Solasodine (aglycone) can be obtained by chemical hydrolysis or microbial reactions of solamargine glycosides^[12]. Solasodine is additionally obtained by catalytic hydrolysis of its glycosides by fermentation of plant staple or their extraction by means of aqueous or alcoholic acids; simultaneously with, or following the extraction, hydrolysis of the glycol-alkaloids occurs and the sugar moiety is dissociated^[13,14]. Solasodine is widely ranked as a protective allelochemical against various pathogens and predators^[15,16]. Aglycone solasodine derivatives are highly cytotoxic against different kind of tumor cell lines^[17].

Solasodine has exhibited variety of pharmacological activities including anticonvulsant, antinociceptive, anti-inflammatory, cardio-tonic, cytotoxic, hepatoprotective, anti-atherosclerotic, antifungal, immune-modulatory, antipyretic, and various other effects on central nervous system^[18].

Pharmaco-therapeutic profiles of solasodine:

Neuroprotective effect of Solasodine:

Neuroprotective effect of Solasodine was experimentaly demonstrated against model of ischemic rats. Solasodine treatment considerably suppressed lipid peroxide (LPO) and nitric oxide (NO) level and heightened the level of antioxidant enzymes such as glutathione (GSH), catalase (CAT) and Thiols in dose- dependent manner. It is revealed by histopathological studies that cerebral infarction was considerably reduced within the solasodine treated rat brains. Based on these results, a part of protective activity of neuron showed by Solasodine could be imputed by its antioxidant (free radical scavenging) properties^[19,20]. Additionally to neuroprotective action, Solasodine was by experimentation proven to possess evidentiary neurogenesis properties in mice. Expression of synaptophysin and differentiation of teratocarcinoma P19 cells into neurons by Solasodine, suggesting its synaptogenesis and neurogensis properties. An interesting boost in utilization of bromodeoxyuridine by ependymal cells was conjointly shown in Solasodine infused left ventricle of brain. In addition, Solasodine treatment activated GAP-43/HuD pathway and heightened the number of GABA-nergic progenitors and neuroblasts in GAD65-GFP mice^[21].

Anti-amnesic effect of Solasodine:

Solasodine expressed a significant antiamnesic activity against scopolamine inducted amnesia in both morris water maze (MWM) and elevated plus maze model (EPM). Solasodine treatment deeply reversed the amnesia induced by scopolamine by decreasing the transfer latency (TL) in aged mice indicating pronounced enhancement of learning and memory. Interestingly, Solasodine treatment reduced the acetyl cholinesterase activity of brain which probably facilitates the cholinergic transmission in aged mice and thereby improving memory^[22]. It has been assumed that solasodine present in leaves of S.torvum has neuro-protective action on Drosophila melanogaster against beta amyloid induced Alzheimer disease^[23].

Anticonvulsant and CNS depressant activity of Solasodine:

Solasodine isolated from S. sisymbriifolium have proven anticonvulsant & CNS depressant properties in rodent models. Solasodine administration expressed a dose dependent anticonvulsant activity by reducing the latency of hind leg tonic extensor (HLTE) phase in the model of maximum electric shock (MES)-induced convulsions. Also in the picrotoxin (PCT) model, Solasodine administration significantly decreased the latency of HLTE phase. However in the pentylenetetrazole (PTZ) model, Solasodine failed to produce antiseizure effects^[24]. Solasodine also potentiate thiopental- induced sleeping time in dose dependent manner which indicating Solasodine as a neurosedative drug^[25].

Anti-inflammatory and anti-nociceptive effects of Solasodine:

Solasodine isolated from Solanum trilobatum were reported as anti-inflammatory drug in a dose-dependent manner using model of carrageenan-induced rat paw oedema^[26,27]. Topically applied Solasodine considerably suppressed ear inflammation evoked by tetradecanoyl-phorbol 13-acetate in mice. Moreover, suppression in volume of exudates, total number of leucocytes as well as neutrophil migration has also been reported in Solasodine treated animals. By solvent evaporation methodology, transdermal patches of isolated Solasodine were developed and screened for anti-inflammatory effect using carrageen induced rat paw edema and skin irritation test studies. Transdermal patches containing Solasodine showed better anti-inflammatory activity when compared to standard indomethacin^[28]. Anti-inflammatory action of Solasodine and Tomatidine were also investigated by using lipopolysaccharide (LPS)-induced macrophages as a model of inflammation. In this study Solasodine showed less potent inhibitory effect than Tomatidine^[29]. Analgesic effect of Solasodine, extracted from Solanum trilobatum has also been assessed in rodents using different experimental models like acetic acid, formalin and hot plate tests. Pretreatment with Solasodine had significant anti-nociceptive effects on writhing and licking reaction inducted by acetic acid and formalin respectively. Solasodine conjointly exaggerated the analgesic effect in hot plate test^[30^].

Antimicrobial effect of Solasodine:

A number of alkaloid including Solasodine were extracted from Solanum dulcamara and evaluated for antimicrobial activity against the test bacteria like Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli, etc. The zone of depressed growth expressed by Solasodine was nearly equal to the reference drug against S. aureus. Duration of action of the Solasodine against microbes was found to be much more as compared to standard drug^[31]. Anti-trypanosomal effect of Solasodine was also demonstrated against Trypanosoma cruzi in LIT medium using Ketoconazole as reference drug^[32]. Larval inhibitory effect of Solasodine was also evaluated on Tribolium castaneum (red flour beetle). Though the individual aglycone Solasodine was ineffective against larval growth but Solasodine with its sugar moieties namely solamargine and solasonine significantly inhibited the larval growth^[33]. Individual effect of aglycone Solasodine as well as its sugar moiety was examined for antifungal activities against a variety of fungal strains such as Candida albicans, Trichophyton, phytophthora species^[34,35,36]. Synthesis and functions of genetic substances in S. cerevisiae and P. wickerhamii were interfered directly or indirectly by Solasodine^[37].

Anti-atherosclerotic effect of Solasodine:

Anti-atherosclerotic and hypo-lipidaemic effects of Solasodine were examined in rabbits fed on atherogenic diet. Solasodine treatment reduced serum cholesterol, LDL-cholesterol and VLDL cholesterol levels in atherogenic diet fed groups. The ratio of cholesterol/phospholipid ratio was significantly decreased while the HDL ratio was increased after treatment with Solasodine. Solasodine treatment also reduced aortic triglycerides and plaque size which restored the lumen to near normal. The cholesterol content of liver and aorta was also decreased in the atherogenic diet fed group after treatment with Solasodine^[38].

Antifertilty effect of Solasodine:

Dixit and Gupta (1982) reported that Solasodine from berries of S. xanthocarpum possessed antispermatogenic/antiandrogenic properties in male dogs^[39]. Testicular lesions, impairments of spermatogenic elements and epididymis free of spermatozoa have been shown in histopathological studies. Solasodine exposure reduced the formation of mature and immature leydig cells, decrement in cauda sperm count as well as decrement in level of testicular proteins, sialic acid and glycogen. These results indicate an antiandrogenic nature of Solasodine^{[40,41,42,43]}. In another investigation, compound Solasodine have shown to develop infertility in male rats and dogs. However, on withdrawal of Solasodine supplement, effect was revoked. Further testing expressed inhibition of spermatogenesis and testosterone production and reduced motility of sperm in Solasodine treated groups ^[44,45]. Kanwar et al., 1990 also observed that Solasodine inhibited the motility of human and bovine spermatozoa in dose and duration dependent manner^[46].

Anticancer activity of Solasodine:

It has been evidenced that Solasodine and its glycosides shows anti-neoplastic activity against several cancer cell lines. In earlier studies, Solasodine and its glycoside with different sugar moieties were synthesized and screened for their cytotoxic effects on a group of cancer cell lines (MCF-7, KB, K562, and PC3 cells). These studies have shown that Solasodine with its rhamnose sugar moiety exhibited potent anticancer activities^[47]. Solasodine presented dose dependent anti-proliferation of the breast cancer cell lines MCF-7. Solasodine upregulated Bax and Bak expression levels (pro-apoptotic) whereas Bcl-2 and Bcl-xL (anti-apoptotic proteins) expressions were declined in MCF-7 cells^[48]. It has cancer cell destroying ability due to induction of apoptosis caused by anti-lysosomal and anti-mitochondrial activity^[49,50]. Solasodine rhamnosyl glycosides which are extracted from solanum plants have also shown anti-neoplastic activity with high specificity^{[51,52,53,54]}. A topical cream formulation containing Solasodine glycosides (Curaderm^R) is available for the treatment of skin cancer without harming healthy skin cells^[55,56,57]. Curaderm cream have been tested (licensed in 1991) in Australia for the treatment of solar keratosis^[58]. Cytotoxic effects of Solasodine were searched with HT29, MCF7 and HeLa cancer cell lines. In that Solasodine had the highest inhibitory effect on HeLa cells^[59]. Solasodine isolated from the unripe fruits of Solanum xanthocarpum) have also demonstrated anti-cancer activities against HeLa and U937 cancer cell lines^[60]. A series of Solasodine derivatives have also been synthesized and evaluated for their activities against the prostate cancer cell proliferation (PC-3 cell line)^[61].

Hepatoprotective effect of Solasodine:

Hepatoprotective effect of Solasodine isolated from S. incanum has been reported against CCl4-inducted hepatotoxicity in mice. After treatment, the decrease levels of transaminase enzymes like Glutamic-oxalacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) were observed in treated animals with Solasodine suggesting that it protected the liver against CCl4 intoxication^[62]. Additionally, Solasodine protected DNA-damage induced by CCl4 in rat liver tissues. Regeneration of liver cells and inhibition of Cyclooxygenase-2 (COX-2) and TNF-α by Solasodine suggest its hepatoprotective actions^[63].

Anti-obesity effect of Solasodine:

Solasodine, isolated from fruits of Solanum xanthocarpum have demonstrated anti-obesity potential in rats with high fat (HF) diet-induced model of obesity. A significant reduction in body weight, weight of adipose tissue (retroperitoneal region) and abdomen circumference were reported in Solasodine administered rat group in comparison to HF control rat group. Solasodine treated group also affected the other biomarkers of obesity including food intake, measurement of total cholesterol triglyceride and glucose level in HF diet group. Attenuated hepatocellular necrosis and reduction in inflammatory cells infiltration have been presented in histopathological studies. Above results are clear indications of anti-obesity effects of Solasodine^[64].

Acute toxicity studies:

Reported acute toxicity studies, oral administration of Solasodine upto 300 mg/kg in Wistar rats, did not show any death in a 24 hours observation periods^[65].

Table 1: Pharmacological activities of solasodine

Pharmacological activity	Dose of solasodine	**In vitro/Animal models**	Affecting parameters	Reference
Antioxidant	1-50µg/ml 100-200mg/kg, po	In vitro Wistar albino rats	ABTS & DPPH free radical scavenging activity. ↑SOD, CAT, GSH & total thiols whereas ↓ LPO and NO levels in the brain.	[19] [20]
Neurogenesis	530nM/Rat via osmotic pump	Rats	Reduced infarction in rat brain	[21]
Antiamnesic	1-4 mg/kg, po	Mice	↓ TL in EPM test	[22]
Anticonvulsant	25-100 mg/kg, ip	Swiss albino mice	↓ latency of HLTE	[24]
Anti-inflammatory	75mg/kg, ip	Wistar rat	↓ paw edema and inflammation	[26]
Anti-nociceptive	2-8mg/kg. po	Swiss albino mice	↑ reaction time (licking response)	[30]
Antimicrobial	MIC-0.625mg/ml	E. coli, S. aureus	↑ Inhibition zone	[31]
Antifungal	MIC->100 µg/ml	Tested fungi	Inhibition zone	[35,37]
Anti-aherosclerotic	50mg/kg, po	Rabbit	↓ Serum cholesterol, LDL VLDL and ↑HDL level. Also ↓aortic triglyceride and its plaque size.	[38]
Antifertility	20-80 mg/kg, po	Rats, Dogs	↓ leydig cells production, cauda sperm count & testosterone production. Testicular proteins, sialic acid and glycogen also reduced.	[39,40, 41,43,44]
Anticancer	10-100µM	HeLa, MCF-7, HT-29 & U-937	Inhibit cell proliferation caused by apoptosis.	[48,59, 60]
Antihepatotoxic	3mg/kg p.o.	Mice & Rats	↓SGOT &SGPT	[62]
Antiobesity effect	50-100mg/kg, p.o.	Wistar rats	↓ Body weight, abdomen circumference and TG level.	[64]
Anti-urolithiatic & Natriuretic activity	80 mg/kg, p.o.	Wistar albino rats	↑ urinary output , ↑ Na+ & ↓K+ ion in urine	[65]
Antipyretic	3mg/kg OD 1mmole/kg OD	Rat Mice	↓ Temperature	[76,77]
Immunomodulator	-	In vitro	Inhibit proliferation of cell cultures	[78,79]

In other studies, LD50 of Solasodine was established to be 2000 mg/kg, body weight per oral in rats^[21]. In another investigation, LD₅₀ of Solasodine was found to be 1500 mg/kg after intraperitoneal administration with a dose of Solasodine ranging from 125 to 2000 mg/kg^[24]. Lethal dose (LD50) of Solasodine was determined to be 30 mg/kg, body weight per oral in another acute toxicity study on mice conducted under class II in the globally harmonized system classes^[30].

Other reported effects of Solasodine:

Solasodine have also been reported to provide a hypotensive effect in cat^[66], cardiotonic effect^[67], and anti-accelerator of cardiac activities^[68]. It mobilizes gluco-corticoids from the adrenals glands of rats^[69], serves as insect growth regulator^[70,71] and enzyme inhibitors^[72]. Diversely, a relatively low terato-genicity ^[73], embryo-toxicity^[74], and benign hapatomegaly^[75] were reported by few studies. Pharmacological activities of solasodine are summarized in the Table1.

CONCLUSION:

The extensive literature survey on Solasodine, as well as its tri-glycosides Solasonine and Solamargine, revealed that these have potential biological activities including the anticonvulsant, CNS depressant, antioxidant, anti-nociceptive, anti-inflammatory, cytotoxic, hepatoprotective, antiatherosclerotic, antifungal and anti-obesity activities. Thus Solasodine and its derivatives seem to be a promising drug for the cure of many diseases and other industrial applications. Solasodine is used as a prototype in the steroid drug industry for the manufacturing of corticosteroids, anabolic steroids including anti-fertility agents and also possess a wide range of application in various disorders.

Further, detail investigations on Solasodine are required to understand the precise mechanism of action in the treatment of several diseases and disorders.

ACKNOWLEDGEMENT:

All authors contributed equally to this work. The authors are thankful to the Integral University & KNIMT-FOP for providing facilities, critical suggestion regarding the improvement of the manuscript and special thanks to research community of Integral University for providing manuscript no. IU/R&D/2018-MCN-000390.

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Received on 26.12.2018 Modified on 14.02.2019

Research J. Pharm. and Tech. 2019; 12(5):2571-2576.

DOI: 10.5958/0974-360X.2019.00432.3