Research Progress in Use Of Traditional Chinese Medicine For Treatment Of Spinal Cord Injury

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Yubao Lua, et al

Background: Spinal cord injury (SCI) is a serious central nervous system disorder caused by trauma that has gradually become a major challenge in clinical medical research. As an important branch of worldwide medical research, traditional Chinese medicine (TCM) is rapidly moving towards a path of reform and innovation. Therefore, this paper systematically reviews research related to existing TCM (traditional Chinese medicine) treatments for SCI, with the aim of identifying deficits and shortcomings within the field and proposing feasible alternative prospects.

Methods: All data and conclusions in this paper were obtained from articles published by peers in relevant fields. PubMed, SciFinder, Google Scholar, Web of Science, and CNKI databases were searched for relevant articles. Results regarding TCM (traditional Chinese medicine) for SCI were identified and retrieved, then manually classified and selected for inclusion in this review.

Results: The literature search identified a total of 652 articles regarding TCM (traditional Chinese medicine) for SCI. Twenty-eight treatments (16 active ingredients, nine herbs, and three compound prescriptions) were selected from these articles; the treatments have been used for the prevention and treatment of SCI. In general, these treatments involved antioxidative, anti-inflammatory, neuroprotective, and/or antiapoptotic effects of TCM (traditional Chinese medicine) compounds.

Conclusions: This paper showed that TCM (traditional Chinese medicine) treatments can serve as promising auxiliary therapies for the functional recovery of patients with SCI. These findings will contribute to the development of diversified treatments for SCI.

Keywords: Traditional Chinese medicine, Spinal cord injury, Nerve repair, Active ingredient, Compound prescription

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1. Introduction

Spinal cord injury (SCI) is a serious central nervous system disorder that has recently been more frequently observed in clinical settings. Data provided by American epidemiologists suggest that the incidence of SCI is approximately 53–54 cases per 1 million people [1]. Because there is a lack of effective clinic-based treatments that can alleviate the paraplegia and excretion dysfunction caused by SCI, this disorder can be a catastrophic experience for the patient, the patient’s family, and society in general. Although developments in the fields of neurobiology, materials science, pharmacology, and other related sciences have produced many breakthroughs for the treatment of SCI, available treatment methods for clinical transformation remain scarce [2].

Routine clinical treatments employed during the early stages of SCI primarily involve surgical procedures, in combination with high-dose methylprednisolone (MP). Although these treatment modalities can improve the survival rate and quality of life of affected patients, they cannot restore damaged nerve function [3]. However, surgery can effectively decompress the damaged spinal cord and remove local stimulants in a timely manner, which stabilizes the condition [4]. Following decompressive surgery for SCI, MP reduces perioperative neurological complications by protecting neurons from inflammation,

as well as by reducing secondary oxidative stress and inflammatory responses without compromising the composition of circulating immune cells [5]. Unfortunately, the use of high-dose MP results in a variety of side effects (e.g., infection, pneumonia, bleeding, and femoral head necrosis) that greatly increase patient mortality [6–7]. Furthermore, a cohort study found that MP has no effects on nerve recovery in patients with SCI [8]; another study showed that MP can inhibit the proliferation of ependymal cells [9]. Therefore, the use of high-dose MP for the treatment of SCI remains controversial.

Accordingly, the identification and development of safe and effective treatments for SCI have significant value in both clinical and social contexts. Many novel treatment concepts have been proposed by researchers in various countries. Of these concepts, stem cells (e.g., neural stem cells, mesenchymal stem cells, olfactory ensheathing cells, and Schwann cells), transplantation therapy, molecular nutrition support therapy, and tissue engineering therapy are the most popular and important research directions [10]. Although these treatment options hold great potential for further development, effective clinical applications remain elusive.

As a “bright pearl” of the world’s “medical crown,” traditional Chinese medicine (TCM) has been actively applied in the clinic for thousands of years; it has spread from China throughout Asia, as well as to Europe and America. The spread of TCM (traditional Chinese medicine) is primarily due to its long history and a rich catalog of medical resources. Accordingly, the use of TCM (traditional Chinese medicine) to treat SCI has received an increasing amount of attention from researchers in a variety of countries; this attention is expected to open a new era in the treatment of SCI. Existing research has demonstrated that active extracts, Chinese herbal medicines, and TCM (traditional Chinese medicine) compounds exert varying degrees of therapeutic effects on SCI [11–13]. However, in the current clinical atmosphere, TCM (traditional Chinese medicine) methods cannot completely replace currently used surgery and hormone therapy techniques; thus, TCM (traditional Chinese medicine) methods are limited to use as auxiliary treatments. This paper systematically reviews research related to the use of TCM treatments for SCI, analyzes existing deficiencies and shortcomings, summarizes feasible directions for future development, and makes recommendations for the continuous development of this field.

2. Pathophysiology of SCI

Pathophysiological processes of SCI can be divided into three phases as follows, based on different pathophysiological reactions: acute, subacute, and chronic. The acute phase of SCI is directly caused by the primary physical injury; the degree of injury is closely related to the intensity of the associated physical factors, including compression, shearing, laceration, and acute stretch/distraction [14].

The subacute phase involves additional damage caused by pathophysiological reactions to SCI. This process occurs within a few minutes to several weeks after the spinal cord is destroyed; therefore, it is referred to as the “secondary injury” [15]. This secondary damage includes a series of cascading changes at the levels of genes, molecules, cells, and tissues that exhibit significant temporal correlations [16]. The following pathological processes represent the various categories of important secondary injuries that occur following SCI:

(1) blood and vessel changes (e.g., hemorrhage, vasospasm, reduced blood flow, blood homeostasis, thrombosis, and blood-brain barrier damage) that primarily cause local edema and ischemic necrosis in the spinal cord [17];

(2) oxidative stress responses, which involve lipid peroxidation and large numbers of oxidative free radicals that contribute to oxidative damage in neurons after SCI and directly lead to elevated levels of nerve damage [18];

(3) neuronal apoptosis, the most recognized pathophysiological response after SCI, which occurs in a wide range of cells (e.g., neurons, microglia, astrocytes, and oligodendrocytes) at different stages of damage [19];

(4) destruction of ionic balances among sodium (Na+), potassium (K+), and calcium (Ca2+), which leads to depolarization of cell membranes [20];

(5) glutamate excitotoxicity, associated with elevated glutamate release and excessive activation of glutamate receptors in nerve cells, which is an important cause of neuronal apoptosis after SCI [21];

(6) inflammation occurring within hours to weeks after SCI, which is associated with infiltration of the injured site by a large number of inflammatory cells (e.g., macrophages, microglia, T cells, and neutrophils), results in the release of tumor necrosis factor-α and subsequent release of inflammatory cytokines (e.g., interleukin-1α, interleukin-1β, and interleukin-6) that elicit a cascade of inflammatory responses.

After several weeks of pathophysiological responses, SCI continues to develop and patients gradually shift from the subacute phase to the chronic phase over the course of several years. During this process, microglia and astrocytes are activated and a large amount of glial fibrillary acidic protein is released to encapsulate the damaged spinal cord tissue through the formation of a cystic cavity and glial scars [22]. These issues are considered the largest obstacles to the recovery of neurological function in patients with SCI.

3. Active TCM (traditional Chinese medicine) ingredients

Active ingredients associated with TCM (traditional Chinese medicine) are shown in Fig. 1 and Table 1.

Fig. 1. The role and related signaling pathways of active ingredients from different traditional Chinese medicines in the repair of spinal cord injury.

3.1. Resveratrol

Resveratrol (RES) is a natural polyphenol with antioxidant properties that is mainly extracted from cassia, gourd, and knotweed; it is also extracted from peanuts, grapes, blueberries, and other foods [23]. Liu et al. [24] investigated the therapeutic effects of RES for SCI and observed significant improvements based on Basso-Beattie-Bresnahan scores. Histological, immunohistochemical, and ultrastructural examinations have also demonstrated the therapeutic effects of RES. For example, Zhao et al. [25] reported that the therapeutic effects of RES on SCI are closely related to activation of the SIRT1/AMPK autophagy signaling pathway; Zhou et al. [26] proposed that RES-induced nerve repair following SCI is achieved through inhibition of the mTOR signaling pathway.

Other studies have shown that RES improves the prognosis of patients with SCI through actions within the SIRT1/AMPK and AMPK/ mTOR pathways; moreover, it exhibits efficacy as a therapeutic agent for SCI. However, the roles of RES in the different stages of SCI and the specific molecular mechanisms underlying these processes require further analyses. Although RES may inhibit the nuclear factor kappa B (NF-κB) signaling pathway, there is no direct experimental evidence that RES can improve the prognosis of SCI in this manner; thus, further experiments are needed. Currently, RES is known to control inflammation, oxidative stress, mitochondrial function, and apoptosis. However, applications of RES for the treatment of SCI are not limited to its existing roles and its benefits may arise from its regulatory role during epigenetic processes.

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3.2. Curcumin

Curcumin is a diketone compound isolated from Zingiberaceae and is primarily found in herbal turmeric [27]. Many studies have shown that curcumin has strong antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antidiabetic effects. Additionally, curcumin influences a variety of molecular targets, including NF-κB, signal transducer and activator of transcription 3, nuclear factor erythroid 2- related factor 2 (Nrf2), reactive oxygen species, and cyclooxygenase-2. Curcumin has therefore been used to treat various chronic diseases such as cancer, diabetes, obesity, cardiovascular diseases, lung disease, neurological disorders, and autoimmune diseases [28].

In the spine, curcumin protects against oxidative stress during SCI by downregulating the expression of glial fibrillary acidic protein [29]; reducing tissue levels of malondialdehyde; increasing the tissue activities of glutathione peroxidase, superoxide dismutase, and catalase [30]; and exerting anti-inflammatory effects [31]. Zhang et al. [32] suggested that the therapeutic effects of curcumin on SCI are associated with reduced expression levels of inducible nitric oxide synthase and Nmethyl-D-aspartate receptors.

Although curcumin has shown great potential for the treatment of SCI, the extremely low bioavailability of oral curcumin cannot meet current clinical needs. Thus, further explorations of routes of drug administration other than the gastrointestinal pathway will close a major gap in this field. However, lipophilic curcumin can easily cross the blood-spinal cord barrier and enter cerebrospinal fluid circulation, which suggests great potential regarding clinical applications of curcumin. Additional unresolved issues involve the adaptation time of curcumin administration and whether curcumin has precise curative effects during each pathophysiological stage of SCI.

3.3. Ginsenoside

Ginsenoside (GS) is a natural sterol compound that is mainly extracted from ginseng. There are more than 150 types of GS [33]; it exerts therapeutic effects on cardiovascular disease, diabetes, cancer, stress, inflammation, and immune stimulation [34]. Kim et al. [35] reported that GS Rb1 promotes the repair of SCI-induced damage by reducing neuronal apoptosis and increasing the expression of aquaporin-4. Additionally, Huang et al. [36]found that GS Rd inhibits apoptosis and inflammatory responses by reducing phosphorylation of mitogen-activated protein kinase; Kim et al. [37] showed that GS Rg3 inhibits the activation of microglia, which provides important positive effects for the treatment of SCI. Zhao et al. [38] demonstrated that GS Rb1 protects against SCI by downregulating the Bax/Bcl-2 ratio and reducing levels of caspase-3 and p-Ask-1.

Although GS is a potential candidate for the treatment of SCI, there is insufficient research regarding its effects and the underlying mechanisms are not fully understood. These issues largely limit the use of GS for the treatment of SCI. Therefore, research regarding the molecular mechanisms of GS for the treatment of SCI is an important direction for its further development.

3.4. (−)-Epigallocatechin-3-gallate

Epigallocatechin-3-gallate (EGCG) is a catechin compound extracted from green tea, which is a traditional Chinese health drink [39]. EGCG has antibacterial, antiviral, antioxidative, anti arteriosclerotic, antithrombotic, antiangiogenic, anti-inflammatory, and antitumor effects; it is also involved in immune regulation and neuroprotection [40]. EGCG can promote recovery after SCI by reducing inflammation and neuronal apoptosis, while significantly improving the recovery of motor function [41,42]. Tian et al. [43] suggested that the therapeutic effects of EGCG on SCI are achieved through upregulation of anti-apoptotic Bcl-2 and downregulation of proapoptotic Bax. Recently, Machova Urdzikova et al. [44] demonstrated that the therapeutic value of EGCG in SCI might involve alterations in macrophage phenotypes, modulation of inflammatory cytokines during the early stage of SCI, and induction of high levels of axonal sprouting.

Although research results regarding EGCG currently remains limited, the literature suggests that this compound can reduce nerve damage after SCI through anti-inflammatory, antioxidative, and anti-biological activities. Nonetheless, existing experimental results are inconclusive and further research with effective results is needed to support these conclusions. Therefore, clinical use of EGCG for SCI will require a long and in-depth research process that includes quantitative studies to elucidate the mechanisms underlying SCI and to assess the efficacy of EGCG for treating SCI.

3.5. Paeoniflorin/albiflorin

Paeoniflorin is a type of water-soluble monoterpene glycoside that is extracted from the root of peony as two isomers: paeoniflorin (PF) and albiflorin (AF) [45]. TCM (traditional Chinese medicine) uses PF and AF as treatments for gynecological problems, cramps, pain, giddiness, and congestion [46]. Wang et al. [47] found that PF can treat SCI by inhibiting the NF-κB signaling pathway. Similarly, in a chronic compression model of sciatic nerve injury, Zhou et al. [48] demonstrated that PF and AF significantly alleviate inflammation and pain by inhibiting activation of the mitogen-activated protein kinase signaling pathway. Additionally, AF inhibits the proliferation of glial cells; thus, it may exert therapeutic effects in SCI.

Because of their anti-inflammatory and neuroprotective properties, PF and AF have the potential for use as future sources of natural treatment strategies that may reduce the progression of secondary injury following SCI. However, clinical and experimental research in this area remains very limited, particularly with respect to AF. Regardless, the biological activities of PF and AF are promising in terms of their applications in the treatment of SCI; additional in-depth research will aid their sustained and rapid development in this field.

3.6. Paclitaxel

Paclitaxel is a major anticancer drug found in the bark of Taxus spp. that is the most widely used chemotherapeutic compound for the treatment of various malignant tumors [49]. Many studies have demonstrated that paclitaxel can also be used in the treatment of skin disorders, renal and hepatic fibrosis, inflammation, axonal regeneration, limb salvage, and coronary artery restenosis [50]. Hellal et al. [51] reported that paclitaxel interferes with Smad-dependent transforming growth factor-beta signaling, reduces extracellular matrix secretion and cell migration, prevents fibrotic scarring, and promotes the growth of axons after SCI. Although Popovich et al. [52] expressed skepticism regarding the neuroprotective effects of paclitaxel, their skepticism has not affected further analyses of this compound for the treatment of SCI. For example, Yin et al. [53] found that paclitaxel-loaded tissue-engineered scaffolds promote neural regeneration in a long-distance transected SCI model. However, based on current research findings, additional studies are needed regarding the therapeutic mechanisms of paclitaxel on SCI.

Although paclitaxel is a commonly used clinical chemotherapeutic drug that has benefitted many patients with malignant tumors, its use is limited in terms of nerve regeneration. Based on the current literature, the neuroprotective effects of paclitaxel are doubtful; however, paclitaxel has been confirmed to inhibit the production of glial scars, which contributes to local and microenvironmental conditions for the treatment of SCI. Therefore, paclitaxel can be used as an effective supplementary therapy for nerve repair after primary SCI. An important premise of paclitaxel application is its combined use with other therapies to ultimately promote nerve growth. Therefore, paclitaxel will presumably constitute an important component of comprehensive treatment strategies for SCI.

3.7. Emodin

Emodin is an indole compound extracted from palm rhubarb that has pharmacological effects on catharsis, cough, and blood pressure; it also exerts antibacterial and antitumor activities [54]. Zeng et al. [55] found that emodin promotes neural pathway reconstruction after SCI by activating the Nrf2-ARE pathway. Unfortunately, there is a lack of further information regarding the effects of emodin on SCI. However, because the Nrf2-ARE pathway is a commonly assessed signaling mechanism in studies of SCI, the value of research regarding the role of emodin in the treatment of SCI is worth affirming.

3.8. Quercetin

Quercetin is a natural flavonoid antioxidant extracted from Aesculus indica fruit, Codonopsis, Chrysanthemum, and Prunella vulgaris [56], which is currently approved for use as a dietary supplement by the United States Food and Drug Administration [57]. Numerous studies have confirmed that quercetin is a direct inhibitor of phosphoinositide 3-kinase (PI3K) and NF-κB, as well as other kinases involved in intracellular signaling [58]. It is generally accepted that quercetin exerts therapeutic effects on malignant tumors, cardiovascular diseases, and cerebrovascular diseases. Song et al. [59] found that quercetin inhibits activation of the p38 mitogen-activated protein kinase/inducible nitric oxide synthase signaling pathway; accordingly, quercetin exerts therapeutic effects similar to those of MP. Furthermore, Wang et al. [60] demonstrated that quercetin promotes neurological recovery after SCI. Although there is no high-quality direct evidence that quercetin can improve nerve repair after SCI, it is reasonable to expect that quercetin plays a neuroprotective role in SCI repair. However, these hypotheses must be supported by experimental data.

3.9. Ligustrazine

Ligustrazine is the primary active ingredient of Chuanxiong [61]; it is mainly used for the treatment of central nervous system disorders, cardiovascular diseases, and kidney diseases [62]. Fan et al. [63] reported that ligustrazine promotes nerve repair after SCI by inhibiting the inflammatory response; Fan and Wu [64] reported that ligustrazine downregulates the expression of miR-214-3p and reduces neuronal apoptosis. Shin et al. [65] proposed that ligustrazine inhibits the activation of microglia, which is its primary mechanism for inhibiting the inflammatory response after SCI. Hu et al. [66] found that the therapeutic effects of ligustrazine on SCI are related to the expression of peroxisome proliferator-activated receptor-γ coactivator-1α, whereas Wang et al. [67] concluded that these effects are achieved by activation of the Akt/Nrf2/HO-1 signaling pathway. Ligustrazine also reportedly inhibits matrix metalloproteinase-2 and matrix metalloproteinase-9 activities, and reduces apoptosis in vascular endothelial cells, thereby promoting nerve regeneration after SCI [68].

Of the various TCM (traditional Chinese medicine) extracts, ligustrazine has considerable potential for the treatment of SCI because it influences many pathophysiological processes and coordinates a variety of links through the regulation of multiple signal pathways. Therefore, clinical trials of ligustrazine are important in the near future; a rational long-term approach to the treatment regimen for ligustrazine is also needed because its dosage and mode of administration have not yet been standardized and its long-term side effects have not been determined. Therefore, the support of in-depth research in these two directions should ensure the safety and reliability of future clinical trials.

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3.10. Ligustilide

Ligustilide is the main active ingredient in Angelica; it exerts anti-tussive, analgesic, anti-inflammatory, antitumor, vasodilatory, and neuroprotective effects [69–71]. Furthermore, Xiao et al. [72] demonstrated that ligustilide treatment promotes functional recovery in SCI rats and suppresses the SCI-induced production of reactive oxygen species, inducible nitric oxide synthase, inflammatory factors, and cJun N-terminal kinase signaling. Although there is a relative lack of studies regarding the effects of ligustilide on SCI, its role in this process is of considerable value based on its effects on other neurological diseases.

3.11. Apocynin

Apocynin is an active ingredient extracted from oleander and Apocynum venetum leaves that acts as a natural inhibitor of nicotinamide adenine dinucleotide phosphate oxidase [73]. Impellizzeri et al. [74] demonstrated that apocynin reduces the SCI-induced alteration of spinal cord tissues and improves motor function. Furthermore, Sun et al. [75] reported that the therapeutic effects of apocynin on SCI are related to the antiapoptotic and anti-inflammatory signaling pathways, downregulation of myeloperoxidase, and malondialdehyde levels, and upregulation of glutathione peroxidase and superoxide dismutase activities. However, the most appropriate dose and route of administration for apocynin remain unknown; the relevant underlying mechanisms have not yet been fully elucidated. Although the conditions for conducting clinical trials are not yet appropriate, it is possible that experimental evidence supporting the effectiveness of apocynin treatment will encourage further development in this area.

3.12. Schisandrin B

Schisandrin B is an active ingredient extracted from Schisandra Chinensis that has protective effects on various organs [76,77]. Furthermore, Xin et al. [78] found that Schisandra B attenuates inflammatory responses, oxidative stress, and apoptosis after SCI through inhibition of the p53 signaling pathway. However, the therapeutic effects of this compound remain uncertain; thus, clinical studies are needed to determine whether Schisandra B is effective for the treatment of SCI through its anti-inflammatory, antioxidant, and anti-apoptotic activities.

3.13. Rosmarinic acid and ursolic acid

Rosmarinic acid and ursolic acid are both diterpene compounds extracted from the rosemary of the Labiatae family, which inhibit pain and exert antioxidative activities [79]. Shang et al. [80] found that rosmarinic acid protects neurons against damage by targeting reactive oxygen species and reactive oxygen species-related inflammatory responses; these targeting activities reduce the nuclear localization of NFkB and increase the nuclear localization of Nrf-2. Similarly, Sahu et al. [81] showed that ursolic acid activates the PI3K/Akt/mTOR signaling pathway after SCI, which inhibits the inflammatory response and promotes the reconstruction of neurological functions

The anti-inflammatory, anti-apoptotic, and antioxidant properties of rosmarinic acid and ursolic acid improve inflammation at the SCI lesion site; thus, they improve structural remodeling and support functional recovery. Although there is a relative lack of research results regarding the specific mechanisms underlying these processes, our research group has recently made a breakthrough in this area. These experimental data have not yet been released, but indicate that rosmarinic acid and ursolic acid have obvious functions in terms of neuroprotection and the promotion of neural function reconstruction; moreover, these effects are directly related to multiple signaling pathways.

3.14. Salidroside

Rhodiola is one of the most commonly used Chinese herbal medicines in China; it is recorded in the Four Pharmacopoeia, as well as the Compendium of Materia Medica. The main active ingredient of Rhodiola is salidroside, which improves cognitive function and exerts antiarrhythmic, anti-inflammatory, and neuroprotective effects [82,83]. Song et al. [84] found that salidroside inhibits microglial polarization and reduces inflammatory responses by regulating the AMPK/mTOR signaling pathway. Although the neuroprotective effects of salidroside exhibit an obvious dose-response correlation, this relationship has not been confirmed; the most appropriate concentration remains unclear, despite the use of a gradient. Another issue associated with salidroside is whether different patients can achieve objective results under the same dose regimen.

3.15. Puerarin

Puerarin is an isoflavone derivative extracted from Pueraria lobata, which causes vasodilation, cardioprotection, neuroprotection, antioxidative effects, anti-cancer effects, anti-inflammatory effects, pain relief, bone formation, alcohol inhibition, and insulin resistance. It is widely used in clinical contexts to treat cardiovascular and cerebrovascular diseases, diabetes, central nervous system disorders, endometriosis, and various types of malignant cancer [85,86]. Tian et al. [87] found that puerarin upregulates the mRNA expression of thioredoxin and reduces neuronal apoptosis. Subsequent continuity studies from the same research group demonstrated that puerarin inhibits glutamate release, reduces the mRNA expression of metabotropic glutamate receptors [88], and reduces the levels of cyclin-dependent kinase 5 and p25 [89]; these changes reduce secondary damage after SCI. Zhang et al. [90] suggested that the therapeutic effects of puerarin on SCI are related to activation of the PI3K/Akt signaling pathway. Thus far, puerarin has been shown to exert neuroprotective effects in an ischemia-reperfusion model and the negotiation model of SCI; thus, there is no obvious correlation between the neuroprotective effects of puerarin and the mode of injury. Accordingly, puerarin is expected to become an important supplementary drug for the treatment of SCI.

3.16. Gastrodin

Gastrodin is the main active ingredient of Gastrodia elata, which is capable of increasing elasticity of the arterial wall, expanding blood vessels in the brain, increasing blood supply, producing calmness, inducing hypnotic effects, and relieving pain [91]. Song et al. [92] found that gastrodin stabilizes the tissue microenvironment after SCI, promotes the expression of neurotrophic factors, and contributes to the uniform distribution of these factors. Additionally, the antioxidant and anti-inflammatory effects of gastrodin have been confirmed; the molecular basis of these effects is known to involve the Nrf2-GCLc/GCLm signaling pathway [92]. Although current research findings indicate that gastrodin promotes the repair of motor function after SCI, this therapeutic effect is not directly induced via enhancements of nerve regeneration; it is induced by improvements in the local microenvironment. Following SCI, the local microenvironment is important for nerve regeneration; thus, the therapeutic effects of puerarin warrant further investigation

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4. Herbs of TCM (traditional Chinese medicine)

4.1. Panax

Panax (PNS) is a mixture of active ingredients extracted from Panax notoginseng (Burk) FH Chen (Araliaceae) that exerts anti-inflammatory, antiedema, antioxidative, and antiapoptotic effects [93]. The primary components of PNS include GS Rb1 (29.86%), Rg1 (20.46%), Rd (7.96%), Re (6.83%), and notoginsenoside R1 (2.74%).

Ning et al. [94] proposed that PNS attenuates the SCI-induced inflammatory cascade by inhibiting the expression of inflammatory factors at the damage site. Wang et al. [95] suggested that the therapeutic effects of PNS on SCI depend on the overexpression of stimulating neurotrophic factors, such as brain-derived neurotrophic factor and nerve growth factor. Moreover, recent findings [96] show that PNS inhibits axonal damage and apoptosis after SCI; it subsequently reduces the degree of damage. Regardless of the underlying mechanisms, the therapeutic effects of PNS on SCI are due to its anti-inflammatory, antiapoptotic, and antioxidative activities.

4.2. Salvia

The genus Salvia is the largest genera of the Lamiaceae family and includes more than 40 Salvia-related herbs that are used in clinical TCM(traditional Chinese medicine) treatments [97]. The major phytochemical constituents of Salvia species include diterpenoids, phenolic acids, triterpenoids, flavonoids, and saccharides [98]. Thus far, many studies have demonstrated that Salvia miltiorrhiza exerts anti-inflammatory, antiviral, antitumor, antioxidative, and antihypoxic effects; it also protects the liver and cardiovascular system [99].

Quality control of Salvia by the Chinese government primarily relies on the detection of tanshinone IIa [100]. Since Zhang et al. [101] first reported that tanshinone IIa reduces SCI-induced damage by increasing the expression levels of HSP70 and Bcl-2 and by inhibiting the expression of Bax, the therapeutic effects of S. miltiorrhiza on SCI have been reported frequently. Additionally, the therapeutic effects of tanshinone IIa on SCI are reportedly closely related to its anti-inflammatory activities, which are presumed to produce the same results as MP [102,103]. Likewise, Wei and Zhang [104] and Yu et al. [105] demonstrated that intraperitoneal and subarachnoid injections of Salvia alleviate inflammatory reactions and apoptosis after SCI.

4.3. Angelica

Angelica plays an important role in TCM (traditional Chinese medicine) in terms of promoting blood circulation, regulating menstruation, and lubricating the intestines [106]. Xu et al. [107] found that Angelica inhibits the release of pro-inflammatory factors after SCI, thereby reducing the degree of injury. Additionally, Yang et al. [108] showed that Angelica can enhance the recovery of evoked potentials after SCI, and can improve motor function. Xie et al. [109] reported that Angelica alleviates oxidative stress-induced damage in nerve cells by inhibiting cyclooxygenase-1 and activating the PI3K/Akt signaling pathway.

4.4. Epimedium

According to TCM (traditional Chinese medicine) theory, Epimedium is the most important herb to “nourish kidney and strengthen yang” [110]. Chemical analyses demonstrated that more than 260 active ingredients (e.g., flavonoids, polysaccharides, essential oils, plant sterols, phenolic acids, and alkaloids) can be extracted from Epimedium [111]. Tohda and Nagata [112] administered a methanol extract of Epimedium to SCI rats, which improved the rats’ capacity for exercise. Similarly, Ren et al. [113] reported that the administration of an Epimedium extract reduces malondialdehyde content, increases superoxide dismutase activity, improves lipid peroxidation, and reduces spinal cord damage. Li et al. [114] showed that Epimedium inhibits neuronal apoptosis and protects damaged spinal nerve functions by activating the PI3K/Akt signaling pathway. Furthermore, Epimedium inhibits the mitochondrial apoptotic pathway to attenuate proinflammatory factors and oxidative stress, which may be a key mechanism underlying the enhancement of exercise recovery after SCI [115].

4.5. Lycium barbarum

Lycium barbarum (LB) is one of the most popular medicinal health foods in China; according to Chinese medicine theory, LB is presumed to delay aging. Experimental studies have shown that LB preserves eyesight [116], is immunomodulatory [117], protects against oxidative stress [118], and exerts antitumor effects [119]. The neuroprotective effects of LB are mainly related to its abilities to reduce cellular oxidative stress, reduce inflammation, protect against neuronal apoptosis, improve neurotransmission, and—potentially the most important mechanism underlying these effects—alter the mitogen-activated protein kinase signaling pathway [120]. Zhang et al. [121] found that the therapeutic effects of LB in SCI are associated with M1 and M2 macrophages. More specifically, in the beginning, stages of SCI, the administration of LB enhances M1 macrophages while suppressing M2 macrophages; beginning in the second week after injury, administration of LB has significant beneficial effects in terms of reducing secondary injury. Niu et al. [122] found that LB might affect apoptosis after SCI via miR-194-mediated activation of the PI3K/Akt pathway.

4.6. Astragalus

Astragalus (AS) is a widely distributed herb in China that has been clinically applied for more than 2,000 years. TCM (traditional Chinese medicine) doctors consider AS to enhance immune functions; protect the liver; induce diuresis; and exert antiaging, antistress, antihypertensive, and antibacterial effects [123]. Zhou et al. [124] found that AS protects nerve fibers after SCI by reducing the expression of aquaporin-4; Yu et al. [125] showed that AS induces the differentiation of bone marrow mesenchymal stem cells into neurons in a rat model of SCI.

4.7. Crocus

Crocus is essentially the upper part and stigma of the style of the iris family; it is a valuable Chinese herbal medicine used for “blood-activating blood stasis, [and] dispelling stagnation.” The pharmacological effects of crocus include immunomodulatory, anti-inflammatory, and antioxidative stress activities [126]; chemical analysis of crocus extract [127] revealed that the main components of crocus are several carotenoids, including crocins, crocetin, picrocrocin, and safranal. Wang et al. [128] performed in vitro and in vivo experiments; they showed that crocus enhances the growth of neurons and promotes the recovery of nerve function after SCI. They also suggested that these effects are not mediated by the anti-inflammatory activities of crocus, but are related to the repair of injury-induced damage to neuronal connections through inhibition of the chondroitin sulfate proteoglycan and NogoA signaling pathways.

4.8. Huang qin

Huang qin is a perennial herb of the genus Scutellaria, which is widely distributed throughout China. Its roots function as an herbal TCM (traditional Chinese medicine) and have a long history of use [129]. Thus far, more than 30 active ingredients have been extracted from its roots (e.g., baicalin, baicalein, wogonin, wogonin 7-O-glucuronide, pyroxylin A, and pyroxylin A 7-Oglucuronide) [130]. Similar to its roots, the stems and leaves of Huang qin are rich in flavonoids and phenolic acids (e.g., ferulic acid, p-hydroxybenzoic acid, caffeic acid, scutellarin, wogonin, p-coumaric acid, baicalin, baicalein, chrysin, and wogonoside) [131]. Yune et al. [132] found that the neuroprotective effects of Huang qin following SCI are related to its anti-inflammatory and antioxidant activities; Zhang et al. [133] showed that Huang qin increases axonal regeneration, inhibits microglial activation, and modulates the bidirectional regulation of reactive astrocytes. Moreover, Li et al. [134] suggested that Huang qin can activate autophagy and inhibit apoptosis through the PI3K signaling pathway.

4.9. Cistanche deserticola

Cistanche deserticola is a parasitic plant that grows in the deserts of northwestern China and is thought to tonify the kidney and strengthen the yang; therefore, it is known as “desert ginseng” [135]. Zhang et al. [136] found that C. deserticola effectively inhibits cellular apoptosis, reduces oxidative stress, and attenuates the inflammatory response after SCI; these changes promote neurological recovery.

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5. Compound TCM (traditional Chinese medicine) prescriptions

5.1. Buyang Huanwu Decoction

Buyang Huanwu Decoction (BYHWD) is a TCM (traditional Chinese medicine) compound prescription recorded by Wang Qingren, who was a well-known medical scientist in the Qing Dynasty. BYHWD acts to tonify qi, as well as to promote blood circulation and collaterals. This compound is primarily used for various types of hemiplegia and paraplegia caused by cardiovascular and cerebrovascular diseases [137]; modern medical experiments have shown that BYHWD has neuroprotective effects [138]. For example, Chen et al. [139] used BYHWD in the treatment of experimental SCI; they found that it promotes the recovery of nerve function by inhibiting neuronal apoptosis after SCI. Wang and Jiang [140] also investigated the therapeutic role of BYHWD in SCI; they reported that its therapeutic effects are closely related to the upregulation of thioredoxin transcription. Xian et al. [141] proposed that the molecular mechanisms underlying BYHWD-induced inhibition of apoptosis in SCI are related to reductions in the expression levels of caspase-3 and Bax, as well as an increase in the expression of Bcl-2. Zheng et al. [142] successfully induced the differentiation of bone marrow mesenchymal stem cells into neurons using BYHWD, which was a seminal finding that provided novel information for the use of this compound to treat SCI. Zhang et al. [143] found that the administration of BYHWD as a supportive treatment can further optimize the therapeutic effects associated with the transplantation of neural stem cells.

5.2. Jisuikang

Jisuikang (Chinese national invention patent: ZL200910026193.7) is a Chinese herbal compound for the treatment of SCI, developed by the Ma Yong research group of Nanjing University of TraditionalChinese Medicine. The compound consists of AS, Salvia, Chuanxiong, Chishao, Angelica, Shuiyu, Sui, Rhubarb, Alisma, Poria, Magnolia, Cistanche, Xianling Spleen, Earthworm, Psyllium, and Yizhi in specific proportions. Wang et al. [144] found that Jisuikang prevents the secondary damage induced by SCI by inhibiting the expression of nitric oxide synthase expression, reducing levels of nitric oxide and tumor necrosis factor-α levels, and reducing superoxide dismutase activity. Additionally, Guo et al. [145] demonstrated that Jisuikang promotes the expression of nerve growth factor and brain-derived neurotrophic factor, improves regeneration of the axonal microenvironment, and enhances the recovery of neurological functions after SCI. You et al. [146] showed that the therapeutic effects of Jisuikang in SCI are closely related to activation of the Nogo-NgR signaling pathway.

5.3. Zhenbao Pill

The Zhenbao Pill is a TCM (traditional Chinese medicine) compound invented by Mongolian doctors in China that serves to clear heat, calm nerves, relax muscles, and remove “Xie Riwusu.” The Zhenbao Pill formula includes valuable Chinese herbal medicines (e.g., safflower, nutmeg, white cardamom, cassia seed, grass nut, castor bean, agarwood, musk, bezoar, buffalo horn, and pearl) [147]. He et al. [148] found that the Zhenbao Pill alleviates neuronal apoptosis by regulating the expression of miR-146a5p/GPR17, which positively influences the recovery of neurological function after SCI. Subsequent continuity research showed that the Zhenbao Pill also reduces the number of Treg cells after SCI; this regulation is closely related to the TUG1/miR-214/HSP27 axis [149,150].

6. Prospects

As a serious central nervous system disorder, SCI can be devastating to patients, their families, and society in general. These issues are reflected in the neurological deficits of patients, as well as in the negative emotions and survival burden associated with the loss of ability to work. Although serious social harm is caused by this disorder, there are currently no effective treatments for reconstructing the severely damaged nerve functions of patients with SCI. Therefore, the basic goals of current SCI research involve helping patients with SCI “stand up” and “care for their own life.” However, the achievement of these goals would not be a true victory because the meaning of existence involves more than simply remaining alive; humans must enjoy life by creating life. This broader goal suggests that treatment for SCI involves more than a simple restoration of the fundamental progression from squatting to standing; it also involves the difficult journey from the use of a wheelchair to the return to work. Thus, joint efforts by many fields are needed to achieve a satisfactory result.

Although it is a difficult challenge, the findings of many studies related to tissue engineering, cell transplantation, and molecules are continually applied to the field of SCI. Accordingly, TCM (traditional Chinese medicine) methods for the treatment of SCI have great prospects for further development. Although research regarding natural TCM compounds is the most rapidly growing area among these various fields, this type of research does not fully implement the concept of “harmony, dialectical development” that is inherent to TCM. Because of their complex compositions, the synergistic actions and multi-target effects of TCM herbs and compound prescriptions can compensate for the inevitable limitations of chemical drug applications. Moreover, research regarding TCM herbs and compound prescriptions continues to be widely published in journals with low influence. This phenomenon indirectly suggests that such studies remain part of an emerging field, rather than an established field; importantly, they have not been systematically assessed. Thus, this research field requires additional in-depth studies to promote better development. Accordingly, we propose the following actions:

(1) in-depth explorations of the relevant indications of compound prescriptions and herbs recorded in ancient Chinese medicine books, as well as identification of appropriate treatments for SCI in Chinese medicine treatment programs;

(2) clarification of the chemical compositions of Chinese herbs and compound prescriptions, as well as the establishment of uniform drug quality control standards;

(3) intensive research assessing the pharmacology and toxicology of Chinese herbs and compound prescriptions to elucidate their underlying mechanisms of action and evaluate their safety characteristics;

(4) use Chinese herbs and compound prescriptions as supplementary treatments, in combination with comprehensive research of tissue scaffolds and cellular and molecular therapies, to fully evaluate the advantages of combining TCM (traditional Chinese medicine) methods with modern Western medical techniques;

(5) use the results of chemical composition analyses and monomer research to improve existing TCM (traditional Chinese medicine) compounds and implement the replacement of expensive medicines with more inexpensive medicines, with the goal of ensuring efficacy and safety to enhance the economic efficiency of treatment plans;

(6) use existing research results to develop novel TCM (traditional Chinese medicine) compounds based on the principle of compatibility of TCM (traditional Chinese medicine) herbs and compounds;

(7) optimize the formulation technology for novel drugs with obvious effects and actively promote their clinical applications.

Cistanche supplements

Author contributions

YB Lu (luyb16@lzu.edu.cn) designed the study and completed the first draft. JJ Yang (yangjj2018@lzu.edu.cn) made corrections in the language. ZJ Ma (974178036@qq.com) and XX Wang(wangxuexi@lzu.e.du.cn) made professional revisions to the article. L Lu (lul@lzu.edu.cn) and S Li (lisheng76@sohu.com) retrieved and compiled the references.

Declaration of interests

The authors declare that there are no conflicts of interest regarding the publication of this article.

Acknowledgments

This work was supported by grants from the Chinese Medicine Administration Research Project of Gansu province (GZK-2019-46), the Science and Technology Plan Project of Qinghai province(2018-ZJ-756, 2019-HZ-819), and the foundation of key laboratory of Chinese medicine innovation and transformation in Gansu Province/Chinese medicine product engineering laboratory of Gansu Province (ZYFYZH-KJ-2016- 004).

From:' Research progress in the use of traditional Chinese medicine for the treatment of spinal cord injury' by Yubao Lua, et al

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