Central Annals of Medicinal Chemistry and Research

Review Article *Corresponding author Sethi J, Department of Physiology, PGIMS, University of Health Sciences, Rohtak, India, Tel: 919-812-040-550; Role of Medicinal Plants as Email: Submitted: 02 March 2015 Immunostimulants in Health Accepted: 20 April 2015 Published: 23 April 2015 Copyright and Disease © 2015 Sethi et al. 1 2 Sethi J * and Singh J OPEN ACCESS 1Department of Physiology, University of Health Sciences, India 2Department of Pharmacology, University of Health Sciences, India Keywords • Immunostimulants • Medicinal plants Abstract • Immunosuppressants Complementary and alternative medicine involves the use of herbs and medicinal • Alternative medicine plants as an alternative to mainstream western medical treatment. A large number of Indian medicinal plants have been reported to possess immunostimulant activity and thus can serve as potential source of drug in various immunocompomised states including AIDS, cancer and for treatment of various chronic infections. This review describes role of plant derived Immunostimulants in health care.

INTRODUCTION which are generally given in combination regimens to treat various autoimmune diseases and to prevent transplant rejection. The immune system evolved to discriminate self from nonself. resist large number of infectious and harmful microorganisms, asImmunostimulants well as adaptive are immune inherently responses nonspecific in healthy and volunteers; enhance enablingImmunity the may body be to defined prevent as or the resist body’s diseases ability and to inhibit identify tissue and Immunostimulantsbody’s resistance to are infection. expected They to serve can as act prophylactic through innate and medical problems. Immunological diseases are rapidly growing promoter agents. In immunocompomised patients they are thatdamage. require Immune aggressive system and mediated innovative diseases approaches are to significant develop expected to act as immunotherapeutic agents. These agents are new treatments. These diseases include various autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, [2]. Both Immunosuppressants and stimulants have serious used to treat serious infections, immunodeficiency and cancer systemic lupus erythematosis, multiple sclerosis, hematological side effects; Complementary or traditional remedies are other malignancies, infectious diseases, asthma, various allergic options to overcome this problem. Herbal medicine (traditional or natural medicine) has always existed in one way or another in different cultures and civilizations such as Ayurvedic (India), syndrome,conditions, uveitis inflammatory and immune bowel system diseases, mediated glomerulonephritis, graft rejection Western, Chinese, Kampo (Japan) and Greco-Arab or Unani- [1].thrombocytopenia, Two arms of immunity myasthenia (innate gravis, and adaptive) polyarteritis, work Behcet’s closely Tibb (South Asia). Traditional medicine all over the world is together. Innate immune system is most active early in an immune currently being evaluated through extensive research activity response and adaptive immunity becoming progressively on various plant species for their potential therapeutic effects. dominant over time. The major effectors of innate immunity The Ayurvedic system of medicine is one of the oldest systems are complement, granulocytes, monocytes/macrophages, of medicine and includes ethnopharmacological activities such natural killer cells, mast cells and basophils. The major effectors as immunostimulation, immunosuppression, tonic, antiageing, of adaptive immunity are B & T lymphocytes. These cells are antirheumatic, anticancer adaptogenic, antistress and Rasayana important in normal immune response to infection and tumors, but also mediate transplant rejection and autoimmunity [1]. devoted to Rasayana (drugs reputed to enhance body resistance). etc [3]. An entire section of the Materia Medica of Ayurveda is Immunomodulators are biological or synthetic substances A number of medicinal plants as Rasayanas have been claimed that can stimulate suppress or modulate any aspect of the to possess immunomodulatory activities [4]. There is a long immune system [2]. Clinically Immunomodulators can be list of plant products which possess immunostimulatory and immunosuppressive activity and these products are in use for the treatment of various immunocompromised conditions immuneclassified stimulants. into 3 categories. They hold Immunoadjuvants the promise of being are theused true to including HIV infections and autoimmune diseases by Ayurvedic enhance efficacy of vaccines and could be considered specific modulators of the immune response. Immunosuppressants are practitioners. This review describes only medicinal plants a structurally and functionally heterogeneous group of drugs possessing immunostimulant activity.

Cite this article: Sethi J, Singh J (2015) Role of Medicinal Plants as Immunostimulants in Health and Disease. Ann Med Chem Res 1(2): 1009. Sethi et al. (2015) Email: Central

Asparagus racemosus Wild (family Asparagacae, Liliaceae)) Hindi name – Satawar, English name – Wild of Th1 type of response [16]. Significant reduction in erythema, asparagus treated with A. indica doses)desquamation has also been and infiltrationreported. This of indicates psoriatic immunostimulatory lesions in patients The protective effect of A. racemosus against myelosuppression properties of A. indica [17] leaf Sai extract Ram et (300 al [18] mg/day have demonstrated in 3 divided induced by single dose (200 mg/kg, sc) cyclophosphamide to mice has been reported by Thatte & Dahanukar 1988 [5]. A. A.indica racemosus itself produced leucocytosis and neutrophilia but inimmunomodulatory increase in polymorphonuclear properties of NIM-76, leukocytes a volatile with fraction decrease from in when compared with control group, A. racemosus prevented lymphocyte. In rats count NIM-76 in blood. single At intraperitoneal120 mg/kg, there injection was enhanced resulted leucopenia produced by cyclophosphamide. These workers macrophage activity and lymphocyte proliferation response. suggested that A. racemosus is a potent immunostimulant with effects comparable to lithium and glucan. In animal models of intraperitoneal adhesions, A. racemosus prevent postoperative primarilyAt higher actsdoses through (300mg/kg) cell mediated there was mechanisms stimulation by of activating mitogen- adhesions [6] Dhuley [7] (1997) reported that A. racemosus macrophagesinduced lymphocyte and lymphocytes. proliferation. Study indicates that NIM-76 Andrographis paniculata Burn F. (Family Acanthaceae) induced suppression of chemotactic activity and production of Hindi name – Charayata, Kalmegh, English name – treatment significantly inhibited carcinogen ochratoxin-A induced A. racemosus Bhunimba excess production of TNF when compared with control. IL-1 and TNF-α by mouse macrophages. Ethanol extract and diterpene andrographolides from A. Aloe vera Linn Burm F. (family – Liliaceae) Hindi name paniculata – Ghrita Kumari, English name – Indian Aloe antibody and delayed type hypersensitivity response to sheep red blood cells have in been mice shown [19] There to induce is stimulation significant of stimulation macrophage of Acemannan (a carbohydrate fraction from gel of A. vera) migration, phagocytosis of 14C leucine labelled E. coli and in vitro proliferation of splenic lymphocytes [19] The stimulation was peripheral macrophages [8]. It also induces nitric oxide (NO) release,has been expression shown to ofincrease surface productionmolecules and of IL-1morphologic and TNF-α changes from presencefound to be of both other antigen substances specific other and non-specific.than andrographolides It was lower which with activation may be accountable for immunostimulating effects of maypurified be andrographolidesresponsible for immunostimulation. than with ethanol extract Andrographolide indicating acemannanin mouse macrophage [9]. Acemannan cell line may (RAW be responsible 264.7) [8] for Macrophage regression from A. paniculata inhibited the induction of NO synthease by of tumors in experimental animals and increased lymphocyte lipopolysaccharide in RAW 264.7 cells [20]. response to alloantigen via IL-1 production. Oligosaccharides from A. vera may prevent ultraviolet induced suppression of Abutilon indicum Linn (Family Malvaceae) Hindi name delayed type hypersensitivity by reducing keratinocyte derived – Jhampi, Kanghi, English name – Indian Hallow immunosuppressive cytokines [10] Essential oil from this plant augments antibody in animals Allium sativum (family Liliaceae) Hindi name – Lasun, showing immunological value [21]. English name -Garlic Cynodon dactylon Linn (family Poaceae) Hindi name Garlic extracts particularly organosulfur compounds have – Dub, Durva, English name – Creeping panic grass, been shown to inhibit growth of tumors in animals probably by Devil’s grass activation of natural killer (NK) cells, stimulation of T lymphocytes A perennial creeping herb, common all over India. Distributed throughout Burma, Sri Lanka, Australia, America and garlic extract enhance cytotoxicity of human peripheral blood warm countries. Fresh extract of cynodon dactylon investigated lymphocytesand enhanced against production both ofNK IL-2 cell [11] sensitive Morioka (K562) et al reportedand resistant that clinically in 10 patients of idiopathic thrombocytopenic purpurea, gave remissions for a longer period of time. Durva also controlled haematuria in a few patients. In patients with bone marrow Garlic(M14) extract cell lines prevented [12] Lau from et ultraviolet al have demonstrated induced suppression that garlic of depression, it increased the platelet count and white blood cells. contactmay augment hypersensitivity macrophage [14] and T lymphocyte functions [13] The drug was safe and had no side effects [22] Azadirachta indica A. Juss (family Meliaceae) Hindi Curcuma longa (family Zingibaraceae) Hindi name – name – Neem, English name – Margosatree Haldi, English name – Turmeric Turmeric has been reported to increase mitogenic responses Recent studies have shown that A. indica immunostimulatory properties [15] In mice intraperitoneal a polysaccharide (Ukonan A-D) which stimulates carbon injection of neem oil mobilizes leukocytic cells possess into nonspecific peritoneal clearanceof splenic lymphocytes [24]. They have [23] Japanese also isolated investigators a lipopolysaccharide have isolated cavity. Peritoneal macrophages exhibited enhanced phagocytic from the root of C. longa which is immunostimulant [25]. Dietary curcumin (40 mg/kg) in rats for 5 weeks enhanced IgG levels but treated mice showed higher lymphocyte proliferative response did not affect delayed type hypersensitivity and NK cell activity. toactivity concanavalin and MHC A class and II tetanus expression. toxoid Spleen compared cells of to neem control. oil Curcumin inhibits NO production in activated macrophages [26]. Treatment of mice splenocytes with A. indica stimulates The anticancer properties of curcumin may be mediated atleast in part by inhibition of inducible form of NO synthase. production of IL-1, interferon-γ- and TNF-α, reflecting activation Ann Med Chem Res 1(2): 1009 (2015) 2/5 Sethi et al. (2015) Email: Central

Embelia ribes Burm (Family – Myrsinaceae) Hindi Punica granatum Linn (family Punicaceae) Hindi name – Vayavidanga, English name – Embelia. name – Anar, English Name – Pomegranate. A large scandant shrub found throughout India, from Aqueous suspension of the fruit rind powder to rabbit (100 Central Himalaya to Konkan, Deccan, Western Ghats and South mg/kg, po) stimulated the cell mediated and humoral components India. Preliminary pharmacological studies demonstrated of immune system. There was an increase in antibody titer to immunostimulant activity of this plant [27]. typhoid H. antigen. It also enhanced the inhibition of leukocyte migration in leukocyte migration inhibition test and in duration Nuctanthes arbor-tristis Linn (Family Oleaceae) Hindi name – Harsinghar, Saherwa , English name – Night Jasmine. of skin in delayed hypersensitivity test with purified protein Picrorhiza kurroa (Family Scrophulariaceae) Hindi A hardy large shrub or small tree, native of India. Puri et al derivative [38]. name – Kutaki, English name – Picrorhiza Ethanolic extract from P. kurroa has been shown to enhance immunity1994 [23]. as Demonstrated evidenced by immunostimulantincrease in humoral activities and delayed from typethis delayed type hypersensitivity by 80% and also antibody hypersensitivityplant extract. Stimulation response and of antigenmacrophage specific migration and nonspecific has been production and phagocytic activity P. kurroa (50% ethanol demonstrated in mice treated with 50% ethanol seed extract extract) produced dose dependent increase in SRBC induced [28]. early and delayed hypersensitivity reaction in mice and rats. It also enhanced humoral immune responses in mice and rats and Ocimum sanctum Linn. (Family – Labiatae) Hindi name – Tulsi, English Holy basil. It augmented responsiveness of murine splenocytes to T cell Radioprotective effect of O. sanctum leaf extract in combination phagocytic function of reticuloendothelial cells in mice [39]. with WR-2721 has been reported [29] O. sanctum (10 mg/kg, ip) isolated from P. kurroa given to mice before immunization with for 5 days were given to mice or 100 to 400 mg/kg WR-2721 or mitogens (Phytohaemagglutinin and Con A & B, LPS) [39]. Picroliv combination of the two, and whole body was exposed to 4.5 or 2 antibody titer, plaque forming cells and delayed type Gy gamma radiation. Protective effect of water extract (10 mg/ hypersensitivitySRBC, resulted in response significant [40]. increase It also increased in haemagglutinating macrophage kg/day) was more than the aqueous-ethanol extract in protecting migration, 14C leucine labelled E. coli, Chemiluminescence of

O. sanctum crude extract was compared with dexamethasone lymphocytes of picroliv treated mice. peritoneal macrophages and higher uptake of 3H-thymidine in inmice the against treatment 11 Gy of of patients Co-60 gamma with acute irradiation viral encephalitis. [30]. Efficacy The of Phyllanthus emblica Linn (Family – Euphorbiaceae) survival in O. sanctum Hindi name – Amla, English name – Indian Gooseberry Piper longum Linn (Family Piperceae) Hindi name – treated group was significantly higher [31]. P. emblica fruit powder was found to enhance NK cell activity Pippali, English name – Indian long pepper. and antibody dependent cellular cytotoxicity in Syngenei Bal G/C A slender, aromatic, climber with perennial woody roots occurs in hotter parts of India from Central Himalayas to Assam, P. emblicamice fearing as compared Dalton’s to lymphoma controls. ascites tumor [41]. There was Travancore. Some clinical trials were carried out with fruit 35% increase in life span in tumor bearing mice treated with extractKhasi and of P. Mikir longum Hills, in Bengal, patients Western with asthma, Ghats chronic from Konkan sinusitis, to Saussurea costus (Falc) (Family-Asteraceae) Hindi giardiasis and for antifertility properties. name – Kuth, English name – Kuth. Agarwal & Kaul (1992) Preliminary pharmacological studies reported of piperine alkaloid from P. longum. Tripathi et al (1999) immunostimulant properties from the plant extracts [41]. demonstrated immunostimulatory[32] reported effect radioprotective of P. longum effect fruit [33] Sida cordifolia Linn (Family – Malvaceae) Hindi name extract. – Kungyi, English name – Country mallow. Panax ginseng (Family Araliaceae) reported immunostimulant activity of P. ginseng is widely used as general health tonic. Extracts sitoindosides fractions from S. cordifolia. Ghosal et al [43] and saponins from Indian Pseudoginseng have been shown to Tinospora cordifolia Wild, T. sagittata, T. malafarica possess potent immunostimulant activity. Fractions of ginseng extract have been reported to possess stimulatory activity on (Family – Menispermaceae), Hindi name – Giloe, reticuloendothelial system, T-cell proliferation by Con A in vitro English name – Gulancha tinospora Oral administration of T. cordifolia extract to mice for 15 [34], Phagocytosis [35], chemotaxis, augmentation of NK cell haemagglutinating antibody titers against Sheep Red Blood Protecive effect of T. cordifolia against myelosuppression Cellsactivity (SRBC) [36], enhancement of antibody forming plaques and induceddays significantly by cyclophosphamide enhanced humoral in rats has immune been responsedemonstrated. [44] , CD and CD cells. Thatte et al (1994) [45] reported that T. cordifolia (100 mg/ [37], production of IL‑1 [36], IL-24 [36], TNF-α,8 Ginseng appears to be a promising agent 3 to be evaluated for immunostimulatoryGM-CSF [36], increase activity in population in humans. of CD activity. T. cordifolia water extracts (100 mg/kg/day × 7 days) kg/day × 10 days) activates macrophages to release GM-CSF Ann Med Chem Res 1(2): 1009 (2015) 3/5 Sethi et al. (2015) Email: Central

Agarwal SS, Singh VK. Immunomodulators: A review of studies on E.coli improved cellular immune functions. Mortality rate following 3. Acad. 1999; 65: 179-204. Treatment with T. cordifolia inhibited ochratoxin induced Indian Medicinal Plants and Synthetic peptides. Proc Indian Natl Sci suppression infection of inchemotactic treated rats activity was significantly and production reduced of (16.7%).IL‑1 and 4. Immunomodulatory therapy. In “Immunomodulation” SN Upadhyay, Thatte UM, Dahanukar SA. Rasayna Concept: Clues from isolated from T. cordifolia editors. Narosa Publishing House, New Delhi. 1997; 141-148. TNF-α by mouse macrophages. Syringin (TC-4) and Cardiol (TC‑7) in serum. Humoral and cell mediated immunity were also found 5. significantly increased IgG antibodies activity of Indian medicinal plants, lithium carbonate and glucan. cordioside (TC-2), Cordiofolioside A (TC-5) and Cordiol (TC-7) Thatte UM, Dahanukar SA. Comparative study of immunomodulating [46].to be increased. Macrophage activation has been reported by 6. Methods Find Exp Clin Pharmacol. 1988; 10: 639-644. Immunotherapeutic modulation of intraperitoneal adhesions by Withania somnifera (L) Dunal (Family – Solanaceae) Rege NN, Nazareth HM, Isaac A, Karandikar SM, Dahanukar SA. Hindi name – Ashwagandha, English name – Winter 7. AsparagusDhuley JN. racemosus.Effect of some J Postgrad Indian Med.herbs 1989; on macrophage 35: 199-203. functions in Cherry ochratoxin A treated mice. J Ethnopharmacol. 1997; 58: 15-20. A number of with anolides isolated from W. somnifera 8. Zhang L, Tizard IR. Activation of a mouse macrophage cell line by have been shown to possess both immunostimulating and acemannan: the major carbohydrate fraction from Aloe vera gel. to increase total WBC count in normal Balb/C mice and in mice 9. immunosuppressive properties. Methanolic extract was found Immunopharmacology. 1996; 35: 119-128. with leucopenia induced by sublethal dose of gamma irradiation Berg AJ, Labadie RP. Effects of low molecular constituents from Aloe [46]. Ashwagandha prevented myelosuppression in mice vera‘t Hart gel LA, on Nibbering oxidative PH, metabolism van den Barselaar and cytotoxic MT, van and Dijk bactericidal H, van den induced by cyclophosphamide, prednisolone and azathioprin. activities of human neutrophils. Int J Immunopharmacol. 1990; 12: Treatment with ashwagandha inhibited ochratoxin A induced suppression of chemotactic activity and production of IL-1 and 10. 427-434. Aloe barbadensis extracts reduce the production of interleukin-10 afterByeon exposure SW, Pelley to RP,ultraviolet Ullrich SE,radiation. Waller TA,J Invest Bucana Dermatol. CD, Strickland 1998; 110: FM. inTNF-α irradiated by macrophages (2 GY whole [47]. body A gamma dose of irradiation) 30 mg/kg ofanimals Withaferin [48]. 811-817. A significantly enhanced the spleen colony forming unit (CFU-S) 11. Mangifera indica Linn (Family – Anacardiaceae) Hindi of garlic on experimental oral precancer and its effect on natural killer name – Aam, English name – Mango tree. cells,Tang T-lymphocytesZ, Sheng Z, Liu S,and Jian interleukin-2]. X, Sun K, Yan Hunan M. [The Yi preventing Ke Da Xue Xuefunction Bao. 1997; 22: 246-248. Alcoholic extract of the stem bark of M. indica (containing 2.6% mangiferin) produced an increase in humoral antibody titer 12. and delayed type hypersensitivity in mice [49]. garlic extracts enhances cytotoxicity and proliferation of human lymphocytesMorioka N, Sze mediated LL, Mortan by interleukin-2DL, Irie RF. A and protein concanavalin fraction from A. Cancer aged

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Cite this article Sethi J, Singh J (2015) Role of Medicinal Plants as Immunostimulants in Health and Disease. Ann Med Chem Res 1(2): 1009.

Ann Med Chem Res 1(2): 1009 (2015) 5/5