Plant Bioactives and Extracts as Feed Additives in Horse Nutrition

Journal of Equine Veterinary Science Volume 69, October 2018, Pages 66-77 Journal of Equine Veterinary Science Review Article Author links open overlay panelMona M.M.Y.ElghandouraPoonooru RaviKanth ReddybAbdelfattah Z.M.SalemaPunuru PanduRanga ReddybIqbalHydercAlbertoBarbabosa-PliegoaDuvvuruYasaswinid a Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma del Estado de México, México b Department of Livestock Farm Complex, College of Veterinary Science, Sri Venkateswara Veterinary University, Proddatur, Andhra Pradesh, India c Department of Veterinary Physiology, College of Veterinary Science, Sri Venkateswara Veterinary University, Gannavaram, Andhra Pradesh, India d College of Veterinary Science, Sri Venkateswara Veterinary University, Tirupati, Andhra Pradesh, India Received 16 May 2018, Revised 5 June 2018, Accepted 12 June 2018, Available online 19 June 2018. crossmark-logo https://doi.org/10.1016/j.jevs.2018.06.004 Get rights and content Highlights • Engaging plant extracts as feed additives is considered to be safe in equines. • Herbal extracts provide therapeutics and nutritional benefits effects to equines. • Plant extracts in regular diets may lessen the chances of stress-related disorders. • Herbal feed additives cannot be applied to horses due to the different susceptibility levels. • More research is required in adapting the dosage, period, and type of herb/plant or its extract. Abstract Despite the extensive availability and use of plant extracts as feed additives in various livestock species, peer-reviewed and scientific evidence of their usage in horses is lacking. This article dealt with the review of reports from recent studies investigating the usage of plant bioactives or extracts in horse nutrition. For the time being, several herbs, either alone or in composites, are being commercialized and openly available in horsemarket stores, which makes it difficult and confusing for horse owners and veterinarians to make a justifiable choice. Usage of ginger extract as a feed additive in sport horses is encourageable as it manages to attain quick recovery after exhaustion in racing and jumping events. Garlic, ginseng, primerose, and rose hip possess potent antioxidative properties, and their supplementation in a regular diet may lessen the chance of occurrence of oxidative stress-related diseases. Owing to their cytoprotective and mucus-stimulatory effects, licorice and Aloe vera extracts have potentiality as feed additives in Standardbred and Thoroughbred racehorses, as they are more prone for equine gastric ulcer syndrome. Echinacea is able to stimulate the equine immunocompetence on addition to the regular diets of equine species. Besides the anti-inflammatory effect, devils claw possess anorexigenic effect, which can limit feed intake, thus keeping the body condition score in check and avoiding obese-related health problems in horses. Regularizing flaxseed meal or its extract as a dietary supplement may support healthy skin and coat condition due to the presence of omega-3 fatty acids as an active component. Aloe vera, well known for cytoprotective and mucus-stimulatory effects, is found to be efficient in protecting the gastrointestinal tract against ulcers or other disorders on administering as a dietary supplement to equines, but the extent of effect depends on the dosage and extent of supplementation. Although, theoretically plant extracts application is safer compared with synthetic antibiotics or drugs, it does not mean they are completely safe, and few considerations should be given for dosage of the drug, period of administration, apart from monitoring parallel drugs given to prevent herb-drug interactions. The plant extracts with potent benefits, and not tested in horses have to be evaluated with a primary objective to verify the negative side effects, if any, followed by standardization of the dosage. Previous article in issue Next article in issue Keywords Herbal extract Horse Anti-inflammatory Antioxidant Immunomodulant 1. Introduction A feed additive is any ingredient or its constituent, other than regular feed material and premixtures, which are purposefully supplemented to feed or water to achieve, in particular, one or more of the tasks. As per the literature available, no scientific well-proven information was ever quoted on the application of antibiotic growth promoters in horses, but incorporation of antibiotic as a feed additive may be helpful for young foals in combating digestive problems, infectious diseases, and environmental and other stress-related factors [1]. According to the Food and Drug Administration, usage of chlortetracycline at 85 mg per head per day is advisable in horses up to 1 year of age for encouraging the growth and feed efficiency. Few field reports revealed beneficial effects on supplementing antibiotics to horses as a safeguard measure to prevent infectious diseases under stressful conditions, but the effects are of short-term benefit and aftermath consequences are not known [2]. Furthermore, the usage of antibiotics as feed additives is more cautious, as their beneficial effects in other livestock could not be promised in equine species; for an instance, horses are particularly susceptible to ionophore intoxications, which needs still higher doses to exhibit toxicity in cattle and swine. Even though the researchers did not warrant the usage of anabolic steroids as feed additives, they are being used by equine athletes to promote muscle development, appetite, aggressiveness, or other desirable effects [3]. However, as per the NRC (1989) guidelines, usage of anabolic steroids in the diet of healthy, young, and growing horses is not suggested because of their negative effects on the testicular development in males and reproductive function in females [2]. The increased perception of potential negative effects of feeding antibiotic growth promoters and steroids in diets of livestock, irrespective of the species, has ensued in an increased interest in the use of plant extracts or herbs as an alternative source. The global herbal products market size is expected to reach $111 billion by the end of 2023 and is projected to grow with a compound annual growth rate of ∼7.2% during 2017–2023. The increase in growth rate is attributed to the increasing preference of consumers toward traditional alternatives for synthetic antibiotics and growth promoters, which are known to have fewer side effects. Nowadays, plant bioactive components or extracts, which are traditionally used against the infections, are being used as feed additives for livestock including cattle, buffaloes, sheep, goat, and poultry. However, the particular herbal extract at a specified dosage fed to any of the aforementioned species cannot be adapted for horses because of the differences in susceptibility levels, pharmacokinetics, and pharmacodynamics compared with other species. As an example, the flavonol quercetin's absorption rate from the gastrointestinal tract in horses is rapid leading to higher amounts of total plasma flavonol levels compared with those in humans, dogs, or pigs [4]. Furthermore, few plant species such as St. John's wort (Hypericum perforatum), mistletoe (Phoradendron flavescens), cherry trees (Prunus serotina), and castor bean (Ricinus communis) are considered to be toxic in equines, which can be reviewed as safe to feed other livestock species [5]. In horse marketplaces, various plant extracts and herbal supplements are being sold with claims of well-being and enhanced performance, but scientific evidence for complete biological effects is very limited in equines. In equines, although, the herbs or their extracts are being used for centuries to improve the performance, their usage, either as an adjunct to drug therapy or unaccompanied, is limited to sporting horses. Besides, as per the regulations of approved national and international equestrian committees, the use of plant extracts in racing contests continues to exist as an ever-debatable and under-researched theme. The phenomenon of disqualifying and elimination of several riders from 2008 Beijing Olympics for using the banned substances illustrates the complications involved in the usage of plant extracts for sporting horses. Furthermore, it is worth mentioning that only a few studies were carried out in equines as experimental animals, and only for a limited number of plant extracts, thus most of the existing evidence on the effects of use of herbal extracts in horses is anecdotal. It has been a traditional practice for horse owners, trainers, breeders, and animal care specialists to use various herbs or their extracts informally either as therapeutic applications or feed additives. Lans et al. (2006) reviewed data on nearly 80 ethnoveterinary plants through key informant interviews; however, their contribution to the existing information on herbal extracts database for equines is not necessarily reliable, as they were based on the personal accounts rather than facts or research [6]. Therefore, a greater understanding and knowledge on utilization of plant extracts in the equines may dispel the concerns over their usage, thus promoting them as feed additives to improve equine health and well being. A survey on US horse owners reported that a total of 58% people are spending $30 or more per horse per month on supplements. Among the respondents, a total of 37% revealed that the supplements are being used as a feed additive to promote overall health and performance, whereas 38% viewed the supplements as a medicine for treating the horse ailments [7]. Although the usage of supplements by horse owners to promote overall performance is as equal as that of treating disorders, almost all the works on herbal extracts in equines were geared toward the therapeutic management of equine disorders rather as feed additives. This article presents a review of the results of various plant extracts utilization in livestock, their properties, and mechanism of action, with special emphasis on the equine research. 2. Plant Herbs or Their Extracts as Feed Additives in Equines Table 1 reviews the active constituent, mechanism of action, negative effects, and equine research existing for the various herbs or their extracts. Table 1. Active components, action, negative effects, and equine research on herbs or herbal extracts. Name of the plant/herb Source of equine research Period fed/administered Findings of the research work Active componentsa Actionsa Negative effectsa Ginseng (Panax quinquefolius, Panax ginseng, and Eleutherococcus senticosus) [8] 28 d Feeding ginseng at 35 mg/kg body weight increased in antibody titer being observed by postvaccination Ginsenosides, glycosidal saponins, essential oils, and phytosterols Anti-inflammatory, antioxidant, and antilipidemic Hypertension, feeding to horses under nonsteroidal anti-inflammatory drugs should be cautiously evaluated. Ginger (Zingiber officinale) [9] A week adaptation with 1 d collection for every trial Feeding ginger extract at 30 g/d reduced the cardiovascular recovery time and increased interferon (IFN)-c and proinflammatory cytokines tumor necrosis factor-1. Gingerols, Shogaols, Zingerone, and Paradols Anti-inflammatory, antiulcerogenic, anticarcinogenic antioxidant, and antithrombotic Caustic effect of ginger extract on the gastrointestinal tract, gastric ulcers, and prolonged bleeding time, platelet dysfunction, and hypertension. Garlic (Allium sativum) [10] 21 d per trial (crossover manner) Decreased respiratory rate without affecting blood hematological and biochemical parameters Organosulfur compounds (alliin, allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, gamma-glutamylcysteine Anti-inflammatory, antioxidant, anticarcinogenic, and immunomodulator Garlic toxicosis occurs on feeding garlic for chronic periods and increased bleeding tendency. [11] 71 d Experimental horses voluntarily consumed an adequate amount of garlic causing Heinz body anemia. Flaxseed (Linum usitatissimum) [12] 18 wk Feeding 10% flaxseed oil increased serum concentrations of alpha-linolenic acid, eicosa pentanoic acid, and malondialdehyde. Omega-3 fatty acids, phytoestrogens (secoisolariciresinol diglycoside), flavonoids, and lignans Anti-inflammatory, antioxidant, and anticholesteremic Excess doses may lead to bloating, gas, abdominal pain, constipation, diarrhea, stomach ache, and nausea. [13] 42 d Supplementation reduced the inflammation, altered the fatty acid profile of hair, and decreased the lesional area of the skin test response of atopic horses. [14] 16 wk Feeding flaxseed at 0.1% body weight increased the serum alpha-linoleic acid concentration without affecting serum chemistry and prostaglandin concentration. [15] 90 d Feeding flaxseed meal (∼38 g of n-3 fatty acid) improved the muscle deposition of alpha-linolenic acid, eicosa pentanoic acid, and docosa-hexanoic acid [16] 90 d Feeding flaxseed meal (∼38 g of n-3 fatty acid), improved the alpha-linolenic acid concentration in serum and synovial fluid without any differences in eicosa pentanoic acid and docosahexaenoic acid concentration. Echinacea (Echinacea angustifolia, Echinacea purpurea, Echinacea pallida) [17] 42 d Feeding 1,000 mg standardized extract increased the lymphocyte count and caused neutrophil mobilization, increase in hemoglobin and erythrocyte count over time. Polysaccharides, glycoproteins, cichoric acid, and alkamides. Anti-inflammatory, antioxidant, immunomodulator, and hematinic agent Excess doses may lead to dizziness, insomnia, gastrointestinal tract problems, and fever. Evening primrose (Oenothera biennis) [18] 8 wk Feeding primrose oil at 150 mL/d reduced lipid peroxidation, decreased lipolysis without altering the muscle homeostasis. Linoleic, gamma-linoleic, palmic, and oleic fatty acids Antioxidant and antilipidemic Excess doses may lead to stomach upset, nausea, and diarrhea. Lavender (Lavandula angustifolia) [19] A week adaptation with 15 min exposure for every trial Aromatherapy: 20% mixture of water and 100% pure lavender essential oil—decreased heart rate and respiratory rate Alpha-pinene, limonene, cis-ocimene, 1,8-cineole, 3-octanone, linalyl acetate, linalool, trans-ocimene, lavendulyl acetate, and camphor. Stress-relieving, antioxidant, and antibacterial Excess doses may lead to increased appetite, and constipation. [20] Adaptation followed by 15 min exposure for every trial Aromatherapy: 20% mixture of water and 100% pure lavender essential oil—decreased the cortisol content Rose hip (Rosa canina) [21] 90 d Top dressing daily diet with 210 gm of rose hip powder increased serum vitamin C within 2 h. Galactolipid, natural vitamin C and E. Anti-inflammatory and antioxidative. Excess doses may lead to heart pain, insomnia, and gastrointestinal tract disorders. [22] 90 d Top dressing daily diet with 25 or 50 gm of rose hip powder increased serum Vitamin-C on long-term basis. Aloe vera (Aloe barbadensis) [23] 28 d Feeding Aloe vera inner leaf gel at 17.8 mg/kg B. wt. was effective in decreasing the equine squamous gastric disease (ESGD). Polysaccharides (acemannan), anthraquinones, saccharides, and salicylic acid. Anti-inflammatory, antioxidative, cytoprotective, and mucus-stimulatory. May stimulate uterine contractions in pregnant mares. Devil's claw (Harpagophytum procumbens) [24] 28 d Feeding devil's claw in combination with dandelion, stinging nettle, burdock, and comfrey mixture reduced the PGE2 production in arthritic joints. Iridoid glycosides (harpagoside), sugars, triterpenoids, phytosterol, and aromatic acids Anti-inflammatory, and anorexigenic Excess doses may lead to hypertension, mild gastrointestinal complaints, and diarrhea. Cranberry (Vaccinium macrocarpon) [9] A week adaptation with 1 d collection for every trial Feeding cranberry extract at 30 g/d reduced the upregulation and expression of tumor necrosis factor alpha mRNA, a major mediator of inflammation. Organic acids (salicylate), vitamin C, flavonoids, anthocyanidins, catechins, and triterpenoids Anti-inflammatory and antioxidant Excess doses may lead to mild stomach upset and diarrhea. Valerian (Valeriana fauriei, Valeriana wallichii, Valeriana edulis, Valeriana officinalis) NRb NRb NRb Sesquiterpenes, valepotriates, valerenic acid, alkaloids, gamma amino butyric acid (GABA), and tyrosine. Sedative and anxiolytic Excess doses cause drowsiness and idiosyncrasies may lead to hepatotoxicity. Yucca (Yucca schidigera) NRb NRb NRb Saponins (spirostanosides), resveratrol, stilbenes (yuccaoles A, B, C, D, and E). Anti-inflammatory, antioxidant, antiprotozoal, antihyperuricemic. Excess doses may lead to gastrointestinal tract disorders, and loose stools. Milk thistle (Silybum marianum) [25] 48 h In vitro laminitis model of the horse: extract at 1000 μg/mL neutralized endotoxins and reduced lipopolysaccharide-induced lamellar separation Silymarin and silibinin Anti-inflammatory and antioxidant — Herbal composite [26] 21 d for each trial Feeding dried composite of five herbs viz. devil's claw, stinging nettle, dandelion, comfrey, and burdock revealed chondroprotective properties in IL-1-stimulated cartilage. Iridoid glycosides, polysaccharides, phenolic steroids, triterpenoids, allantoin, polysaccharides, inulin, and phenolics Anti-inflammatory, analgesic, and chondroprotective. It is not known the extent of contribution of individual phytochemical in the amalgamation for the effect. [8] 21 d for each trial Feeding herbal composite constituting garlic, boneset, fennel, licorice, white horehound, aniseed, hyssop, and thyme reduced elevated respiratory rate. Organosulfur compounds, gamma-glutamylcysteine Anti-inflammatory and analgesic. [27] 30 d Feeding herbal mixture containing fleawort, Aloe vera, fenugreek, licorice extracts at 85 g/d reduced the number and severity of ulcerative lesions in horses affected by Equine Gastric Ulcer Syndrome. Acemannan, anthraquinones, saccharides, and salicylic acid. Anti-inflammatory, antioxidative, cytoprotective, and mucus-stimulatory. a Information compiled from [8], [9], [10], [11], [12], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. b NR–No research was ever conducted in horses. 2.1. Garlic Garlic is known to exert health-promoting effects and documented as an essential ingredient of the human food over 5,000 years ago in India, China, and Greece. The active components include various organosulfur compounds such as alliin, allicin, diallyl sulfide, diallyl disulfide, and diallyl trisulfide (Fig. 1A and B), which can synergistically influence each other. Garlic is one of the most common feed additive used in poultry industry; however, in equines, its usage is primarily limited as an insect repellent followed by the exploitation of its expectorant function to assist disintegration of mucous [29]. Administering a polyherbal composite (Breath) with garlic as a dominant ingredient to horses suffering from a characteristic chronic obstructive pulmonary disease resulted in a decreased rate of respiration without affecting blood hematological and biochemical parameters [30]. Download high-res image (56KB)Download full-size image Fig. 1. Active components of garlic extract. (A) Allicin [28]. (B) Alliin [28]. Garlic extract decreases the production of reactive oxygen species by influencing both antioxidative enzyme activity and cellular glutathione level besides improving mitochondrial functions [31]. Allicin aids in reducing serum levels of triglycerides, cholesterol, and glucose levels, besides decreasing the hepatic cholesterol storage. Allicin is also known to surge the production of reactive oxygen species and caspase-3 expression and causes DNA fragmentation along with glutathione depletion leading to apoptosis induction in pancreatic tumor cells [32]. Another mechanism stated is that allicin induces the transfer of Baz, a proapoptotic factor, to mitochondria subsequently releasing the cytochrome C from mitochondria to the cytosol, thus triggering apoptosis combined with DNA fragmentation .[33] According to in vitro studies, garlic derivatives reduce the expression of inducible nitric oxide synthase enzyme and therefore contribute to the reduction of peroxynitrite formation and the suppression of oxidative stress in cells [34]. Although garlic supplementation promises improved health benefits, its usage as a feed additive should be monitored carefully as the ad libitum feeding or overdosage of garlic is related to Heinz body anemia identified by reduced free hemoglobin, red blood cell count, haptoglobin, and hematocrit in horses [35]. 2.2. Ginseng Ginseng is one of the commonest supplements available in equine market, which is traded for use in stress amelioration, improving the performance, and stimulating the immune system [29]. Among various ginseng species, the American ginseng (Panax quinquefolius), Asian ginseng (Panax ginseng), and Siberian ginseng (Eleutherococcus senticosus) are of primary interest. The bioactive constituents of all species comprise ginsenosides, glycosidal saponins, phytosterols, essential oils, peptides, amino acids, vitamins, and minerals (Fig. 2). The ginsenosides predominantly possess antioxidant properties that care for the immune and nerve cells' membranes. Download high-res image (107KB)Download full-size image Fig. 2. Active component of ginseng extract (ginsenoside) [36]. Dietary ginseng, at a daily dose of 35 mg/kg BW for 2 weeks before and 2 weeks after parenteral equine herpesvirus-1 vaccination, significantly improved the magnitude of the antibody response in horses apart from the positively influenced serum electrolyte balance [8]. The ginseng extract exerts an inhibitory effect on proinflammatory cytokines, IL-6 and IL-1b gene expression, COX-2 expression, and increases the expression of MHC class II, which may enhance the differentiation and proliferation of lymphocytes [37]. Orally administered ginseng-water extract showed antileukemia activity through DC11c+ cell-mediated antitumor immunity [33]. More recently, it has been proven that heated ginseng decreases the plasma adipokine levels by promoting the lipolysis and inhibiting excessive lipogenesis in obesity-induced hyperlipidemia condition [38]. Furthermore, it is essential to remember that the use of ginseng in horses under nonsteroidal anti-inflammatory drugs (NSAIDs) should be cautiously evaluated due to their potentiality to interact with each other [39]. 2.3. Ginger Ginger is classified by the Food and Drug Administration as a safe food additive, which is regularly used for the treatment of asthma, diabetes, nausea, and pain in tropical countries. The active constituents' viz. gingerols, shogaols, zingerone, and paradols (Fig. 3A and B) possess potent anti-inflammatory properties through inhibiting the cyclooxygenase 1 and 2, blocking leukotriene production, and negatively affecting the cytokine genes [11]. Ginger extract and its main constituents, gingerol and shogaol, markedly enhanced the cytoplasm vacuolization and activated AMP-activated protein kinase, a positive regulator of autophagy, revealing its strong anticancer activity [41]. Download high-res image (58KB)Download full-size image Fig. 3. Active components of ginger extract. (A) Gingerol [40]. (B) Shogaol [40]. Nine horses were used in a crossover design to study the postexercise effects of ginger extract at 30 g/day, supplemented by water an hour before testing. Ginger extract reduced the recovery time for VO2 (time to recover from the peak observed at fatigue to a postexercise plateau) without affecting the other physiological responses, which is a beneficial tool for horses competing in racing or jumping events. Furthermore, the extract caused a tendency of increased proinflammatory cytokines tumor necrosis factor-1, interferon (IFN)-c and creatine kinase with a single dose of ginger extract; however, the increased kinase levels were related to the gastrointestinal tract irritation with caustic effect of ginger extract [9]. 2.4. Primrose The essential oil of primerose constitutes primarily unsaturated fatty acids viz. linoleic acid (74.6%), gamma-linolenic acid (9.6%), palmic acid (6.6%), and oleic acid (6.1%) (Fig. 4A and B). Cyclooxygenase and lipoxygenase enzymes use these FAs as substrates, converting them into local hormones (eicosanoids), which further affect a sort of metabolic functions of the organism such as inflammation, vasodilation, vasoconstriction, bleeding, platelets aggregation, immune functions or blood pressure [43]. Primerose oil is also known to contain various potent antioxidants such as gallic acid, alpha-tocopherol, catechin, and epicatechin [42]. In an investigation, Granica et al. (2013) reported that primerose extract displayed anti-inflammatory activity by inhibiting lipoxygenase and hyaluronidase enzymes in a dose-dependent manner, and related the specific effect to the presence of oenothein-B content [44]. An 8-week experiment performed by Mikesova et al. (2014) in 10 healthy horses by supplementing evening primerose oil at 150 mL/day increased the total antioxidant reactivity and reduced the thiobarbituric acid reacting substances revealing an overall reduced lipid peroxidation. The supplementation also decreased lipolysis without disturbing the muscle homeostasis [18]. Download high-res image (63KB)Download full-size image Fig. 4. Active components of primerose extract. (A) Linoleic acid [42]. (B) Gamma-linolenic acid [42]. 2.5. Rose Hip The rose hip powder possesses the fruit including all the seeds and entire shell. The active ingredients of rose hip powder (Fig. 5) comprise an anti-inflammatory substance belonging to the galactolipid family, vitamin C, and E. Winther et al. (2010) top dressed the rose hip powder at 250 g (standardized for 1,000 mg vitamin C) onto the standardized daily diet of 2–3 years trotter for a 3-month period and stated that rose hip extract improves vitamin C status and is effective as an anti-inflammatory and antioxidative agent in horses. They suggested that some “cofactors” or “carriers” within the matrix of rose hip powder might have facilitated the absorption of vitamin C from the gastrointestinal tract [21]. In a secondary study by the same authors, the prolonged effects of the rose hip powder were tested at low doses by feeding rose hip powder at 25 or 50 g (standardized for 125 or 250 mg vitamin C) for a period of 3 months. It was revealed that the rose hip powder at even low doses were sufficient to increase serum vitamin C concentration and decrease the release of oxidative anions [22]. In horse, oxidative stress is more commonly occurred during exercise, and is involved in the etiology of various equine disorders such as recurrent airway obstruction, joint disease and muscle damage, and exercise-induced pulmonary hemorrhage, which may be prevented by supplementing rose hip powder in the regular ration as a feed additive. Download high-res image (66KB)Download full-size image Fig. 5. Active component of rose hip extract (galactolipid) [45]. 2.6. Yucca Yucca is a commonly sold herb for horses to reduce pain without any gastric side effects, and to ease discomfort due to arthritis, bone and joint problems, and soft tissue swelling. Saponins (mostly steroidal saponin) (Fig. 6) contribute to a large extent (about 10% of stem) among the active components of Yucca, followed by polyphenols such as resveratrol and yuccaols A–E [47]. The examination of physical data and spectroscopic analysis of Yucca extract revealed the presence of particular spirostanol saponins, which were stated to have broad bioactivities, such as anti-inflammatory, antiproliferative, antibacterial, anti-HIV, antifungi, and antihyperuricemic activities [46]. Apart from the production perspective, Yucca extract has received much attention in the manure deodorization and gas mitigation programs of livestock rearing [48]. Incorporation of Yucca extract at 100 mg/kg diet enhanced the IL-6 and IFN-c concentration, and antibody titers against Newcastle disease virus in both grower and finisher period of broilers [49]. Feeding Yucca extract in combination with microbial preparation (probiotics) shows synergistic action further resulting in best results [50]. Download high-res image (72KB)Download full-size image Fig. 6. Active component of yucca extract (steroidal saponin) [46]. 2.7. Echinacea Despite not approved as a drug by the Food and Drug Administration, Echinacea is the third most sold herb in the United States, and its extract is being marketed for management of upper respiratory tract infections in humans. The equine industry usually uses Echinacea as an immune booster to complement a healthy immune system. The three species used most frequently in dietary supplements are Echinacea purpurea, Echinacea pallida, and Echinacea angustifolia, offered as capsules and teas. The principal active components of Echinacea include caffeic acid derivatives (cichoric acid, caftaric acid, echinacoside, caffeic acid, chlorogenic acid, and chlorogenic acid) polysaccharides, and alkamides (Fig. 7A and B). In a double-blind, placebo-controlled, crossover trial, O'Neill et al. (2002a) investigated the effect of standardized Echinacea extract on eight horses. Echinacea treatment increased the lymphocyte counts, improved the phagocytic ability of isolated neutrophils, and stimulated neutrophil migration, thus stimulating the equine immunocompetence. The supplement also acted as a hematinic agent by increasing the hemoglobin levels and total erythrocyte count, which may be related to improve the exercise performance by increased oxygen transport [17]. In a review, Barrett (2003) concluded no adverse effects of either overdoses or drug interactions on feeding Echinacea extract [52]; however, allergic rashes, hypereosinophilia, and autoimmune diseases and leucopenia were encountered with Echinacea usage for more days or with overdosage. Download high-res image (116KB)Download full-size image Fig. 7. Active components of Echinacea extract. (A) Cichoric acid [51]. (B) Echinacoside [51]. 2.8. Valerian Valerian supplements are usually sold for the treatment of anxiety, stress, and insomnia in humans. In equine industry, the valerian root extract has been sold with a caption, “Equine Calmer”, claiming its effect in relieving nervousness, restlessness, stress, and fear without affecting performance on feeding 15 g per day/horse. They also claim that Valerian eases the cramping associated with hormonal issues and retain a relaxing and calming effect on the gut by slowing down the passage of food through gut. More recently, a pilot survey on the horse owners' perception toward the usage of equine calming products in the north of Scotland revealed the regular use of valerian by few respondents to induce calming effect, thus mitigating the undesirable behavior during diverse situations [53]. Valerian extract contains at least 150 active constituents, the major include valepotriates, which comprise valtrate, volatile oils, valerenic acid, valeranone, and valerenal, alkaloids and lignans (Fig. 8A and B). Valerian causes a sedative effect by acting mainly as a depressant on nervous system followed by muscle relaxant [55]. In a human study, valerian extract at 600 mg/day valued superior to placebo on the Clinical Global Impression scale, with 66% of patients rating valerian effective for sleep as compared with 26% with placebo [56]. Furthermore, the administration of valerian extract at 1,000 mg/kg reduced the sleep latency period in Wistar rats [57]. Download high-res image (94KB)Download full-size image Fig. 8. Active components of valerian extract. (A) Valerenic acid [54]. (B) Valerenal [54]. 2.9. Devil's Claw In humans, devil's claw has been used as a herbal medicine for various fevers, allergies, appetite stimulation, and dyspepsia since ancient days; currently, it is more popular as an anti-inflammatory and analgesic agent for osteoarthritis. Among the major elements of the extract (iridoid glycosides, sugars, triterpenoids, phytosterol, and aromatic acids), harpagoside (Fig. 9), a monoterpene iridoid glycoside, exert anti-inflammatory effects by interacting with both lipoxygenase and cyclo-oxygenase mediated pathways, as well as with the release of cytokines and nitric oxide production [58]. Furthermore, a close association between serum harpagoside levels and inhibition of leukotriene biosynthesis was observed in human subjects [59]. Although extrapolation of these results in humans to horses is challenging, the usage of devil's claw in horses is common for pain originating from degenerative joint disease [59]. According to Torres-Fuentes et al. (2014), oral supplementation of devil's claw is efficient for the effective treatment of inflammation, osteoarthritis, rheumatoid arthritis, tendonitis, and dyspepsia [60]. Download high-res image (80KB)Download full-size image Fig. 9. Active component of devil's claw extract (harpagoside) [33]. Exposure of C57BL/6 mice to devil's claw root extract demonstrated an increase in cellular calcium influx without inducing subsequent GHS-R1a receptor internalization, indicating full receptor activation and anorexigenic effect [60]. This notion may be applied to limit feed intake and keep the body condition score in check by avoiding an obese condition in sport horses at latency period by using H. procumbens extract as a feed additive. Administration of devil's claw was associated with hypertension, possibly as a consequence of the persistent inhibition of endogenous prostaglandins synthesis [61]. Furthermore, Torfs et al. (2008) documented mild gastrointestinal complaints and diarrhea as most common side effects on reviewing all clinical studies on devil's claw extract usage [59]. Excessive dose of devil's claw may also interfere with parallel treatment for cardiac disorders [62]. 2.10. Flaxseed Flaxseed has been used for ages as a dietary supplement for horses because of its high fat content. The active components include omega-3 fatty acids, phytoestrogens (secoisolariciresinol diglycoside), flavonoids, and lignans (Fig. 10A and B). In the recent past, the importance of omega-3 fatty acid supplementation has gained much importance in food industry, especially in designer food production. In this regard, flaxseed can be viewed as a cost-effective and economical way to boost omega-3 fatty acid in the feed. Supplementation of flaxseed oil to horses for 18 weeks did not show any differences in their body weight, plasma fibrinogen levels, blood count, and electrolyte (Na, K, and Cl) concentrations, except for plasma levels of alpha-linolenic acid, eicosa pentanoic acid, and malondialdehyde contents, which could potentially improve the chronic inflammatory disorders such as equine metabolic syndrome, osteoarthritis, and laminitis in horses [12]. In another study, the supplementation of flaxseed (∼38 g alpha-linolenic acid) to growing horses leads to higher incorporation of n-3 eicosa pentanoic acid and docosahexaenoic acid in skeletal muscle, which was still higher compared with both control and marine alpha-linolenic acid supplementation [15]. In a similar feeding design, Ross-Jones et al. (2014) estimated the synovial and plasma fatty acid levels for eicosa pentanoic acid and docosahexaenoic acid. Although the plasma levels were higher than control, the levels of eicosa pentanoic acid and docosahexaenoic acid in synovial fluid was far lower than those of marine alpha-linolenic acid supplementation, showing that direct supplementation of these fatty acids is obligatory if the greater levels of those fatty acids are needed in synovial fluid for the management of joint pains [16]. Download high-res image (82KB)Download full-size image Fig. 10. Active components of flaxseed extract. (A) Eicosapentaenoic acid (EPA) [63]. (B) Docosahexaenoic acid (DHA) [63]. Direct supplementation of eicosa pentanoic acid and docosahexaenoic acid to exercised horse diets were associated with lower plasma glycerol, heart rate, free fatty acids, and cholesterol compared with those fed with corn oil containing diets [64]. Furthermore, the clinical studies revealed that omega-3 fatty acids supplementation aids in improved lung function in the horses suffering from chronic lower airway inflammatory disease. Feeding mares with flaxseed at 0.1% body weight for 16 weeks did not influence progesterone and any of the serum biochemical parameters, except for alpha-linolenic acid concentration, which was higher compared with control [14]. Interestingly, flaxseed usage as a feed additive is identified to play a role in maintaining the health of skin coat apart from treatment of symptoms of dermatitis in horses, probably, due to modifications in fatty acid profile of the sebum secreted by sebaceous glands [65]. In connection with this, O'Neill et al. (2002b) reported that feeding flaxseed meal significantly reduced the lesional area of skin test response of atopic horses with an altered fatty acidprofile of hair and reduced inflammation in horses, which previously showed a positive skin test for allergy to extract from Culicoides sps [13]. 2.11. Aloe Vera Aloe vera, an oldest known natural herb that is used in the field of cosmetology in humans, is also tested to be potent for regulating hoof health and ulcer-related gastric disorders in horses. Aloe vera–based formula was successfully used as emollient on horses' hooves [66]. The extract or gel contains 75 potentially active constituents viz. anthraquinones, saccharides, polysaccharides (acemannan), salicylic acids, saponins, vitamins, enzymes, minerals, sugars, lignin, and amino acids [67] (Fig. 11A and B), providing a variety of possible mechanisms including antioxidant activity, anti-inflammatory properties, cytoprotective, and mucus-stimulatory effects. Few studies in monogastric animals specify that the Aloe vera extract can improve the ecosystem of intestinal microflora by decreasing the total E. coli count and increasing the Lactobacillus count [69]. More recently, Bush et al. (2018) compared the gastrointestinal tract protective effect of Aloe vera inner leaf gel with omeprazole in 40 horses diagnosed with grade ≥2 lesions of the squamous and/or glandular mucosa. Although improvement in lesions was seen, the healing rate was only 17% in Aloe vera group compared with 85% of the omeprazole group; the lower efficacy of extract may be related to the low dosage and short period of exposure (only 28 days) [23]. Aloe vera gel is contraindicated and should not be fed to pregnant mares as it may stimulate uterine contraction, thus increasing the risk of fetal loss [65]. Download high-res image (180KB)Download full-size image Fig. 11. Active components of flaxseed extract. (A) Anthraquinone [68]. (B) Acemannan [68]. 2.12. Other Plant Extracts A disk diffusion and microdilution methods based in vitro study conducted by using nine essential oils viz. cinnamon, peppermint, palmarosa, oregano, Madagascar and Indonesian cloves, niaouli, oregano, sauce thyme, and rosemary, against the Staphylococcus xylosus isolates from nasal mucosa of horse revealed a potent antimicrobial activity by all the oils tested, except for rosemary [70]. Owing to their antimicrobial properties, essential oils are traditionally being used to control respiratory and gastrointestinal infections, and nowadays their usage as food additives have been gaining importance in humans. The dried composite of five herbs viz. devil's claw, stinging nettle, dandelion, comfrey, and burdock showed a significant protective effect against IL-1–induced glycosaminoglycan (GAG release) and nitric oxide production, suggesting its potentiality as an adjunct to the NSAIDs, but care should be taken regarding the dosage due to the narrow safety margin [26]. Another study conducted by the same author by means of using a herbal composite constituting garlic, boneset, aniseed, white horehound, licorice, fennel, hyssop, and thyme indicated this amalgamation as a possible strategy in safely reducing the elevated respiratory rate in horses suffering from recurrent airway obstruction [8]. Remarkably, the lavender aromatherapy was shown to signal a shift to the sympathetic nervous control from the parasympathetic system, decreased heart rate and respiratory rate [19], and suppressed cortisol levels [20] in horses subjected to stress. The authors stated that lavender usage, being not an illegal substance, in stressed horses is of utmost importance, as there are limited legal medications available for racing horses as per the rules and regulations of Federation Equestre Internationale. Cranberry extract at 30 g/kg body weight attenuated the upregulation and expression of tumor necrosis factor -α mRNA, a major mediator of inflammation, after a small and intense session of exercise in horses [9]. In a field trial, Luca et al. (2017) fed herbal mixture, constituting fleawort, Aloe vera, fenugreek, and licorice extracts, to the horses diagnosed with equine gastric ulcer syndrome for a period of 30 days. They confirmed that the herbal mixture was effective in reducing both the number and severity of ulcerative lesions, presumably due to the beneficial effects of mucilages in protecting the mucosa from acidity apart from the antiulcerogenic activity of the herbs [27]. Although no scientific evidence was found, anecdotal usage of fenugreek in horses seems to be very common for treating various disorders in horses. Meanwhile, Salem et al. (2017) evaluated the effect of different doses of aguamiel (Agave atrovirens) sap, having both probiotic and prebiotic characteristics, on in vitro degradation of various forage species. Aguamiel at 34 μg/g enhanced the fermentability of Caesalpinia coriacea forage, indicating enhanced feed intake, which was predicted with relation to gas production. Furthermore, the extract at a higher dose (64 μg/g) caused a decreased time for lag phase compared with control suggesting an induced microbial adaptation [71]. Another study was conducted in nine Standardbred mares with a speculation that decaffeinated black tea and orange peel extracts would alter indicators of exercise performance. The extract of orange peel administered 60 minutes before exercise in horses, which were exercised until fatigue on the treadmill, decreased interferon-γ (IFN-γ) expression and recovery time of cardiovascular parameters because of the anti-inflammatory effect of citrus-derived polymethoxylated flavones. Black tea extract also lessened mRNA expression of tumor necrosis factor-α and IFN-γ due to the tea flavin, a polyphenol having potent inhibition effect on IL-8 gene expression [72]. Furthermore, Bergero (2006) acknowledged ginkgo (Ginkgo biloba) extract can ameliorate the performance loss during “sport horse anemia” condition, which decreases oxygen distribution to muscle cells throughout the performance [73]. Torfs et al. (2018) claimed willow (Salix) and blackcurrant (Ribes nigrum) as phototherapeutic and potential alternatives of NSAID in horses, but yet to be researched completely [59]. Despite lack of any experimental studies in horses, spices such as fenugreek (Trigonella foenum), cinnamon (Cinnamomum zeylanicum), and turmeric (Curcuma domestica) were promoted to use as feed additives in horses as they may provide health benefits other than just increasing the palatability [5]. Parsley (Petroselinum crispum) extract, a complex mixture of coumarins, terpenoids, and phenylpropanoids, is another promising feed additive in horses and even has long back history of feeding the whole herb to war horses by warriors [6]. Milk thistle (Silybum marianum) extract was able to neutralize endotoxins and reduce lipopolysaccharide-induced lamellar separation in a well-established in vivo/in vitro laminitis model, presumably due to the antioxidative and anti-inflammatory properties of the active components such as silymarin and silibinin [25]. Furthermore, silymarin may increase the serum levels of glutathione, and also known to use for horses suffering from ragwort poisoning or liver damage [65]. The active principles of various herbs with potentiality to use as feed additives are presented in Fig.12. Download high-res image (565KB)Download full-size image Fig. 12. Chemical structure of active components of few plant herbs to be used as feed additives in equines [74]. Although feeding all the aforementioned herbs or their extracts has their own confines, many herbs growing naturally in hedgerows and pastures provide free access to grazing horses. Hawthorn (Crataegus), an antistressor and mild diuretic and known to possess beneficial effects on the cardiovascular system because of the active ingredient vitexin, growing near paddocks seem particularly appetizing to horses. Dandelion, a perennial weed available ad libitum in the grazing tracts of horse, is known to possess antidiuretic and hepatoprotective effects [65]. 3. Problems Associated with the Utilization of Herbs as Feed Additives in Equines Most herbs are not scientifically evaluated for their beneficial and adverse effects. The absence of controlled measures either to diagnose or prevent adulteration of herbs or their extracts, in horsemarkets is a considerable problem in exploiting their usage. Adulteration is merely a replacement of various herbs with other unrelated herbal ingredients or incorporation of active components, pathogens, drugs or pollutants. 3.1. Herbs as Feed Additives during Competition As per the Equine Anti-Doping and Controlled Medication Regulations, any materials, either natural or synthetic, having the potentiality to enhance performance on administering at considerable levels are considered to be banned, have no legitimacy to use, and should not be found in body fluids of sport horses at any level. Scarth et al. (2010) considered that the increased usage of herbal products as feed additives or therapeutic agents may become one of the important threat that greatly influences the future of equine drug metabolism in the area of doping research [75]. However, the UK rules of racing (2010) announced that any feed supplement or medications, including herbal extracts, can be freely fed to horses on training, but the usage should be terminated few days before the sport to prevent their detectability on race days [76]. This thought needs thorough study to know the detection time and withdrawal periods of various herbs, and there is a necessity for developing new approaches for analytical screening by including the principles of the safety of margin, pharmacokinetics, and pharmacodynamics. Furthermore, confusion does exist pertaining to the list of banned substances; although capsaicin, a secondary metabolite of chili pepper with analgesic property, is not listed as class A list of banned substances by Federation Equestre Internationale, its usage was related to disqualifying and elimination of the riders from 2008 Beijing Olympics. Another important consideration is inconsistent regulations regarding the usage of supplements or medicines by the equine regulatory authorities. As an illustration, the usage of phenylbutazone, along with Regumate, Gastroguard, and antibiotics were banned by the German Equestrian Federation, which are still allowed in Federation Equestre Internationale competitions. 3.2. Herb-Drug Interaction Herb-drug interactions are no more than the drug interactions that occur between conventional drugs and herb extracts because of the interrelationship among normal drug administered and multiple pharmacologically active ingredients in the plant extract. Although most of the herbal extracts are not associated with drug interactions, few are able to cause clinically significant consequences [77]. Extensive reviews on herb-drug interactions were given by Posadzki (2013) [77], Harman (2002) [78], and Izzo et al. (2005) [79]. Furthermore, critical evaluation of causality assessment of various herb-drug interactions in human patients can be found in a review by Awortwe et al. (2018) [80]. The most common interactions with considerable potentiality in equine health and well-being are discussed below. The herbs containing salicylates viz. meadowsweet (Filipendula ulmaria), wintergreen (Gaultheria procumbens), willow (Salix alba), poplar (Populus tremuloides), ginseng (Panax quinquefolius), licorice (Glycyrrhiza glabra), and sage (Salvia officinalis) have to be cautiously administered as their interaction with various drugs can create various side effects ranging from mild to severe, depending on the concentration [29]. Feeding devil's claw (Harpagophytum procumbens) as a feed additive in horses administered with NSAIDs, antiarrhythmic agents, hypoglycemic medications, anticoagulants, or digoxin, may lead to drug interactions leading to an increased risk of gastrointestinal tract bleeding, hypoglycemia, and arrhythmias [61]. Valerian can interact with alcoholic beverages, barbiturates, benzodiazepines, antihistamines, or anesthetics, and because of these interactions, the same is strictly prohibited to be fed in postsurgical conditions [81]. Two systematic reviews found scientific evidence of Echinacea as a triggering agent of pharmacokinetic drug interactions along with induction of cytochrome P3A enzymes–mediated drug metabolism [82]. Although the overall herb-drug interaction risk for garlic is low, prolonged exposure of concentrated extracts may reduce the efficacy of drugs whose deposition depends on the efflux transporter ABCB1 gene [83]. Furthermore, in equines, feeding excess garlic without a proper check on the levels may lead to Heinz body anemia [35]. Many herbs have been related to the adverse reactions with bronchodilators including cardospermum (Cardospermum halicacabum), ginkgo (Ginkgo biloba), and St. John's wort (Hypericum perforatum) [84]. 4. Conclusion Although the positive results found with all the aforementioned herbs or their extracts as feed additives were mostly in species other than equines, they could also potentially adapted for horses, but with a principal evaluation for suitability of the respective herb at a specified dosage, especially in pregnant and lactating horses. Definitive conclusions can be made on conducting equine-specific studies. Within the equine studies, although few herbs were tested as feed supplements, the outcome and adaptability should be evaluated based on the variations in methods used in the study such as quantity, extraction procedure, form of feeding, and length of the trial period. In addition to alleviating symptoms and treating chronic diseases of horses, these herbal/plant extracts can be used in maintaining health and improving performance by exploiting them as feed additives, if nourished at desired levels, but a large extent of lacunae exist for equines, demanding a vast scope for future studies regarding feed additives application. Exploiting new knowledge of the constituents of various plant extracts, the focus of herbal extract research should shift from currently used therapeutic management to feed additive purpose. Again, the prohibited medications list from the Federation Equestre Internationale has to be taken into account while formulating any herbal-based feed additive for horses at international competitions. Furthermore, natural will not always guarantee safe; hence, the proposal of administration of herbal extracts together with any synthetic drugs should be reconsidered on the background of herb-drug interactions. References [1] M.H. 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