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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Research progress in use of traditional Chinese medicine for treatment of
spinal cord injury
Yubao Lu
a,1
, Jingjing Yang
a,1
, Xuexi Wang
b,
*, Zhanjun Ma
a,
**, Sheng Li
c
, Zhaoyang Liu
d
,
Xuegong Fan
b
a
The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
b
School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
c
Lanzhou First People's Hospital, Lanzhou, Gansu 730000, China
d
Department of Medical Imaging, Shanxi Medical University, Jinzhong, Shanxi 030600, China
ARTICLE INFO
Keywords:
Traditional Chinese medicine
Spinal cord injury
Nerve repair
Active ingredient
Compound prescription
ABSTRACT
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 treatments for SCI, with the aims 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 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 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 an-
tioxidative, anti-inflammatory, neuroprotective, and/or antiapoptotic effects of TCM compounds.
Conclusions: This paper showed that TCM treatments can serve as promising auxiliary therapies for functional
recovery of patients with SCI. These findings will contribute to the development of diversified treatments for SCI.
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 ef-
fectively decompress the damaged spinal cord and remove local sti-
mulants in a timely manner, which stabilizes the condition [4]. Fol-
lowing decompressive surgery for SCI, MP reduces perioperative
neurological complications by protecting neurons from inflammation,
https://doi.org/10.1016/j.biopha.2020.110136
Received 14 February 2020; Received in revised form 17 March 2020; Accepted 30 March 2020
Abbreviations: AF, Albiflorin; AS, Astragalus; BBB, Basso-Beattie-Bresnahan; BMSCs, Bone marrow mesenchymal stem cells; Burk, Panax notoginseng; BYHWD,
Buyang Huanwu Decoction; CAT, catalase; TCM, Traditional chinese medicine; EGCG, Epigallocatechin-3-gallate; GFAP, Glial fibrillary acidic protein; GPx,
Peroxidase; GS, Ginsenoside; GSH, Glutathione; LB, Lycium barbarum; MDA, Malondialdehyde; MP, Methylprednisolone; OS, Oxidative stress; PF, Paeoniflorin; PNS,
Panax; RA, Rosmarinic acid; RES, Resveratrol; SCI, Spinal cord injury; SOD, Superoxide dismutase; TNF-α, Tumor necrosis factor-α; UA, Ursolic acid
⁎
Corresponding author at: School of Basic Medical Sciences of Lanzhou University, School of Medicine 205 Tianshui Rd South Lanzhou, Gansu 730000, China.
⁎⁎
Corresponding author at: The Second Clinical Medical College of Lanzhou University, No. 82 Cuiyingmen Lanzhou 730030, Gansu 730000, China.
E-mail addresses: wangxuexi@lzu.edu.cn (X. Wang), 974178036@qq.com (Z. Ma).
1
These authors contributed equally to this study and share first authorship.
Biomedicine & Pharmacotherapy 127 (2020) 110136
0753-3322/ © 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T
as well as by reducing secondary oxidative stress and inflammatory
responses without compromising the composition of circulating im-
mune 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]. Further-
more, 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 treatment of SCI remains controversial.
Accordingly, the identification and development of safe and effec-
tive treatments for SCI have significant value in both clinical and social
contexts. Many novel treatment concepts have been proposed by re-
searchers 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 im-
portant 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 is primarily due to its long
history and rich catalogue of medical resources. Accordingly, the use of
TCM 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 compounds
exert varying degrees of therapeutic effects on SCI [11–13]. However,
in the current clinical atmosphere, TCM methods cannot completely
replace currently used surgery and hormone therapy techniques; thus,
TCM 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 fea-
sible 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 patho-
physiological reactions to SCI. This process occurs within a few minutes
to several weeks after the spinal cord is destroyed; therefore, it is re-
ferred to as the “secondary injury”[15]. This secondary damage in-
cludes 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 re-
sponse after SCI, which occurs in a wide range of cells (e.g., neu-
rons, microglia, astrocytes, and oligodendrocytes) at different
stages of damage [19];
(4) destruction of ionic balances among sodium (Na
+
), potassium
(K
+
), and calcium (Ca
2+
), which leads to depolarization of cell
membranes [20];
(5) glutamate excitotoxicity, associated with elevated glutamate re-
lease 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-αand
subsequent release of inflammatory cytokines (e.g., interleukin-1α,
interleukin-1β, and interleukin-6) that elicit a cascade of in-
flammatory 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 fi-
brillary acidic protein is released to encapsulate the damaged spinal
cord tissue through 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 ingredients
Active ingredients associated with TCM are shown in Fig. 1 and
Table 1.
3.1. Resveratrol
Resveratrol (RES) is a natural polyphenol with antioxidant proper-
ties 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 ob-
served significant improvements based on Basso-Beattie-Bresnahan
scores. Histological, immunohistochemical, and ultrastructural ex-
aminations 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 sig-
naling pathway.
Other studies have shown that RES improves the prognosis of pa-
tients 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 fur-
ther 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 in-
flammation, 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.
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, anti-
viral, 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
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
2
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 expression of glial fibrillary acidic protein [29];
reducing tissue levels of malondialdehyde; increasing the tissue activ-
ities 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 N-
methyl-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 ad-
ministration 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 cur-
cumin. 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 ex-
tracted 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 treatment of SCI, there is
insufficient research regarding its effects and the underlying mechan-
isms are not fully understood. These issues largely limit the use of GS
for treatment of SCI. Therefore, research regarding the molecular me-
chanisms 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 ex-
tracted from green tea, which is a traditional Chinese health drink [39].
EGCG has antibacterial, antiviral, antioxidative, antiarteriosclerotic,
antithrombotic, antiangiogenic, anti-inflammatory, and antitumor ef-
fects; 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,
Fig. 1. The role and related signaling pathways of active ingredients from different traditional chinese medicines in the repair of spinal cord injury.
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
3
Table 1
Active ingredient of TCM potential therapeutic effects on spinal cord injury.
Name Source Molecular Structure Anti-
inflammatory
Antiapoptosis Antioxidant
stress
Promote
axonal
growth
Signal path Model References
Resveratrol cassia, gourd,
knotweed.
√√√ ①SIRT1 /
AMPK
①Rat model of
spinal cord
contusion；
[23] Rauf et al.
(A) cis-resveratrol; ②AMPK/
mTOR
②Allen's rat SCI
model；
[24] Liu et al.
(B) trans-resveratrol. [25] Zhao et al.
[26] Zhou et al.
Curcumin turmeric √√√√NF-κB Rat model of
spinal
hemisection；
[27] Akter et al.
(A)Demethoxycurcumin; Rat model of
spinal
compression；
[28]
Kunnumakkara
et al.
(B) Bisdemethoxycurcumin. Rat model of
spinal cord
contusion；
[29] Lin et al.
Olfactory
ensheathing
cell
[30] Cemil et al.
[31] Ormond
et al.
[32] Zhang et al.
Ginsenoside ginseng √√√- eNOS/
Nrf2/HO-1
Spinal cord
ischemia-
reperfusion
model in rats；
[34] Biswas T
et al.
Ocotillol; Rat model of
spinal cord
contusion；
[35] Kim et al.
Protopanaxadiol; Rat model of
spinal
compression；
[36] Huang
et al.
Protopanaxatrial; [37] Kim et al.
Olenanolic acid. [38] Zhao et al.
Epigallocatechin-
3-gallate
green tea √√√√-①Rat model of
spinal cord
contusion；
[39] Chu et al.
②Balloon
compression
model
[40] Singh et al.
[41] Khalatbary
et al. [42]
Khalatbary and
Ahmadvand
[43] Tian et al.
[44] Machova
Urdzikova et al.
Paeoniflorin Peony √---①NF-κB Rat model of
spinal
compression；
[45] Wang et al.
Albiflorin
Taxol Taxus spp √--√-①Rat model of
spinal
hemisection
[49] Howat
et al.
(continued on next page)
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
4
Table 1 (continued)
Name Source Molecular Structure Anti-
inflammatory
Antiapoptosis Antioxidant
stress
Promote
axonal
growth
Signal path Model References
②Long-
distance spinal
cord complete
transection in
canines
[50] Zhang et al.
[51] Hellal et al.
[52] Popovich
et al.
[53] Yin et al.
Emodin Rhubarb √√- Nrf2/ARE Allen's rat SCI
model；
[54] Yang et al.
[55] Zeng et al.
Quercetin Aesculus indica
fruit; Codonopsis;
Chrysanthemum;
Prunella vulgaris
√√-√p38MAPK/
iNOS
Allen's rat SCI
model；
[56] Zahoor
et al.
[57] Nutrient
Data Laboratory
[58]
Chirumbolo
[59] Song et al.
[60] Wang et al.
Ligustrazine Chuanxiong √√-√Akt/Nrf2/
HO-1
①Spinal cord
ischemia-
reperfusion
model in rats；
[62] Zou et al.
②Allen's rat SCI
model；
[63] Fan et al.
Rat model of
spinal
compression；
[64] Fan and
Wu
Rat model of
spinal cord
contusion；
[65] Shin et al.
[66] Hu et al.
[67] Wang et al.
[68] Hu et al.
Ligustilide Angelica √- - - - Rat model of
spinal
hemisection；
[69] Zuo et al.
[70] Su et al.
[71] Li et al.
[72] Xiao et al.
Apocynin Oleander
；Apocynum
venetum leaves
√√√- - Rat model of
spinal
compression；
[73] Qin YY
et al.
[74]
Impellizzeri
et al.
[75] Sun et al.
Schisandrin B Schisandra
chinensis
√√√- P53 Rat model of
spinal cord
contusion；
[76] Lam and
Ko
[77] Leong PK
and Ko KM
[78] Xin et al.
(continued on next page)
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
5
and induction of high levels of axonal sprouting.
Although research results regarding EGCG currently remain limited,
the literature suggests that this compound can reduce nerve damage
after SCI through anti-inflammatory, antioxidative, and antibiological
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 uses PF and AF as treatments for gynecolo-
gical 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 al-
leviate 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 potential for use as future sources of natural treatment
strategies that may reduce the progression of secondary injury fol-
lowing 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 ap-
plications in 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 treatment
of various malignant tumors [49]. Many studies have demonstrated that
paclitaxel can also be used in treatment of skin disorders, renal and
hepatic fibrosis, inflammation, axonal regeneration, limb salvage, and
coronary artery restenosis [50]. Hellal et al. [51] reported that pacli-
taxel 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 ex-
ample, 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, pacli-
taxel has been confirmed to inhibit the production of glial scars, which
contributes to local and microenvironmental conditions for the treat-
ment of SCI. Therefore, paclitaxel can be used as an effective supple-
mentary therapy for nerve repair after primary SCI. An important
premise of paclitaxel application is its combined use with other thera-
pies 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 me-
chanism in studies of SCI, the value of research regarding the role of
Table 1 (continued)
Name Source Molecular Structure Anti-
inflammatory
Antiapoptosis Antioxidant
stress
Promote
axonal
growth
Signal path Model References
Rosmarinic acid Rosemary √√√- Allen's rat SCI
model；
[80] Shang et al.
Ursolic acid PI3K/Akt /
mTOR
Mouse model
of spinal
compression；
[81] Sahu et al.
Salidroside Rhodiola √√- - AMPK/
mTOR
Rat model of
spinal
compression；
[84] Song et al.
BV-2
inflammation
model
Puerarin Pueraria lobata √√√- PI3K/Akt Spinal cord
ischemia-
reperfusion
model in rats；
[87–89]Tian
et al.
Allen's rat SCI
model；
[90] Zhang,
et al.
Gastrodin Gastrodia elata √√- Nrf2-
GCLc/
GCLm
Allen's rat SCI
model；
[92] Song et al.
[93] Du et al.
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
6
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 in-
tracellular 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 ther-
apeutic 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] re-
ported 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 acti-
vation of microglia, which is its primary mechanism for inhibiting the
inflammatory response after SCI. Hu et al. [66] found that the ther-
apeutic effects of ligustrazine on SCI are related to the expression of
peroxisome proliferator-activated receptor-γcoactivator-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 extracts, ligustrazine has considerable potential
for treatment of SCI because it influences many pathophysiological
processes and coordinates a variety of links through 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, support of
in-depth research in these two directions should ensure the safety and
reliability of future clinical trials.
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] demon-
strated 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 c-
Jun 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 dis-
eases.
3.11. Apocynin
Apocynin is an active ingredient extracted from oleander and
Apocynum venetum leaves that acts as a natural inhibitor of nicotina-
mide 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 ac-
tivities. However, the most appropriate dose and route of administra-
tion for apocynin remain unknown; the relevant underlying mechan-
isms 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 treat-
ment 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]. Fur-
thermore, Xin et al. [78] found that schisandrin B attenuates in-
flammatory responses, oxidative stress, and apoptosis after SCI through
inhibition of the p53 signaling pathway. However, the therapeutic ef-
fects of this compound remain uncertain; thus, clinical studies are
needed to determine whether schisandrin B is effective for treatment of
SCI through its anti-inflammatory, antioxidant, and antiapoptotic ac-
tivities.
3.13. Rosmarinic acid and ursolic acid
Rosmarinic acid and ursolic acid are both diterpene compounds
extracted from rosemary of the Labiatae family, which inhibit pain and
exert antioxidative activities [79]. Shang et al. [80] found that ros-
marinic acid protects neurons against damage by targeting reactive
oxygen species and reactive oxygen species-related inflammatory re-
sponses; these targeting activities reduce the nuclear localization of NF-
kB 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 pro-
motes reconstruction of neurological functions.
The anti-inflammatory, antiapoptotic, 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 pro-
motion 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 medi-
cines 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 antiar-
rhythmic, 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 sig-
naling 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
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
7
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, anti-
oxidative effects, anticancer effects, anti-inflammatory effects, pain
relief, bone formation, alcohol inhibition, and insulin resistance. It is
widely used in clinical contexts to treat cardiovascular and cere-
brovascular diseases, diabetes, central nervous system disorders, en-
dometriosis, and various types of malignant cancer [85,86]. Tian et al.
[87] found that puerarin upregulates the mRNA expression of thior-
edoxin and reduces neuronal apoptosis. Subsequent continuity studies
from the same research group demonstrated that puerarin inhibits
glutamate release, reduces the mRNA expression of metabotropic glu-
tamate receptors [88], and reduces the levels of cyclin-dependent ki-
nase 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, in-
ducing hypnotic effects, and relieving pain [91]. Song et al. [92] found
that gastrodin stabilizes the tissue microenvironment after SCI, pro-
motes 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 mole-
cular 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 micro-
environment. Following SCI, the local microenvironment is important
for nerve regeneration; thus, the therapeutic effects of puerarin warrant
further investigation.
4. Herbs of TCM
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 in-
flammatory cascade by inhibiting 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 neuro-
trophic 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, an-
tiapoptotic, 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
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, anti-
oxidative, and antihypoxic effects; it also protects the liver and cardi-
ovascular 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 ex-
pression of Bax, the therapeutic effects of S. miltiorrhiza on SCI have
been reported frequently. Additionally, the therapeutic effects of tan-
shinone IIa on SCI are reportedly closely related to its anti-in-
flammatory 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 in terms of promoting blood
circulation, regulating menstruation, and lubricating the intestines
[106]. Xu et al. [107] found that Angelica inhibits the release of
proinflammatory factors after SCI, thereby reducing the degree of in-
jury. 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 theory, Epimedium is the most important herb to
“nourish kidney and strengthen yang”[110]. Chemical analyses de-
monstrated that more than 260 active ingredients (e.g., flavonoids,
polysaccharides, essential oils, plant sterols, phenolic acids, and alka-
loids) can be extracted from Epimedium [111]. Tohda and Nagata [112]
administered a methanol extract of Epimedium to SCI rats, which im-
proved the rats’capacity for exercise. Similarly, Ren et al. [113] re-
ported that the administration of an Epimedium extract reduces mal-
ondialdehyde 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 ex-
ercise 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 oxi-
dative stress, reduce inflammation, protect against neuronal apoptosis,
improve neurotransmission, and—potentially the most important me-
chanism 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
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
8
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 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-acti-
vating 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 car-
otenoids, 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 re-
lated 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 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, oroxylin A, and oroxylin A 7-O-
glucuronide) [130]. Similar to its roots, the stems and leaves of Huang
qin are rich in flavonoids and phenolic acids (e.g., ferulic acid, p-hy-
droxybenzoic 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 sig-
naling 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.
5. Compound TCM prescriptions
5.1. Buyang Huanwu Decoction
Buyang Huanwu Decoction (BYHWD) is a TCM compound pre-
scription 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 cardio-
vascular and cerebrovascular diseases [137]; modern medical experi-
ments have shown that BYHWD has neuroprotective effects [138]. For
example, Chen et al. [139] used BYHWD in treatment of experimental
SCI; they found that it promotes the recovery of nerve function by in-
hibiting neuronal apoptosis after SCI. Wang and Jiang [140] also in-
vestigated 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 mechan-
isms 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] suc-
cessfully 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 sup-
portive treatment can further optimize the therapeutic effects asso-
ciated 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 Traditional
Chinese 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 sec-
ondary damage induced by SCI by inhibiting expression of nitric oxide
synthase expression, reducing levels of nitric oxide and tumor necrosis
factor-αlevels, and reducing superoxide dismutase activity. Ad-
ditionally, 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 compound invented by Mongolian doc-
tors 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-146a-
5p/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 reg-
ulation 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 re-
flected in the neurological deficits of patients, as well as in the negative
emotions and survival burden associated with the loss of ability to
Y. Lu, et al. Biomedicine & Pharmacotherapy 127 (2020) 110136
9
work. Although serious social harm is caused by this disorder, there are
currently no effective treatments for reconstructing the severely da-
maged 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, 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
simple restoration of the fundamental progression from squatting to
standing; it also involves the difficult journey from 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 methods for
the treatment of SCI have great prospects for further development.
Although research regarding natural TCM compounds is the most ra-
pidly growing area among these various fields, this type of research
does not fully implement the concept of “harmony, dialectical devel-
opment”that is inherent to TCM. Because of their complex composi-
tions, 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 jour-
nals 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 establishment of uniform drug
quality control standards;
(3) intensive research assessing the pharmacology and toxicology of
Chinese herbs and compound prescriptions to elucidate their un-
derlying mechanisms of action and evaluate their safety char-
acteristics;
(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 methods with modern Western
medical techniques;
(5) use the results of chemical composition analyses and monomer re-
search to improve existing TCM compounds and implement the
replacement of expensive medicines with more inexpensive medi-
cines, 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 compounds
based on the principle of compatibility of TCM herbs and com-
pounds;
(7) optimize the formulation technology for novel drugs with obvious
effects and actively promote their clinical applications.
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 lan-
guage. 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),
Science and Technology Plan Project of Qinghai province(2018-ZJ-756,
2019-HZ-819), and 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).
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