal parasites of ruminants, it is applied externally against fleas and lice [21]. People benefit from decoction of fruit by internal use to treat cough [52]. Crushed cones are used as an appetizer by internal use [25]. In a study comparing the wound-healing effects of some plants from the family Cupressaceae, essential oil of J. oxycedrus subsp. oxycedrus showed strong woundhealing and antiinflammatory effects [93]. Antimicrobial activity with antibacterial and anticandidal effects of the methanol extract of J. oxycedrus was displayed [94].  Furthermore, Kozan et al. [95] revealed that the ethanolic extract of leaves and fruits of J. oxycedrus has remarkable in vivo anthelmintic activity.

Berberis crataegina DC. (Berberidaceae)
B. crataegina is another plant species mainly used in parasitic diseases. Infusion of roots is regarded as efficient in the treatment of cough, gastrointestinal parasites, fasciolosis, and worms by indigenous peoples [18,21,51]. Decoction of roots is used internally as an anthelmintic and antiparasitic. It is also used against dysuria [34,49,50]. Leaves and fruits are used for the treatment of respiratory diseases and reproductive diseases [15]. The usage of the plant to treat endoparasites, liver pain, and mastitis was recorded but information about used parts and preparation methods was not given in an ethnobotanical study [24]. An experimental study indicated that B. crataegina roots have antiinflammatory, antinociceptive, and antipyretic activity owing to berberine, berbamine, and palmatine, which are the main alkaloids [96]. The antiinflammatory, analgesic, and antipyretic effects of roots were studied in a different study and findings supporting traditional use were achieved [97]. Moreover, the methanolic extract of fruits and aerial parts exhibited significant antioxidant activity in diverse studies [98,99].

Pinus brutia Ten. var. brutia (Pinaceae)
Resin of P. brutia var. brutia is used externally for the treatment of wounds and cuts of animals [32,61,74]. Tar is applied externally to treat fistulas, ticks, and wounds [20,32,36]. Decoction of leaves is used for pains [42]. The usage of the plant to treat colds, enteric disorders, low birthrate, and endoparasites was mentioned but information about used parts and preparation methods was not given in the study [24]. Dığrak et al. [100] investigated the antibacterial activity of the various extracts of the bark, resin, and cones of P. brutia var. brutia by disk diffusion method. In another study, the antimicrobial activity of tar obtained from the stems and the roots was evaluated and results showed that the crude extract of the tar had the most effective activity [101]. Essential oils obtained from resins of P. brutia var. brutia revealed in vitro antimicrobial, antioxidant, phytotoxic, and insecticidal activities [102]. On the other hand, according to Süntar et al. [103], essential oils of the cones and needles showed weak wound-healing effects in their investigation. These reports confirm the traditional utilization of tar and resin of P. brutia var. brutia for dermal and parasitic diseases.

Sambucus ebulus L. (Adoxaceae)
S. ebulus is commonly used against parasitic and dermal diseases of animals in Turkey. Aerial parts are traditionally used to treat mastitis and inflammatory swellings [27,28]. The fruit, flower, and stem are also reported as herbal medicines for gastrointestinal diseases, respiratory diseases, dermal diseases, and wounds [15]. Leaves are prepared by different methods. Crushed leaves are used externally to treat inflamed wounds [26], and heated leaves are applied externally for chick diseases [29]. To relieve pain, animals are exposed to the smoke of the leaves [27]. Leaves and stem are also used for the treatment of chick diseases and as acaricide [30]. Studies proving these effects have been conducted by many researchers. In one of these studies, the antiinflammatory activity of leaves and roots of S. ebulus was demonstrated, and the antioxidant activity of flowers was investigated in another study [104,105]. In addition, herbaceous parts of S. ebulus were studied in terms of anti-Helicobacter pylori activity by using the agar dilution method [106], and wound-healing effects of the methanolic extract of leaves were found [107].

Cydonia oblonga Mill. (Rosaceae)
Fruits, leaves, and seeds of C. oblonga are generally used against gastrointestinal and respiratory diseases. However, its antidiarrheal activity is the best known effect in folk medicine. Infusion of leaves is administered internally to treat diarrhea and distemper [17,19,41]. Infusion of fruit peel is used to treat diarrhea [18]. Crushed seeds are used externally for the treatment of cracked nipples [16]. Furthermore, fruit and seeds are traditionally used to treat gastrointestinal diseases and respiratory diseases [15]. Regarding antidiarrheal activity, the aqueous and methanolic extracts of seeds were investigated, and the seed extract was found to contain effective compounds for constipation cases. The bronchodilator activity of the seed extract has also been demonstrated [108]. The antibacterial and antifungal activities of fruits and seed extract have been proven in many studies [109][110][111]. Leaves and peels were observed to have antiinflammatory effects by some researchers [112,113].

Olea europaea L. (Oleaceae)
Last but not least, O. europaea is one of the most cited herbs in ethnoveterinary medicine. This plant has a very broad spectrum of usage. Olive oil obtained from its fruits is used externally to treat sunstroke, sunburn, and mange [16]. It is offered as a drink for constipation in animals [19]. It is also used for the treatment of abscesses, burns, tympany, swelling, mastitis, and breast lumps [17,18]. For the treatment of gastrointestinal diseases and reproductive diseases, people also benefit from the leaves of the plant by internal use [15]. Poisoning, abdominal distention, and colds are other ailments in which O. europaea is used [24]. Many studies have been performed on the antioxidant, antimicrobial, antibacterial, antifungal, and antiparasitic properties of this plant. The leaves and olive oil have particularly shown these effects [114][115][116].

Toxicology
Some plants contain toxic components that adversely affect animal health. Overdose or side effects of these plants can be dangerous. Therefore, particular attention should be paid to the use of them and dose adjustment should be done well. Examples of the most common toxic effects are given below. All parts of Nerium oleander are toxic, and ingestion of clippings from the plant is a common cause of poisoning in animals. Among the reasons for toxicity are several cardiac glycosides. It also has a negative effect on the central and peripheral nervous systems. Massive doses (30-60 g) of the leaves may kill an animal within 1 h. Members of the family Araceae contain insoluble calcium oxalate crystals that cause pain and irritation during chewing. Some taxa of Chenopodium and Rumex also have oxalate crystals in their leaves and stems. Hypocalcemia is the most common side effect of calcium oxalates. Isocupressic acid, which is found in Juniperus spp., Pinus spp., and Cupressus spp., may cause premature parturition or abortion in late-term cows following internal administration. Toxic quinones and furanocoumarins are associated with the families Apiaceae, Hypericaceae, and Polygonaceae. These compounds induce photosensitization when plants are eaten in large quantities by animals. The triterpenoid saponins are quite common in Caryophyllaceae and Araliaceae. In most cases, the usage of Hedera helix can lead to transient diarrhea and vomiting. Moreover, severe vomiting and diarrhea have been observed in animals consuming Sambucus ebulus. Beta vulgaris causes nitrate poisoning, especially in sheep and horses. Brassica spp. contains S-methyl cysteine sulfoxide, which significantly reduces the number of red blood cells and packed cell volume. Diterpene esters present in Euphorbia spp. directly irritate the skin, mucous membranes, and gastrointestinal tract on contact. The sap is toxic in both fresh and dried plants. Blistering can cause salivation, irritation of the upper gastrointestinal tract, and diarrhea. β-Amino proprionitrile exists in green parts and seeds of some Lathyrus spp. The early clinical signs of poisoning in animals include labored breathing and depression, followed by coma and death within a day or sometimes several days later. Diterpenoid alkaloids that are toxic to animals are found in the family Ranunculaceae (mostly in some Delphinium spp. and Aconitum spp.). Poisoning with Helleborus species is similar to Digitalis poisoning. It is characterized by effects on the cardiovascular and nervous system. Gastrointestinal tract disorders are also observed. For horses, 1 kg of H. niger leaf is lethal. In horses and cattle, severe poisoning occurs with 8-10 g of roots, and in sheep and goats with 4-12 g of roots. Tropane alkaloids, found in members of the family Solanaceae, are responsible for parasympatholytic action in animals. Dry mucous membranes, gastrointestinal atony and tympany, tachycardia, and convulsions may occur at low doses. Melilotus spp. and Daphne spp. contain significant amounts of coumarin, which cause severe pain, vomiting, and collapse. Pyrrolizidine alkaloids have been identified in the family Asteraceae (Tussilago farfara, Senecio spp.). It possesses carcinogenic and mutagenic properties that may result in death [117,118].

Conclusion
Despite modern innovations and the development of synthetic drugs, the use of plants in ethnoveterinary medicine by local people is still continuing. Traditional herbal medicines are a common alternative in the treatment of animal diseases. However, there is insufficient evidence to conclude that traditional use of plants is beneficial to animal diseases. In this study, it was seen that most plants could be used in more than one animal disease and also various parts of the plants may be therapeutically effective. We determined the eight most popularly cited medicinal plants. Many of them are poorly studied in terms of pharmacological activity. No clinical studies have been carried out. Our study shows that Helleborus orientalis, Allium sativum, and Juniperus oxycedrus subsp. oxycedrus var. oxycedrus are the most cited medicinal plants for the treatment of animal diseases. Although H. orientalis is used to treat various animal diseases, pharmacological studies have focused solely on the antiinflammatory, antinociceptive, and antioxidant activity of the plant. Further pharmacological studies are therefore needed, particularly studies evaluating the antidiarrheal and immunostimulant activity of this species. Internal administration of plant was recorded in some ethnobotanical studies. Due to the toxic effect of this plant, further evaluation and classification of its safety is important. Clinical studies should be performed to evaluate the anthelmintic and antimicrobial properties of A. sativum. Our review also indicates that the most prevalent usage of plants is for wound-healing and people have usually preferred ethnoveterinary practices for dermatological diseases. Future research to clarify the wound-healing effects of medicinal plants is required. Considering the traditional usage of the reported medicinal plants, advanced in vitro and in vivo studies and clinical trials are recommended for confirming the efficacy and safety of these herbal remedies. Our data emphasize the efficacy of plants used in veterinary medicine. Thus, we hope that this review will contribute to the development of new plant-derived drugs for the treatment of animal diseases.