Journal of Acute Disease (2013)92-98 92

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Document heading doi: Medicinal significance, pharmacological activities, and analytical aspects of solasodine: A concise report of current scientific literature Kanika Patel1, Ravi B. Singh2, Dinesh K. Patel3*

1G.L.A Institute of Pharmaceutical Research, Mathura, India

2Institute of Pharmacy, Harish Chandra P.G. College, Varanasi-221002, India

3Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi-221005, India

ARTICLE INFO ABSTRACT

Article history: Alkaloids are well known phytoconstituents for their diverse pharmacological properties. Received 5 March 2013 Alkaloids are found in all parts like roots, stems, leaves, , and seeds. Received in revised form 24 March 2013 Solasodine occurs as an aglycone part of glycoalkloids, which is a nitrogen analogue to Accepted 20 May 2013 sapogenins. family comprises of a number of with variety of natural products Available online 20 June 2013 of medicinal significance mainly steroidal lactones, glycosides, alkaloids and flavanoids. Keywords: It is a steroidal alkaloid based on a C27 cholestane skeleton. Literature survey reveals that solasodine has diuretic, anticancer, antifungal, cardiotonic, antispermatogenetic, antiandrogenic, Allelopathy immunomodulatory, antipyretic and various effects on central nervous system. Isolation and Pharmacological activity P Phytochemical isolation quantitative determination was achieved by several analytical techniques. resent review Review highlights the pharmacological activity of solasodine, with its analytical and tissue culture Solanaceae techniques, which may be helpful to the researchers to develop new molecules for the treatment Solasodine of various disorders in the future.

1. Introduction as the starting material for the production of steroidal Solanum hormones[2]. Various species of like Solanum khasianum S. khasianum Solanum lyratum S. lyratum Genus (Solanaceae) is rich in steroidal ( ), ( ), Solanum xanthocarpum S. xanthocarpum Solanum nigrum glycoalkloids, an important group of plant secondary ( ), S. nigrum Solanum gracile S. gracile Solanum tuberosum metabolites. These compounds are used as starting ( ), ( ), S. tuberosum Solanum laciniatum S. laciniatum material for the synthesis of steroidal drugs. In majority ( ), ( ) are of solanaceous plants, solasodine occurs as aglycone being extensively used for the treatment of various ailments part of glycoalkloids, which is a nitrogen analogue of like asthma, liver diseases and inflammation in the sapogenins. Solasodine (C27 cholestane skeleton) (Figure traditional system of medicine. Glycoalkaloids are nitrogen 1) can be readily converted to 16-dehydropregnenolone, a containing secondary metabolites found in plants belonging key intermediate in the synthesis of steroidal drugs such to Solanaceae and Liliaceae family. More then 100 different as progesterone and cortisone[1]. Solasodine is obtained types of glycoalkaloids have been isolated from more than Solanum by chemical or microbial hydrolysis of solamargine. It is 350 species[3]. S. tuberosum a potential moiety to be used as a substitute for diosgenin Plant such as contains glycoalkaloids as in the semi-synthetic production of steroidal hormones in the main phytoconstituents along with chaconine and pharmaceuticals. Therefore, steroidal glycoalkaloid from solanine. Glycoalkaloids concentration depends upon Solanaceae plants have become increasingly important species as well as part of plant such as leaf, root, and stem. The amount of glycoalkaloids increases due to [4] *Corresponding author: Dinesh K. Patel, Department of Pharmaceutics, Institute of injury and exposure to light . Glycoalkaloids play key Technology, Banaras Hindu University, Varanasi-221005, India. role in defense mechanism of plants against invading Tel: +91 9919192440 E-mail: [email protected] microbes. Glycoalkaloids have antimicrobial, insecticidal and fungicidal properties which account for their activity Kanika Patel et al./ Journal of Acute Disease (2013)92-98 93 against several insects, pests and herbivores. Small Steroidal glycoalkaloids have antimicrobial, insecticidal quantities of glycoalkaloids are known to improve flavour, and fungicidal properties which provide resistance against but at levels above 200 mg/kg these compounds may impart several insect pests and herbivores[9]. Solasodine is an the bitter taste[5]. Glycoalkaloids exhibited toxicity in living important phytochemical of Solanaceae plant including S. lyratum organism at higher concentrations mainly because of their Thunberg, which is commonly used in the anticholinesterase activity and disruption of cell membranes traditional Chinese medicines in China, Taiwan and Korea. coupled with some other effects including teratogenicity, It has been used to regulate immune function and treat embryotoxicity and genotoxicity. Glycoalkaloids toxicity allergic responses for generations[10]. Further, it is also used not only depends upon its amount but also on the type of to treat cancer of liver, lung, esophagus and blood, as well glycoalkaloids[5,6]. Symptoms of glycoalkaloid poisoning as tumours and warts[11-14]. includes abdominal pain, vomiting and diarrhea[4]. In A number of analytical methods like high performance contrast, some glycoalkaloids can also have positive effects thin-layer chromatography, high-performance on plant growth and human diet. They may provide plant liquid chromatography, capillary electrophoresis, gas protection from damage by insects and fungi, and are chromatography have been developed and used for the reported to elicit anti-inflammatory and anticancer effects determination of solasodine from plant materials[15]. in humans[6]. Solanaceae family comprises a number of plants widely known for the presence of variety of natural products Solanum tuberosum 燐 of medicinal significance mainly steroidal lactones, 燐 Lycopersicon esculentum S. nigrum Solanum melongena glycosides, alkaloids and flavanoids. L. a 燐 Solanum khasianum member of the Solanaceae, has a wide range of medicinal 燐 Solanum xanthocarpum application[16]. Literature survey reveals that solasodine has Solanum nigrum 燐 wide range of pharmacological activity such as diuretic, 燐 Solanum gracile 燐 Solanum laciniatum anticancer, antifungal, hepatoprotective, cardiotonic, antispermatogenetic, antiandrogenic, immunomodulatory, antishock, antipyretic and central nervous system related activity[17]. Because of pharmaceutical importance, its isolation and quantitative determination was achieved 燐 Overview of solasodine by several researchers using an array of analytical 燐 Antimicrobial activities of solasodine techniques like spectroscopy, thin layer chromatography, 燐 Antiinflamatory activities of immunostaining usingmonoclonal antibodies, solasodine gas chromatography and high performance liquid 燐 Anticancer activities of solasodine chromatography and most recently, using non aqueous 燐 Antiandrogenic activities of capillary electrophoresis[1]. solasodine 燐 Effect of solasodine on CNS 燐 Effect of solasodine on body temperature 2. Pharmacological activities of solasodine 燐 Enzyme and other activities of solasodine 2.1. Antimicrobial activities of solasodine Solasodine Antifungal activity of Solasodine was investigated using Prototheca wickerhamii Saccharomyces cerevisiae GL7 and P. wickerhamii Tissue culture techniques ( ). Solasodine directly or indirectly interfered with the synthesis and function of genetic substance in S. cerevisiae P. wickerhamii and [18]. In another study, Trypanosoma solasodine was tested as growth inhibitors of Analytical techniques cruzi in LIT medium using ketoconazole as a positive Figure 1. Chemical structure and overview of solasodine. control[19]. Evaluation of solasodine on larvae of the red Tribolium castaneum The steroidal glycoalkaloids are the family of secondary flour beetle, , was investigated. Larval metabolites produced by Solanaceous plants, including growth was inhibited on diets containing solasodin as one potato, tomato and eggplant[7]. Steroidal glycoalkaloids component and found that solasodine is inactive[20]. Effect of are nitrogen containing compounds which have the C27 aqueous suspensions of glycoalkaloids including solasodine skeleton of cholestane and are the product of steroidal on herpes simplex virus Type I in tissue culture was also biosynthesis pathway[5]. Synthesis of steroidal alkaloids investigated and found to be inhibited by prior incubation involves glycosylation of the alkamine steroidal skeleton with solasodine[21]. (aglycone) at C-3b to form steroidal glycoalkaloids[8]. Kanika Patel et al./ Journal of Acute Disease (2013)92-98 94 2.2. Anti-inflammatory and antinociceptive activities of S. xanthocarpum [30] S solasodine control . olasodine obtained from the berries was administered to Rhesus monkeys for 150 d to Solanum trilobatum evaluate its effect on testicular cell population dynamics. Solasodine isolated from has been Solasodine brings about an interference with spermiogenesis examined for anti-inflammatory activity in acute and at the stage XII of late spermatids. No significant change chronic inflammatory animal models. Solasodine exerted was found in the population of spermatogonia/primary and statistically significant and dose-dependent anti- secondary spermatocytes. The production of immature and inflammatory activity in carrageenan-induced rat paw mature Leydig cells was decreased. The testicular protein, oedema. Topical application of solasodine significantly sialic acid and glycogen contents were depleted following inhibited the ear inflammation induced by multiple solasodine treatments to rhesus monkeys[31]. Chronic 13 [22] applications of tetradecanoyl-phorbol Solanum -acetate trilobatum. administration of solasodine caused testicular lesions Solasodine, isolated from the roots of resulting in a severe impairment of spermatogenic elements. Linn., was tested for antinociceptive activity using several The epididymides were devoid of spermatozoa. Total experimental murine models, viz. the writhing, formalin, protein, sialic acid and glycogen contents of the testis and and hot plate tests. Solasodine exhibited a significant and epididymis were reduced significantly whereas the testicular dose-dependent decrease in the nociception induced by cholesterol was elevated. Solasodine administration in dogs an intraperitoneal injection of acetic acid. Furthermore, definitely rendered the male infertile as evidenced by the the alkaloid produced a significant increase in the reaction absence of sperms in the cauda epididymis and ductus time in the hot plate test[23]. LPS-stimulated macrophage as deferens[32]. a model of inflammation was used to investigate the anti- 2.5. Effect of solasodine on CNS inflammatory effects of tomatidine and solasodine whereby it was found that tomatidine exhibited a more potent in vitro E anti-inflammatory effect than solasodine in the tested in vivoffect of solasodine to promote neurogenesis and [24] T P19 concentration . he anti-inflammatory effect of solasodine in mouseIn vivo embryonic teratocarcinoma cells was was evaluated in another study and was found to elicit investigated. , a 2-week infusion of solasodine into the significant anti-inflammatory activity[25]. left ventricle of the rat brain followed by a 3-week washout 2.3. Anticancer activities of solasodine resulted in a significant increase in bromodeoxyuridine uptake by cells of the ependymal layer, subventricular zone, and cortex that co-localized with doublecortin Natural molecules structurally close to diosgenin including immunostaining, demonstrating the proliferative and solasodine have been tested for their biological activities differentiating properties of solasodine on neuronal 1547 [26] I [33] A CNS on human osteosarcoma cells . n an another study, progenitors . n anticonvulsantS. sisymbriifolium and depressant effect solasodine has been utilized to determine the role of of solasodine isolated from using several T C3 T carbohydrate moiety in the mechanism’ of apoptosis.’ ’he experimental models was investigated. he results showed side chain of solasodine contains 4 Rha-Glc-Rha2 , 4 Rha- that intraperitoneal injection of solasodine significantly Glc and H, respectively[27]. In another study, solasodine delayed latency of hind limb tonic extensor (HLTE) phase in PLC PCT I MES showed significantin vitro cytotoxic effects against human / the -induced convulsions. n the model, solasodine PRF/5 cells [28]. significantly reduced duration of HLTE in a dose-dependent P 2.4. Antiandrogenic activities of solasodine manner. rior treatment of solasodine significantly potentiated thiopental-provoked sleep in a dose-dependent manner[34]. O ral administrationS. xanthocarpum of solasodine isolated from the berries 2.6. Effect of solasodine on body temperature of the to dogs significantly decreased T the epithelial cell height of cauda epididymides. he cells S. laciniatum became atrophic and the lumen was devoid of spermatozoa. Effect of solasodine from Ait., was studied Castration followed by the adminstration of solasodine on normal and pyretic body temperature of rats and mice. In further reduced the epithelial cell height in comparison rats, single dosage depressed the normal temperature for 24 h. to castrated controls. Total protein, sialic acid, glycogen With larger dosages or longer treatment the effect could not and acid phosphatase activities were significantly reduced be intensified and tolerance was also not observed. In mice, in solasodine treated cauda epididymides. These results the temperature decrease and effect was reproducible by suggests the anti-androgenic potency of solasodine[29]. repeated treatment[35]. E ffect of solasodine derived from solasonine in eggplants 2.7. Enzyme and other activities of solasodine was evaluated for their effects on liver weight increase in non-pregnant and pregnant mice and on fecundity in pregnant mice fed for 14 d. In non-pregnant mice, observed UDP-glucose-dependent glucosylation of solasodine ratios of liver weights to body weights were found to be and diosgenin by a soluble, partially purified enzyme significantly greater in solasodine treated group than the fraction from eggplant leaves is affected in a markedly Kanika Patel et al./ Journal of Acute Disease (2013)92-98 95 different way by some phospholipids. The glucosylation of investigated. The hairy roots could produce medicinal solasodine is unaffected or slightly stimulated. Significant secondary metabolites solasodine and the amount of inhibition of diosgenin glucoside synthesis and stimulation solasodine in the hairy root cultures[45]. The role of plant PC N C of solasodine glucosylation was found only with growthin vitro regulators and various concentrations of a l during molecular species containing fatty acids with chain length production of solasodine were studied. Solasodine 12 18 [36] A 31 of - carbon atoms . series of side-chain- content was maximum in regenerative callus whenin vitro grown on modified analogues of steroidal alkaloids solasodine was medium added with 150 mM NaCl; followed by raised (S) L [46] L 15 studied as inhibitors of -adenosyl- -methionine:delta leaf of microshoot . eaf and hypocotylS. laciniatum explants of d old 24(25)-sterol methyl transferase (SMT) enzyme activity aseptically grown seedlings of were cultured S [37] S MS NAA from accharomyces cerevisiae . olasodine, a steroidS. on medium supplemented with and kinetin for T presentviarum in the mucilaginous exotesta of the seed in callus initiation. he solasodine content in callus culture was Dunal is a major source of steroidal raw material. maximum after 30 d of incubation. Organogenesis promoted E R vidence for the site of solasodine synthesis was sought S. solasodine accumulation in the cultures. egenerated shoots throughviarum reciprocal grafts involving steroid-bearing yielded higher solasodine content than undifferentiated as ( ) [47] bothS. diploidmelongena and autotetraploid and steroid- well as organogenic callusPhysalis. minima L ( ) T H L free, edible . brinjal . he results indicate airyAgrobacterium root cultures rhizogenesof . were developed that the synthesis of solasodine is scion-specific[38]. The using , strain ATCC 15834 mediated increase in relative liver weight induced by solanidine and transformation and grown in half strength of Murashige and solasodine is a reversible adaptive response. These findings Skoog medium containing sucrose. Media supplementation and the apparent effects of structure on biological activity with naphthalenacetic acid and benzyladenine increased 20 should serve as a guide for the removal of the most toxic solasodine glycoside which was times higherS. avicularethan that compounds from plant foods[39]. Impregnated CD2 transgenic in the native root[48]. Hairy root clones of mice, which contain multiple copies of a lambda gt10lacZ which were transgenic for hmgr typically grew faster than construct integrated into the genome of each cell, were those which did not contain extra copies of this gene given a predetermined estimated maximum tolerated dose of and also accumulated up to 4.2 times more solasodine [40] E [49] T several steroidal alkaloids including solasodine . mbryos when grown under dark, but not light conditionsAlternaria . he of two species of fish Japanese rice fish, medaka (Oryzius effect of a fungal elicitor obtained from sp. on ) (O ) latipes and the rainbow trout ncorhynchus mykiss were growth and solasodineS. eleagnifolium production by free and alginate- also evaluated for their suitability as model systems for entrapped cells of Cav. was studied. The steroidal alkaloid toxicity including solasodine[41]. Effect solasodine production increased in suspension cultures of several potato glycoalkaloids and aglycones in the frog and in entrapped cells. In both cases, about 50%-60% of X (FETAX) [50] embryo teratogenesis assay-- enopus with and intracellular solasodine was released‘ into the medium ’. A 1254 P without metabolic activation by roclor -induced rat roceduresS. aviculare were developed for self-immobilisation liver microsomes was investigated. The aglycones solasodine of cells to eliminate the need for artificial was found to be less toxic than the glycosides[42]. Isolation immobilisation supports. Most of the product was stored in of the glycosyltransferases that catalyze the transfer of sugar the aggregates to reach a maximum concentration of 0.3% dry molecules to steroidal compounds will help to clarify the weight; this is between 1.5 and 10 times the levels reported mechanisms that produce diverse saponins and control their for suspended cells under similar conditions. A substantial activities in plants. Gene expression analysis revealed that amount of solasodine was produced after growth ceased. A the accumulation of SaGT4A transcripts showed a unique simple air-driven bioreactor was tested for culture of the response to wounding stress indicating the involvement of aggregates; solasodine yields were comparable to those SaGT4A in plant defense system[43]. measured in shake flasks[51].

3. Tissue culture techniques 4. Analytical methods to identify and isolate solasodine

S ( F ) T ingle chain fragment-variableS. khasianum sc v enhanced solasodine he mass fragmentations of solasodine were studied using glycoside accumulation in hairy root cultures the Orbitrap Fourier transform (FT) mass spectrometer[52]. transformed by the ScFv solamargine (As)-scFv gene. The The development of sequential injection analysis with expressed anti-solamargine scFv protein could be useful lab-at-valve semi-automated system on-line liquid- for determination of total solasodine glycoside content in liquid extraction is demonstrated for spectrophotometricSolanum plant samples by ELISA[44]. In another study using genetic determination of solasodine in various species A T transformation of grobacterium rhizogenes andS. nigrum liquid fruits. he method performances, including reproducibility, culture, induction and culture conditions for linearity, sensitivity and accuracy were also evaluated[53]. L. var. pauciflorum Liou hairy roots and its solasodine Quantitative estimation of solasodine was carried out using production and consumption changes of N resource a novel HPTLC method, which is validated for its recovery and calcium in the medium during liquid culture were and precession. The proposed HPTLC method showed a Kanika Patel et al./ Journal of Acute Disease (2013)92-98 96 good linear relationship in the concentration ranges[46]. traditional medicines are derived from medicinal plants, A prechromatographic derivatization of solasodine was minerals and organic matter. According to the World done by forming an ion-pair complex of the heterocyclic Health Organization (WHO) more than 21 000 plants are nitrogen using the acidic dye methyl orange and acetate used for medicinal purposes in the world[64-66]. Due to buffer of pH 4.7. Detection could be made in the visible presence of diverse phytoconstituents, many medicinal range at 530 nm in this method. The method has good plants have excellent pharmacological actions and could reproducibility and was found to be suitable for estimation lead to the development of new classes of possibly safer [54] C P Solanumof solasod ine . oncomitant extraction and hydrolysis of agents for the treatment of disease. lants have been used steroidal glycoalkaloids in a two-phase system as a source of drugs, and many of the currently available containing an aqueous mineral acid and an organic water drugs have been derived directly or indirectly from [67] immiscible° solvent, and having a boiling point under them . 100 C A S is described. pplicationSolanum of the khasianumprocess to fruits, everal medicinal plants have been used as dietary leaves, and tissue cultures of using supplements and in the treatment of numerous diseases a two-phase aqueous hydrochloric acid-toluene system, without proper knowledge of their mode of action. Only a proved to be very suitable for continuous production of few herbs and bioactive chemical moiety have attracted pure solasodine which is a valuable raw steroid for the the interest of scientists and have been put forward for preparation of steroidal drugs[55]. investigations. Therefore, there is a need of more well- Nonaqueous capillary electrophoresis coupled to UV documented clinical trials and more laboratory work to detection is described for the separation and determination justify their pharmacological actions and toxicity for safe of steroidal alkaloids. After optimization of electrophoretic and effective treatment[68,69]. Solasodine may have all these parameters, including the electrolyte nature and the actions and could be used for the treatment of various organic solvent composition, a reliable separation of complications in the near future. The present review solasodine and solanidine was achieved in a methanol- comprises updated information regarding pharmacological acetonitrile (20:80, v/v) mixture containing 25 mM activity and analytical techniques of solasodine. Moreover 1 M [56] GC MS ammonium acetate and acetic acid . - Solanum analysis tissue culture techniques on solasodine have been also of hydrolysates of purified extracts of the test discussed. The overall information provided in the species revealed that solasodine was a principal or sole present review article may prove as an important source aglycone of the alkaloidS. tuberosum glycosides in each of the test of information to the researchers in the research area of [57] G species except S. Sodomaeum. lycoalkaloids were natural product. extracted from plant material of L. High- performance liquid chromatographic studies indicated that Conflict of interest several glycoalkaloids were present. Mass spectral analyses showed that all the glycoalkaloids contained solasodine[58]. A potentiometric nonaqueous titration procedure was The authors declare they have no conflict of interests. developed for theSolanum quantitative determination of solasodine [59] I in fruits of the speciesS. platanifolium. n another study [60] T solasodine has Liliumbeen isolated brownii from . he References fresh bulbs of var. colchesteri were found to contain five steroidal saponins including solasodine along with several phenolic constituents[61]. High-pressure liquid chromatography was used to separate the steroidal [1] Pawar Pankaj K, Borse Tushar P, Pinjari Rizwan Z, alkaloids including solasodine. The method was used to Maheshwari Vijay L. A simple technique for rapid quantitative determination of solasodine from cultured hairy roots of prepare crystalline solanidineS. chacoense from a crude mixture of Solanum urattense J Herb Med Toxicol 2 aglycones obtained from , and to separate s . 2008; (1): 7-10. [2] Solouki M, Hoshyar H, Ramroudi M, Tavassoli A. Comparison radioactive solanidine from extracts of potato plants in vivo in (4 ) [62] and evaluation of steroid alkaloid solasodine on and fed with -C cholesterol . A combined derivatization vitro Solanum surattense Afr J Microbiol Res cultures of Burm L. method for gas chromatographic-mass spectrometric 5 (GC-MS) analysis of steroidal glycoalkaloid including 2011; (23): 3981-3985. [3] Sun F, Li S, He D, Cao G, Ni X, Tai G, et al. Effects of solasodine was developed using both trimethylsilylation Solanum [63] glycoalkaloids from plants on cucumber root growth. and pentafluoropropionylation . Phytochemistry 71 2010; (13): 1534-1538. 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