IngredientsSmilagenin is a naturally occurring steroidal sapogenin — the aglycone (sugar-free) backbone liberated when certain plant saponins are hydrolysed. Sarsasapogenin is a steroidal spirostanol sapogenin, that is the aglycosidic portion of a plant saponin, and smilagenin is its direct epimer. The epimer of sarsasapogenin with a (25R)-configuration is known as smilagenin. In systematic nomenclature, smilagenin is designated 5β,20α,22α,25R-spirostan-3β-ol. Its CAS registry number is 126-18-1.
Sarsasapogenin (and by extension smilagenin) was one of the first sapogenins to be identified and the first spirostan steroid characterised. Sarsasapogenin is unusual in that it has a cis-linkage between rings A and B of the steroid nucleus, as opposed to the more usual trans-linkage found in other saturated steroids. The (S)-configuration at C-25 found in sarsasapogenin contrasts with smilagenin, which carries the (25R)-configuration. Structural analysis shows that smilagenin's structure is similar to estrogen and isoflavone of wood, both of which can play roles via inhibiting histone acetylation, suggesting smilagenin might have an analogous role.
Smilagenin (abbreviated SMI) is described in the literature as a small steroidal saponin extracted from Asparagus cochinchinensis. It is also identified as a small-molecule steroidal sapogenin from Anemarrhena asphodeloides and Pelargonium hortorum, widely used in traditional Chinese medicine for treating chronic neurodegeneration diseases. At the botanical genus level, smilagenin (also known as PYM50028 and Cogane) is a constituent of Jamaican sarsaparilla (Smilax ornata).
Within the broader genus Smilax, smilagenin belongs to the isospirostane subclass of steroidal saponins. Isospirostane-type saponins are monodesmosidic glycosides characterised by an equatorial oriented methyl or hydroxymethyl (C-27) on the F ring; the isospirostane-type saponins can be classified into four subtypes on the basis of sapogenin structures, including diosgenin, laxogenin, tigogenin, and smilagenin. The variations of these sapogenins mainly comprise dehydrogenation between C-5 and C-6, carbonylation at C-6, hydroxylation at C-17 or C-27, and cis/trans fusion between rings A and B.
Smilagenin is encountered in several forms in both research and commercial contexts. As a pure isolated compound it is available as a laboratory reference standard (CAS 126-18-1) from chemical suppliers for research use. Smilagenin is described as a novel non-peptide, orally bioavailable neurotrophic factor inducer. Under its pharmaceutical code name PYM50028 (trade name Cogane™), it was developed as an oral tablet formulation by Phytopharm plc (United Kingdom) for clinical investigation of neurodegenerative diseases. In traditional contexts, it is encountered within crude rhizome preparations of its parent plants — dried rhizome slices, decoctions, and powdered extracts — rather than in an isolated, purified form.
The primary historical context for smilagenin is the use of its botanical sources within East Asian medical traditions. Anemarrhena asphodeloides has been commonly used in traditional medicine in China, Japan, and Korea for thousands of years. The rhizome of A. asphodeloides, belonging to the family Liliaceae, is known as 'Zhi-mu' in TCM and is mainly distributed in China, Mongolia, Korea, Japan and other eastern Asian countries. It is first recorded in 'The Book of Songs Erya (诗经·尔雅)', also known as Dishen, Maozhimu, and Yanghuzi in China, Jimo in Korea, and Chimo in Japan.
The traditional curative functions of Anemarrhena asphodeloides are to treat febrile diseases, fever, cough, and diabetes. It is a medicinal plant that has long been used as a tonic agent in various ethnomedicinal systems in East Asia, especially China, and also for treating arthralgia, hematochezia, tidal fever, night sweats, cough, dry mouth and tongue, and hemoptysis. Traditional Chinese medicine classifies this herb as cold (yin) and bitter, and it is used to treat heat disorders, which are caused by excessive yang or insufficient yin functions.
A. asphodeloides has been used as an anti-inflammatory, antipyretic, anti-platelet aggregation, anti-depressant, and anti-diabetic agent in traditional Chinese medicine. It has been processed in various ways such as baking, stewing, frying, frying with wine, frying with salt, frying with honey, and frying with ginger juice. It is combined with other TCM products, such as Guizhi Shaoyao Zhimu tang, Suanzaoren tang, and Er Mu San, to form prescriptions with definite curative effects.
Its clinical features in ancient Chinese medicine books are similar to those of "Lily disease" in the ancient Chinese medicine book Synopsis of the Golden Chamber written by Zhang Zhongjing in the Han Dynasty; the Baihe Zhimu (Lilium lancifolium bulb and Anemarrhena asphodeloides rhizome) decoction is the first prescription of "Lily Disease" in this book. It has also been used in combination with various other herbal ingredients for the purpose of prevention and management of acute lung infection, sterility, and climacteric syndrome.
The genus Smilax (Liliaceae family) comprises about 300 species of climbing shrubs, widely distributed in tropical regions and also found in warm areas of East Asia and North America. The sarsaparilla species of the Americas have been used in traditional medicine for centuries. Smilax has been traditionally used for centuries to treat a range of ailments, including diabetes, gout, rheumatism, skin disorders, and syphilis. Smilax species are extensively used in traditional medicine around the world and in Brazil for the treatment of rheumatism and syphilis and as a diuretic. It is important to note that these traditional uses refer to the whole plant or its crude preparations, not to isolated smilagenin.
The plants of the genus Smilax are widely spread in China; their medical use for the treatment of inflammation and rheumatism has a long history in folk China. The rhizomes of S. china and S. glabra, called "Jin Gang Teng" and "Tu Fu Lin" respectively in the Pharmacopoeia of the People's Republic of China, are clinically used to treat chronic pelvic inflammatory disease and rheumatic arthritis. The rhizomes of S. riparia, S. nipponica, S. bockii, S. microphylla, and S. discotis were recorded in Chinese Herbal Medicines to treat joint pain, edema, and rheumatoid arthritis.
The compounds isolated from Anemarrhena asphodeloides mainly include steroidal saponins, flavonoids, norlignans, and polysaccharides. Among these, smilagenin is a member of the steroidal sapogenin class — specifically an isospirostane-type sapogenin. Steroidal saponins are characteristic bioactive components of the genus Smilax in terms of chemotaxonomic value and biological activities.
The details of the mechanism of action of smilagenin are incomplete but involve the upregulation of neurotrophic factors including Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF).
GDNF pathway (dopaminergic neuroprotection): Tyrosine hydroxylase immunohistochemical analysis revealed that in cultured mesencephalic dopaminergic neurons, smilagenin (SMI), added prior to MPP+, protected against the drop of neuron number and neurite outgrowth length caused by MPP+. Addition of anti-GDNF and/or anti-GFR alpha 1 functional antibodies to the medium prior to SMI eliminated mostly, though incompletely, the action of SMI; the expression of GDNF mRNA in MPP+-intoxicated neurons was markedly elevated as early as 2 hours after the addition of SMI, with a peak at 24–48 hours — therefore, an important route of the protective action of SMI on dopaminergic neurons is to stimulate intrinsic GDNF expression.
BDNF pathway and epigenetic remodelling: Smilagenin exerted neuroprotective effects by promoting the histone acetylation level in the promoter region of the BDNF gene and increasing its transcription. Mechanistically, SMI enhanced BDNF mRNA expression, elevated the global level of H3AC and H4AC, and increased the expression of P300 in Alzheimer's disease models; chromatin immunoprecipitation results showed that SMI could increase the levels of H3AC and H4AC at the promoter of BDNF promoters II and IV, indicating that SMI epigenetically regulates BDNF expression through histone acetyltransferase (HAT) enhancement. Research demonstrated for the first time that SMI showed neuroprotective effects by increasing the expression of P300 protein, thus upregulating histone acetylation levels in the promoter region of BDNF and promoting its transcription.
Muscarinic receptor upregulation: The Y-maze avoidance task showed that oral administration of smilagenin significantly improved spatial memory performance in aged rats; mechanistic studies showed that smilagenin was neither a ligand of the M receptors nor a cholinesterase inhibitor, while radioligand binding assays revealed that smilagenin significantly increased the M1-receptor density, an increase that correlated with memory improvement. Real-time PCR revealed that m1 mRNA in m1 gene-transfected CHO cells increased significantly, and the average half-life of m1 mRNA was approximately doubled by smilagenin treatment — these results suggest that smilagenin improves memory of aged rats at least partially by increasing the stability of m1 mRNA. Since ChAT activity in the cortex of aged rats was also elevated by smilagenin, it cannot be excluded that the increase of intrinsic acetylcholine excretion also plays a role in the memory-improvement effect.
Protein synthesis stimulation (P58): In the context of its pharmaceutical development as PYM50028, smilagenin's activity has been characterised as that of a protein synthesis stimulant that acts by restoring levels of proteins altered in the ageing brain, reversing the loss of nerve receptors in the ageing brain, and potentially allowing for the regrowth of neural connections — providing a novel mode of action with potential importance for diseases associated with ageing of the brain.
Nuclear action: It is believed that smilagenin acts primarily on cell nuclei. Experiments indicated that smilagenin was able to increase the number of muscarinic receptors expressed on the surface of CHO cells cultured in vitro; the effect was not antagonised by tamoxifen, indicating that the mechanism involved did not involve the oestrogen receptor.
The body of laboratory evidence for smilagenin in AD models is substantial, though it remains primarily preclinical (animal and cell-based). Pre-clinical work with smilagenin showed it to be neuroprotective against beta-amyloid and glutamate damage which contributes to Alzheimer's disease.
In a 2023 study using APP/PS1 double-transgenic mice (an established genetic AD model): using APP/PS1 double transgenic mice selected as AD animal models in vivo, researchers first found that smilagenin could significantly rescue the learning and memory dysfunction of APP/PS1 mice. The same study defined an epigenetic mechanism: smilagenin exerted neuroprotective effects by promoting the histone acetylation level in the promoter region of the BDNF gene and increasing its transcription. Behavioral experiments showed that the improvement effects of SMI on cognitive impairment were abolished after P300 inhibition in APP/PS1 mice, corroborating the BDNF/P300 pathway as a key effector.
With respect to amyloid pathology specifically: behavioral tests confirmed that SMI could significantly improve the learning and memory ability of APP/PS1 mice; moreover, immunofluorescence and ELISA results showed that SMI pretreatment could effectively reduce the deposition of β-amyloid plaques in the cortex and hippocampus of APP/PS1 mice (at 26 mg/kg/day for 60 days).
In aged (non-transgenic) rat models, long-term studies showed that smilagenin can improve the learning and memory ability of aged rats and up-regulate the transcription of BDNF in Aβ-intoxicated SH-SY5Y cells.
Smilagenin (also known as PYM50028 and Cogane) is a constituent of Jamaican sarsaparilla (Smilax ornata) and is a neuroprotectant that has been evaluated in Phase II clinical trials in Parkinson's disease and Alzheimer's disease. However, published peer-reviewed reports of statistically significant primary outcomes from these Alzheimer's disease Phase II trials with smilagenin/PYM50028 are not available in the public literature as of the time of writing. The clinical evidence base for smilagenin in AD in human subjects therefore remains incomplete.
Current therapies for Parkinson's disease only offer limited symptomatic alleviation but fail to hamper the progress of the disease; it is therefore imperative to establish new approaches aimed at protecting or reversing neurodegeneration in PD. Recent work has examined whether smilagenin (SMI), a steroidal sapogenin from traditional Chinese medicinal herbs, can have a neuroprotective effect on dopaminergic neurons in a chronic model of MPTP/probenecid mice. Researchers reported for the first time that SMI significantly improved the locomotor ability of chronic MPTP/probenecid-lesioned mice.
In an earlier cell-culture study supporting the GDNF mechanism: tyrosine hydroxylase immunohistochemical analysis revealed that in cultured mesencephalic dopaminergic neurons, smilagenin, added prior to MPP+, protected against the drop of neuron number and neurite outgrowth length caused by MPP+. The expression of GDNF mRNA in MPP+-intoxicated neurons was markedly elevated as early as 2 hours after the addition of SMI with a peak at 24–48 hours, establishing that stimulation of intrinsic GDNF expression is an important route of SMI's protective action on dopaminergic neurons.
In a pre-clinical model funded by the Michael J. Fox Foundation for Parkinson's Research: in a model more closely mimicking human PD, it was demonstrated that once-daily oral administration of Cogane™ for 18 weeks significantly reduced the median parkinsonian disability by 43 percent, and this reduction was still increasing at the time of assessment.
The CONFIDENT-PD trial (NCT01060878) was a Phase II, randomised, double-blind, placebo-controlled study to investigate the efficacy, safety, and tolerability of PYM50028 in subjects with early-stage Parkinson's disease administered once daily for 28 weeks, with a primary completion date in December 2012. This study tested the therapeutic benefit of PYM50028 versus placebo in treating early-stage Parkinson's disease, with therapeutic benefit assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). It was hypothesised that PYM50028 would be safe and well-tolerated and demonstrate therapeutic benefit in this patient population. Peer-reviewed publication of the full CONFIDENT-PD results has not been located in the public literature at the time of this article's composition; the evidence strength from this trial therefore cannot be fully characterised.
On 27 September 2011, orphan designation (EU/3/11/914) was granted by the European Commission to Phytopharm plc, United Kingdom, for smilagenin for the treatment of amyotrophic lateral sclerosis. The sponsorship was subsequently transferred to QRC Consultants Ltd. in October 2013, and then to Quality Regulatory Clinical Ireland Limited in February 2019. Orphan designation by the EMA is not an approval for clinical use; it provides regulatory incentives for development of treatments for rare diseases. No published clinical trial results for smilagenin in ALS have been identified in the peer-reviewed literature.
Smilagenin improves memory of aged rats by increasing the muscarinic receptor subtype 1 (M1) receptor density. This mechanism is notable because deficits in muscarinic M1 receptor signalling are associated with the cognitive impairments seen in Alzheimer's disease. The aged-rat memory studies (described in section 3.2 above) represent robust preclinical evidence; however, no published controlled human trials specifically evaluating cognitive function or memory in healthy aged individuals or those with mild cognitive impairment have been identified in the sources reviewed.
Six smilagenin glycosides were evaluated for their antifungal activities against pathogenic species; compounds 42–46 demonstrated moderate antifungal activity with MIC values between 12.5 and 50 μg/mL. With regard to structure–activity relationships, the closed F ring was suggested to be essential for antifungal activities. This evidence is in vitro only; no clinical studies for antifungal use have been identified.
Smilagenin is noted as an active ingredient extracted from the roots of asparagus that has various anti-inflammatory, antiviral, and other active effects. Smilagenin has anti-inflammatory and antiviral properties reported in the literature, though these observations are based on in vitro and cell-based work. No clinical trials evaluating smilagenin specifically for inflammatory conditions have been identified.
Sarsasapogenin and its C-25 epimer smilagenin lowered blood sugar and reversed diabetic weight gain in experiments within mice with a mutant diabetes gene (db). Some previous studies have reported that smilagenin has a therapeutic effect in diabetes in preclinical models. This evidence is animal-only and no human clinical trials for metabolic conditions have been identified.
Based on the verified scientific literature, smilagenin has been studied in relation to the following body systems and health domains:
The following dosages appear in the reviewed scientific literature. These are reported only as documented in the cited sources and are not recommendations.
The safety profile of smilagenin as an isolated compound, at the doses used in human clinical trials, has not been comprehensively described in the publicly available peer-reviewed literature. The following observations are drawn from verifiable sources:
The scientific investigation of smilagenin is characterised by a solid foundation of mechanistic in vitro and animal (rodent) studies, particularly in the fields of neurodegenerative disease and cognitive ageing. These preclinical data provided the rationale for pharmaceutical development and Phase II clinical trials (CONFIDENT-PD for Parkinson's disease; additional Phase II work in Alzheimer's disease), as well as an EMA orphan designation for ALS. However, the publicly available evidence base lacks published, peer-reviewed reports of the primary outcomes of these clinical trials. The antifungal, anti-inflammatory, antidiabetic, and antiviral activities documented in the literature are predominantly in vitro or animal-level findings. In summary, the current state of evidence is preliminary to Phase II clinical level for neurodegenerative indications and preclinical only for all other proposed uses.
Health conditions that Smilagenin may help support.
Body systems that Smilagenin may help support.
Go back