Cryptotanshinone - Phytonutrient Focus #2

SUMMARY

1.??????Introduction

2.??????Cardiovascular benefits

3.??????Effects on Cognitive Aging

4.??????Application opportunities in Nutraceuticals

5.??????Pharmacological & toxicological data

6.??????Conclusion

7.??????Scientific references

1. INTRODUCTION

Dan Shen (丹參) or Red Sage (Salvia miltiorrhiza) is one of the most renowned medicinal plants in Traditional Chinese Medicine. Red sage is recognized as a therapeutic drug in several Asian countries, where it is recommended for Cardiovascular Health, and more specifically for angina pectoris and all ischemia and atherosclerosis -related issues.

Red Sage root owes its bioactivity?to a myriad of phytonutrients, among which are salvianolic acids and tanshinones - two relatively specific categories of molecules.

Tanshinones are diterpenoids of the abietane type. Tanshinone IIA is the best known but it is far from being the only tanshinone of interest. Among the other molecules in this class, cryptotanshinone is probably the most extensively studied: it has shown promising therapeutic potential, in oncology in particular [1]. It was identified as a natural inhibitor of STAT3 [2] and has been investigated in many fields of health, from cardiovascular health to dermatology and neuroprotection.

In this article, we summarize cryptotanshinone's bioactivity and highlight its potential in the context of nutraceutical innovations.

2. CARDIOVASCULAR BENEFITS

Recognized as a medicinal drug against angina pectoris in Asia, red sage (Salvia miltiorrhiza) and its active constituents have been the subject of multiple studies in the area of cardiovascular health. Cryptotanshinone is no exception and appears to show multi-target benefits on this health sphere:

2.1. Cryptotanshinone limits atherosclerosis phenomena

Cryptotanshinone is an inhibitor of STAT3 [2], but also inhibits the NF kappaB inflammatory cascade [3;4], limits the production of reactive oxygen species (ROS) via inhibition of NOX-4 [5;6] and inhibits the LOX-1/TNFalpha cascade [6-8] (involved in atherosclerosis). All of these activities seem to lead to a decrease in atherosclerotic phenomena [8;9] and therefore present an opportunity for innovation in this context.

2.2. Cryptotanshinone limits platelet aggregation

Cryptotanshinone appear to limit platelet aggregation [10-12], an activity that was already demonstrated for Salvia miltiorrhiza extracts [13] which could contribute to improving a diversity of cardiovascular health issues. This inhibitory effect could partially?be explained by cryptotanshinone's interaction with the P2Y12 protein, involved in the aggregation phenomenon [14].

Although this activity may prove interesting in many cases, cryptotanshinone-based dietary supplements should nevertheless be used with caution when combined with anti-platelet aggregation treatments such as clopidogrel. Even more so since a Salvia miltiorrhiza extract containing tanshinones has been demonstrated to interfere with the pharmacokinetics of clopidogrel [15].

2.3. Cryptotanshinone has a cardioprotective effect

In addition to its potential capacity to limit cardiovascular risks, cryptotanshinone has also been identified as a cardioprotector [16-20] and an anti-cardiac fibrosis agent [21-23], a dual property that further contributes to its benefits on cardiovascular health.

Cryptotanshinone's protective effect, more specifically in the case of cardiac ischemia, also seems to be partially applicable in the context of cerebral ischemia [24-27]. This last activity extends the possibilities of innovation to the neurovascular sphere, leading to its second major area of interest: cerebral aging.

3. EFFECTS ON COGNITIVE AGING

Given its known benefits on vascular health, it is no surprise that cryptotanshinone could hold potential for neurovascular applications. Nevertheless, its interest in the neurological sphere is not limited to this specific area; several studies report its activity in various models of neurodegenerative pathologies (Alzheimer's disease in particular), a medical context in which cryptotanshinone could show significant potential [28-33]. More broadly, some studies have also shown its benefits on cognitive function [34] and depression [35].

4. APPLICATION OPPORTUNITIES IN NUTRACEUTICALS

Cryptotanshinone - and more widely, red sage root extracts - hold a "food supplement" status in Europe. Although it is included in the Belgian & Italian authorized lists, Red sage is still not recognized as a traditional herbal medicine, as the EMA considers extracts composiiton to be too variable. Several Asian countries have, on the other hand, granted red sage extracts the status of medicinal drug, which differs both in terms of dose and administration methods.

Despite cryptotanshinone's strong pharmacological potential, its oral bioavailability remains limited. Achieving "recognized medical efficacy" therefore requires to either use a high dose or a more "direct" method of administration (in China, the intravenous use of tanshinones is quite common). In a nutraceutical context, the use of a limited oral dose allows for proactive support rather than actual therapeutic applications.

The interest of Cryptotanshinone in Nutraceutical applications is well established. However, it is often not the pure molecule but rather the whole extract of Salvia miltiorrhiza roots that is used; preserving the full spectrum composition allows other tanshinones and salvianolic acids to complete Cryptotanshinone's activity. Please note that the concentration of cryptotanshinone is negligible in most red sage extracts on the market, and that only certain active ingredients contain more than 0.5% of it. While this factor is not critical for all applications, it will be appreciable in most of them and particularly crucial in formulas targeting dermatological disorders such as psoriasis.

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4.1. Cardiovascular Health

Cryptotanshinone's potential in the context of cardiovascular health could make it a great partner to other phytonutrient typically associated with the cardiovascular sphere. A combination with olive tree hydroxytyrosol (Olea europaea) could be an example of an original tandem. A significant dose of Omega-3 could further complete the formula for a simple and effective support to cardiovascular health.

4.2. Cognitive Aging?

Due to its regulatory effect on inflammation and its interest in the neurovascular sphere, cryptotanshinone has unique potential in the field of cerebral and cognitive aging. In this field, an association with other phytonutrients - like OPC from maritime pine (Pinus pinaster) or grapes (Vitis vinifera) - could offer an interesting and unique approach to brain health. Once again, the integration of a significant dose of Omega-3 in the formula could easily complete the concept.

4.3. Joint Health

A lesser known area in which cryptotanshinone has shown significant benefits in the scientific litterature is joint health [36-43]. Cryptotanshinone's long-term activity is of particular interest in the preservation of cartilage and could benefit from the support of a highly bioavailable anti-inflammatory molecule, such as an optimized absorption curcumin (e.g. Turmipure gold from our colleagues at Naturex).

4.4. Skin Health

Cryptotanshinone has also been identified as a potentially interesting agent in psoriasis treatment [44]. Its combined anti-inflammatory and STAT3 inhibitory properties make it a potential active ingredient of choice in this area. Although data is currently limited to topical application, the idea of a nutricosmetic (nutridermatological?) formula could be interesting to consider.

5. PHARMACOLOGICAL & TOXICOLOGICAL DATA

As previously mentioned, cryptotanshinone has low oral bioavailability and its pharmacokinetics are relatively well known [2;45]. On the other hand, precise data on the acceptable daily intake (ADI) could not be precisely identified. However, it should be noted that Salvia miltiorrhiza extracts are administered in China and that a sub-chronic evaluation on rats carried out with this type of administration indicates a NOAEL of 5760 mg/kg/day - a high dose but which refers to the extract [46]. In addition, the toxicological risk assessment of the EMA (European Medicines Agency) shows results for non-toxic doses of tanshinones in sub-chronicity of 10 mg in mice, 50 mg in rats and 2.4g/kg in rabbits [47]. A relatively conservative assessment could therefore lead to an IDA of 90 mg/day of tanshinone in a 60 kg adult, with a safety margin of 100.

It is important to note that there is some evidence for a developmental toxicological risk in zebrafish [48]. Therefore, red sage should not be recommended to pregnant women. It should also be added that consumption of this phytonutrientis is not recommended to patients under anticoagulant drug treatment [15].

6. CONCLUSION

Cryptotanshinone, is a relatively rare phytonutrient with singular physiological activity, particularly prized in oncology research. Its potential in various areas of health make it an interesting and unique active ingredient, but one that should be used in reasonable doses and under very specific conditions.

In the context of nutraceutical innovation, a full spectrum red sage should always be prefered to any purified extract, as it will contain a great diversity of natural active ingredients, therefore offering numerous opportunities for formula development and a greater safety of use. Particular attention should be paid to the stability of the selected molecular profile, which - as concluded by the European Medicines Agency evaluation - is crucial for an efficient and safe use.

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