Introduction

Multiple sclerosis (MS), one of the most common inflammatory demyelinating diseases in the central nervous system (CNS), is becoming the major cause of chronic disability, especially in young adults. Advances have been achieved in understanding the pathogenesis of MS in the past few years, yet exact mechanisms remain to be elucidated [1]. Currently approved drugs for baseline therapy of MS, including glucocorticosteroid, interferon-beta, glatiramer acetate, teriflunomide, fingolimod, natalizumab, and mitoxantrone are only partly effective in halting disease activity and disability progression. And some of them show obvious side effects and resistance [2]. Therefore, more attention should be paid to exploring the complementary and alternative therapies for MS.

As an empirical medical system independent of Western medicine, traditional Chinese medicine (TCM) has established its own unique method of diagnosis and treatment for over thousands of years. TCM has become the most popular modality of complementary and alternative medicine (CAM) in chronic diseases, treatment resistance, and intolerance of synthetic modern drugs, either in China or abroad [3, 4]. In recent years, clinical practices have confirmed that TCM is effective to alleviate clinical symptoms, prevent recurrence, delay the disease progression, and improve quality of life (QOL) in MS patients [5,6,7,8]. Widely applied as part of the integrative therapy in China, TCM anticipate in all the aspects of MS including prevention, acute period, and remission [7, 8]. However, the intersection and consistency in the cognition of TCM and Western medical system in MS still need to be clarified. This review will summarize TCM in MS treatment from its own theory and relate mechanism annotation by modern western medicine.

The Essential Theory in TCM

Different from Western medicine reduction theory (scientific evidence for the diagnosis and treatment of a specific disease), TCM doctors understand disease from the concept of holism (a reflection of the integrity of the human body, the natural and the social environment) [9••, 10, 11]. It compares the physiological and pathological changes of the human body with the natural normal or abnormal status by analogy and classification and infers the internal essence according to external symptoms and signs [11, 12]. That is, TCM emphasizes the harmony of the human body itself and its related surrounding environment. Therapies of TCM are based on syndrome differentiation (a summarization of physiological function and pathological changes of the disease at different stages) [12,13,14]. In a TCM prescription, doctors should address the status of various organs and tissues in the human body and their relevant circumstance. They can treat different diseases with the same prescription or treat the same disease with different therapies (the treatment method changed mainly based on function status of related organs and tissues) [9••, 12]. Hence, there is always no quantitative diagnosis in TCM as that of Western medicine, which mainly focuses on the disease itself. The theory of yin-yang (positive and negative syndrome) is the principle of syndrome differentiation [9••, 12]. In TCM, the occurrence and development of diseases lie in the imbalance between yin and yang. Based on the concept of holism, TCM doctors developed different therapeutic methods (including herb medicine, acupuncture, Qigong, cupping glass, etc.) to balance excessiveness or deficiency of yin and yang, among which, herbs (natural medicine) is the most popular. They may neglect the building components of herbal medicine and their detailed mechanisms with drug targets (the prescriptions were harmonizing but the medicines were not) [12, 15]. To some degree, TCM is a mixture of Chinese philosophy, culture, ritual, and medical practices [15, 16].

The Pathogenesis of MS in TCM

In Yellow Emperor’s Canon of Medicine (a classic of internal medicine written during the period 770–221 bc) [9••], the pathological locations of MS are encephala, spinal cord, and governor meridian (which run along the middle of the vertebra column till the head and get into the brain) [17]. They influence the viscera including heart, spleen, liver, lungs, kidneys, and various tissues (not the anatomical organs and tissues in Western medicine) [18]. According to the holism theory, the interactions of these vital organs and tissues in the human body and other external factors such as daily rhythmicity, seasons change, and surrounding stress decide the occurrences, development, and remission of MS [7, 8, 9••].

From syndrome differentiation perspective, MS is defined belonging to deficiency, stasis, and toxin syndrome [7, 8, 15]. Deficient syndrome is body resistance weakness. The clinical manifestation of deficiency syndrome in MS may be fatigue, heavy limbs, paralysis, and laziness [7, 8, 9••]. Deficient syndrome is closely associated with immune function in MS patients, and deficiency tonification (strengthening the body resistance) is a fundamental TCM therapy in MS [7, 8]. The stasis syndrome is caused by the obstruction of Qi (the vital substance that comprises the human body and maintains life activities and physiological functions of the viscera) and blood [19]. The most frequently cited stasis syndrome in MS patients exhibits with a dark purple tongue, face, and eye with purple black shadow, fixed pain, blurred vision, etc. [7, 8, 19]. Invigorating Qi and promoting blood circulation to remove stasis is always powerful in MS treatment. The toxin can impede and weaken the function of viscera and tissues, lead to senility and degeneration, which could manifest as pain and numbness, changing emotion and cognition, and make the diseases become lingering or chronic [7, 8]. Meanwhile, toxicity syndrome can be seen in the whole course of MS patients and detoxication method of TCM runs through in MS therapy [7, 8].

In essence, deficiency, stasis, and toxin syndrome in MS patients is the imbalance of yin-yang, the core theory of TCM. Thus, the balance of yin and yang from syndrome differentiation (deficiency tonification, remove stasis removal, and detoxication) is the principle treatment of MS patients. TCM doctors use individualized treatment plans for different MS patients (“tailored to the patients”) to improve different symptoms. The concept of holism is always appreciated as the ancient wisdom of herb medicine combination in MS patients. Although the complexity of the herbs combination used in MS patients is different from Western medicine, an increasing body of scientific data has begun to reveal their commonalities (Fig. 1).

Fig. 1
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Diagram shows Chinese holism theory and Western medicinal mechanisms of Traditional Chinese Medicine in multiple sclerosis

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Are Yin-Yang Balance Effects of TCM Consistent with Immunomodulatory Effects of Western Medicine in MS Patients?

From TCM perspective, the pathogenesis of MS is the imbalance of yin and yang, then the disharmony of internal pathophysiologic functions and the external natural environment. Therefore, the treatment of MS is to regain a new dynamic balance of yin and yang through pattern identification to recuperate and avoid further damage [7, 8, 9••]. Yin-yang imbalance mechanism of MS defined by TCM has a similar pathological mechanism to that defined by Western medicine. MS is an autoimmune disease defined by Western medicine. The abnormal shift of immune cells particularly Th1/Th2 or Th17/Treg cells is the fundamental immune dysfunction in MS patients. The management strategy is immune-regulatory therapy [1, 2]. The aberrant Th1/Th2 and Th17/Treg cell shift is imbalance between yin and yang in the view of TCM to some degree. Regaining yin-yang balance for MS treatment by TCM is similar to promote Th1/Th2 and Th17/Treg cell in expectant shift in Western medicine. Previous researches had found that Chinese herbal medicines or their extracts could balance yang and yin as well as keep Th1/Th2 and Th17/Treg normal shift in MS patients. Among them, Liuweidihuang pill and Jinkuishenqi pill are the typical prescriptions which have yin-yang balance effects in MS treatment [20,21,22]. Both of the formula contains Radix Rehmanniae and Fructus Corni (preparata in Liuweidihuang pill but not in Jinkuishenqi pill), Rhizoma Dioscoreae, Cortex Moutan, Rhizoma Alismatis, etc. Although the formula seems similar, the differences of ingredients and processing methods produce different pharmacological effects. Liuweidihuang pill have clinical efficacy for treatment of yin deficiency syndrome while Jinkuishenqi pill is a classical Yang-reinforcing prescription [20, 21]. TCM doctors prescribe Liuweidihuang pill or Jinkuishenqi pill alone or in combination according to the yin-yang theory. Modern pharmacological studies have shown that both Liuweidihuang pill and Jinkuishenqi pill could suppress experimental autoimmune encephalomyelitis (EAE, a well-established animal model of MS) by promoting Th17 to Treg cell shift via regulating the cytokines of tumor necrosis factor-α (TNF-α),TGF-β, and IL-17 [20, 21].

Ginseng (the root of Panax ginseng), one of the most well-known oriental medicinal herbs, has been widely used as a herbal remedy for various disorders such as MS. Ginseng contains various pharmacological components such as ginsenosides, polyacetylenes, polyphenolic compounds, and acidic polysaccharides. Ginseng itself has yin-yang balance effects in TCM. As an immune-enhancement agent, ginseng has been extensively reported to maintain homeostasis of the immune system in modern medicine [23]. It could improve the activity of natural killing cells, stimulate T cell proliferation, and promote the generation of Treg cells in EAE mice. Moreover, ginseng was reported to increase serous IL-4, reduce interferon-gamma (IFN-γ), IL-1β, and IL-17, promote Th2 shift, and attenuate the severity of MS [23].

From the TCM perspective, herb itself or in combination with other herbs (as form of decoction, pills, capsules, tablet, etc.) is the most popular prescription in MS patients. However, most of the mechanistic studies of their effects on MS have been done based on the active components which always worked as a monomer in modern science. Artemisinin is an active component of Artemisia annua. It is cold in character and acrid in taste, which belongs to yin from drug properties of TCM. Artemisinin could shift the immune responses from Th1 to Th2 and promote the proliferation of Treg cells, then decrease severity of EAE progression [24,25,26,27]. Triptolide is the most active ingredients in Tripterygium wilfordii Hook (a climbing shrub with a long history of diverse use in TCM). It has cold character and bitter taste, which belongs to yin in nature as Artemisia annua. Previous studies have demonstrated that triptolide could ameliorate EAE development by regulating Th1-, Th2-, and Th17-related cytokine, therefore regulating T cell proliferation and activation [28,29,30,31,32,33]. Yang in nature, astragalosides is the principle bioactive component extracted from the roots of Radix Astragali. It has a warm character and sweet taste and has been used widely as a key remedy in TCM for enhancing yang. It was found that astragalosides could attenuate severity of EAE and prevent inflammatory cell infiltration in spinal cords of EAE mice [34, 35]. The mechanism was decreased mRNA expression of transcriptional factors RORγt and up-regulation of Foxp3 to modulate Th17/Treg cell differentiation [34, 35]. Other monomers such as baicalin from Scutellaria baicalensis and arctigenin from Arctium lappa (both belongs to yin) have similar immunomodulatory effects, which are mainly summarized in Table 1 [36,37,38,39].

Table 1 Summary of selected herb medicine for EAE and their biofunction
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From above, we can see that the yin-yang balance treatment in MS/EAE by TCM is similar to the immunomodulatory effects in Western medicine to some degree. Apparently, the prescription underlying philosophical systems of TCM theory in MS patients is more complex than “one drug, one target, and one disease” approach in modern medicine [12]. And benefits of TCM treatment in MS patients cannot be disregarded due to inadequate international treatment standardization and quality control from the view of modern science [40].

Does the Function of Deficiency Tonification, Stasis Removal, and Detoxification of TCM Act as Anti-inflammatory, Anti-oxidative, and Neuroprective Effects in MS Patients?

From syndrome differentiation, MS was defined belonging to deficiency, stasis, and toxin syndrome [5,6,7,8]. They can interact and transform with each other and decide the occurrence, progress, and remission of MS [7, 8]. The biomarkers of deficiency, stasis, and toxin syndrome detected by modern science are different combinations of IL-6, IL-1, TNF-α, IFN-γ, IL-4, IL-10, NF-κB, SOD, GSH-Px, iNOS, MDA, NGF, etc. [5,6,7,8]. There are also biomarkers to detect the inflammatory, oxidative stress, and neuroprotective effects of Western medicine in MS treatment.

Bushengusui Fang is a traditional Chinese formula used to tonify deficiency for MS patients. The ingredients are Epimedium Linn, Radix Salviae miltiorrhizae, Rehmannia glutinosa, Radix Curcumae, Cistanche deserticola, and other herbs. It could improve symptoms and signs of MS patients and reduce recurrent frequency (Table 2) [41, 42]. Bushengusui Fang could remarkably reduce incidence of EAE, inhibit inflammation and demyelination of brain and spinal cord, and reduce serum IL-6 and TNF-α in EAE mice [41, 42]. Erhuang Fang is a classical TCM formula that has the tonic effects in MS patients. It consists of Radix Rehmanniae, Radix Rehmanniae Preparata, Leech (the dried body of Whitmania pigra), bulbus Fritillariae thunbergii, scorpion (the dried body of Buthus martensii), and Radix Polygoni Multiflori. Erhaung Fang could relieve inflammatory reaction and demyelination in EAE rats, reducing the activities of NK cells and serum IL-6 level to attenuate EAE [43]. Moreover, Erhaung Fang could reduce the relapse rate and annual relapse rate in MS patients (Table 2) [44]. Icariin is a primary active component of Epimedium extracts (a tonic medicine of TCM), which has the anti-inflammation and neuroprotective effects in degeneration disease including MS. It is effective in ameliorating neurological signs of EAE via mediating estrogen receptor β, modulating HPA function and glucocorticoid receptor expression [45]. Catalpol is from Radix Rehmanniae, a tonic medicine of TCM. It could improve neurological function, reduce inflammatory cell infiltration and demyelination, and promote the expressions of Olig1 and Olig2 transcription factors in EAE mice [46]. Both the above-mentioned formulas and monomer can improve MS/EAE through tonifying deficiency from syndrome differentiation.

Table 2 Summary of RCTs using herbal therapy for patients with multiple sclerosis
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Buyang Huanwu Tang is a popular TCM formula to invigorate Qi and promote blood circulation then remove stasis in MS patients. The formula consists of Radix Astragali, Radix Angelicae Sinensis, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Flos Carthami, Semen Persicae, and Pheretima. Recent studies showed that Buyang Huanwu Tang could provide anti-inflammation and neuroprotective effects in EAE mice. It could inhibit the inflammatory cell infiltration and demyelination in the spinal cord of EAE [47, 48]. It could also regulate the proportion of peripheral T cell subsets, promoted the conversion of M1 macrophages into M2 phenotype in the spinal cord and spleen, and inhibited ROCKII/TLR/NF-κB signaling pathway [47, 48]. Total glucosides of peony (TGP) is an active compound extracted from the roots of Paeonia lactiflora Pall which can remove stasis in TCM. TGP has been used in the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus [49, 50]. Additionally, pharmacological studies have shown the antiallergic, anti-inflammatory, anticancer, antioxidant, immunomodulatory, and neuroprotective properties of this medicinal herb [51]. In our recent study, TGP can effectively ameliorate EAE through reducing secretion of IFN-γ, upregulating of BDNF and CNPase expression [52•]. From above, removing stasis can alleviate MS and EAE from syndrome differentiation in TCM.

SanHuangXieXin Tang (Samhwangsasim-tang in South Korea and San’o-shashin-to in Japanese) is a traditional herbal medicinal formula containing coptidis rhizome, rhei rhizome, and scutellariae Radix which has effects of detoxication from TCM. According to previous laboratory and clinical studies, SanHuangXieXin Tang has anti-inflammatory, anti-oxidative, and anti-apoptotic activities and plays an important role in the treatment of cardiac disorder, hepatic, and Parkinson’s disease [53, 54]. It exerts a protective effect on EAE mice through reduction in BBB permeability, inhibiting recruitment of Th1 cells, increasing Tregs cells and significantly down-regulating expression of p-IkBa, NF-kB (p65), p-ERK, p-JNK, and p-P38 in the spinal cords in EAE mice [55]. Berberine is an isoquinoline derivative alkaloid isolated from Berberis vulgaris which has the function of detoxication. Our previous study showed that berberine could reduce the permeability of BBB, suppress the increased expression of MMP-9 [56] and provide a neuroprotective effect by inhibiting gelatinase activity and reducing laminin degradation [57]. Meanwhile, berberine has also been reported to suppress demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway [58]. These findings further support that berberine can be a potential therapeutic agent for MS. Osthole is a bioactive coumarin derivative from Cnidium monnieri Cuss, which has detoxication effects in TCM and possesses a variety of pharmacological and biochemical properties of anti-inflammation action or immunomodulatory effects [59, 60]. Osthole was found to ameliorate clinical severity of EAE mice by inducing the expression of NGF and inhibiting the expression of IFN-γ both in the brain and sera of mice in vivo and in splenocytes in vitro [61•]. Recently, osthole has been further reported to confer a potent anti-inflammatory capacity to neural stem cell-based therapy in EAE [62]. From above, detoxication can alleviate MS and EAE from syndrome differentiation. Other monomers such as luteolin and apigenin from Achillea millefolium L, matrine from Sophora flavescens has similar effects which are mainly summarized in Table 1 [63,64,65,66,67,68,69,70].

Syndrome differentiation which emphasizes individualized treatment is dynamic and flexible in MS therapy. TCM doctors practice different kinds of herb medicine and matched different MS patients with their own characteristics [7, 8, 14]. Undoubtedly, the therapy of syndrome differentiation has positive effectiveness in MS patients. Because the concept is difficult to be comprehend from a modern biomedical perspective which builds on evidence-based theoretical interpretations and solid evidence of syndrome-based effects, syndrome differentiation is often avoided or underestimated, which reduces the potential benefits [14]. From above, we found that the concept of tonifying deficiency, removing stasis, and detoxication, which is the principle of TCM treatment, could work by their anti-inflammatory, anti-oxidative, and neuroprotective effects in MS patients.

Are Treatments for MS with Concept of Holism in TCM Consistent with Disease-Modifying Therapy in Western Medicine?

In the perspective of the holism theory of TCM, everything is interconnected and grasping the whole nature of MS is very important [9••, 10]. Based on the pathogenesis, syndrome patterns, and different disease stages, TCM doctors prescribe various formulas for MS patients with different characters. The therapy goals are balancing yin-yang and harmonizing of internal function and external circumstances. The TCM doctors emphasize both “regulation” and “cure” to maintain stabilization of aberrant immune system in MS patients, to ameliorate symptoms and signs, minimize disability, and reduce relapse or progression [7, 8, 9••, 10].

The prescription emphasizes the unity of herb or formulas (multiple herbs). The combination of several herbs exhibits various biological activities and is not the heap of medicines. In modern pharmacology, the mechanism of formula of TCM can be explained by the following hypothesis: TCMs render effects and weaken toxicities through the additive effects of numerous effective forms (including their constituents or/and metabolites) on the same target, the synergistic effects are based on the overall action of the additive effects on individual targets and their toxicities’ scattering effects [12, 16, 71]. The advantages of multitarget including anti-inflammatory, immune-regulatory, anti-oxidative, and neuroprotective effects on MS, gradually improve patient’s resistance and prevent possible adverse effects [5, 6]. For TCM, the formula should be evaluated as a whole and any separation will inevitably result in a decrease or even an offset in its performance.

The holism theory agrees with disease-modifying therapy (DMT) in MS patients at current time [5, 6]. DMT is defined as an intervention that alters the expected natural course of MS other than simply improve symptoms, thereby gradually improving patient’s QOL [3, 5, 6, 72]. QOL is an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns. It is a multidimensional concept related to physical, psychological, and social functioning and worked as an evaluation index for health and the curative effect of disease [72]. QOL evaluation system is consisted of the core theory of holism which emphasizes harmony of human body, the nature, and the society [72]. Treatment concept of MS which fuse TCM and Western medicine will pay more attention to analyzing the nature of each patient and produce more effective strategies.

Why Not Integrate the TCM and Western Medicine to Produce Better Effects on MS Patients?

TCM emphasizes the holistic nature of the body and the subjective experiences of patients and doctors [40, 73]. The effect of MS treatment always depends on the practitioners’ own experiences and patient feedback, as well as the internal logic and systematic basis of Chinese medicine’s philosophy. It is relatively flexible and versatile. And the therapeutic efficacy cannot be verified by single standardized intervention necessary in randomized clinical trials (RCTs) [74]. The difference between TCM and modern medicine is significant, and the TCM, which is under the guide of integral view, is in great “incommensurability” with the modern science and technology, which is under the guide of reduction theory [11, 12, 75, 76]. The modern methods are not always suitable for TCM research. As Prof. Xueseng Qian said, the theory of TCM is not natural science. It is natural philosophy which is based on phenomenological cognition and demands a comprehensive understanding which is not restricted to science [77].

Fortunately, the development of technology provides a new possibility to the modern transformation of TCM study [78,79,80]. Techniques including biospecific cell extraction, serum pharmacochemistry, and TCM network pharmacology are widely used for screening and analysis of TCM prescriptions [81]. Other researches on syndrome element differentiation based on phenomenology and mathematical method are also used to integrate TCM and Western medicine [76]. At present, a lot of work has been done to recognize and separate the active components in herbal medicines effective for MS. And many classic formulas have been modified by modern techniques and applied in clinical practice. The mechanism about these single agents and modified formulas has been implied. However, it must be noticed that the compounds in herbal medicines often modulate and modify the effects of the active ingredient in the herbs, so an extracted active ingredient from the herb alone may not ensure the therapeutic effect in clinic.

Even so, integrating TCM with modern medicine have great promise for inspiring new ideas and therapies for preventing and treating MS [4,5,6], a disease which has complex etiology and pathophysiology without specificity and effective treatment. Appropriate combination of Eastern and Western concepts may have positive effects. Recent research has shown that Icariin has synergistic effects with methylprednisolone to ameliorate EAE. The combination of Icariin and methylprednisolone could modulate HPA functions, promoting anti-inflammatory and anti-apoptotic effects via decreasing serum IL-17 and CORT concentrations, up-regulating the expression of GR in cerebral white matter and attenuating the cell apoptosis in spinal cord [82]. Other clinical practice such as Shuganjianpigusui Fang (mainly consisted of Bupleurum chinense, Paeonia lactiflora Pall, Angelica sinensis, Atractylodes macrocephala, rhizoma smilacis glabrae, Glycyrrhiza uralensis Fisch), Yiqihuoxuehuatan soup, or Buyang Huanwu Tang can be combined with methylprednisolone in MS patients is in practice. The combination significantly reduced the annual relapse in the treatment group (Table 2) [83,84,85,86]. The appropriate combination cannot only improve treatment efficacy but also reduce drug dosages and adverse reactions in MS patients [87].

Conclusions

In conclusion, although TCM and Western medicine have evolved on distinct philosophical foundations and reasoning methods, an increasing body of scientific data has begun to reveal their commonalities. This review provides a new insight in intergradations of the TCM and western medicine in MS management, and appropriate combination is promising. Because herbal medicines have diversified ingredients and probably cause interactions when combined with chemical medicines, attention should be paid to mutual metabolism interference between herbals and drugs then to avoid potential side effects.