4 | CAP RELATED DISEASES AND CHINESE HERBAL
MEDICINE
According to existing research reports, diseases related to CAP mainly
include sepsis, ALI, AD, cardiovascular and cerebrovascular diseases,
arthritis, diabetes, etc. The relevant inflammatory diseases treated by
CHM summarized in this review are shown in Figure 3. In connection with
these diseases, the external treatment of vagal nerve stimulation such
as acupuncture or CHM can be intervened from anti-inflammatory methods.
Among them, due to the multicomponent-multitarget-multipathway
characteristics of CHM, its anti-inflammatory mechanism may be exerted
by multiple pathways. That is, through CAP alone, through
non-cholinergic anti-inflammatory pathways, or their common effect.
Whether it exerts anti-inflammatory effects through CAP and becomes a
potential drug for more diseases has been further developed. Information
on the role of CHM through CAP treatment is shown in Table 1.
4.1 | ALI
ALI is a common critical illness in respiratory medicine. It represents
one of the earliest complications with the highest incidence after
infection or severe trauma. The disease is swift and susceptible to turn
into acute respiratory distress syndrome (ARDS). The mortality rate of
ARDS is still high at 40%, ALI and sepsis are important causes of ARDS.
In COVID-19, ALI and ARDS are the main pathophysiological changes in
critically ill patients. Lung is a place where inflammatory cells
activate and accumulate. Endotoxin activates pulmonary vascular
endothelial cells and macrophages, releasing large amounts of cytokines
and inflammatory mediators. Lung tissue is first damaged by the
excessive inflammatory response due to excessive inflammation of lung
(Wallace & Donnelly, 2002). α7nAChR is also found on lung epithelial
cells, endothelial cells, alveolar macrophages, and neutrophils in ALI
mice induced by LPS and live E. coli (Su, Matthay, & Malik, 2010).
During lung infection and inflammation, alveolar macrophages produce
MIP-2 and attract neutrophils to migrate into alveoli, and these
neutrophil infiltrations also express α7nAChR. The release of ACh from
vagal nerve endings in distal airways, lung epithelial cells, immune
cells, and neuroendocrine cells also produce non-neuronal ACh. Positive
feedback between ACh and α7nAChR helps maintain ACh concentration (Wu,
Li, & Su, 2014). The anti-inflammatory effect of CAP in ALI is closely
associated with α7nAChR activation, as well as its downstream NF-κB and
JAK/STAT pathways. Moreover, ROS-induced oxidative stress and cell
damage are also related to the development of lung injury. α7nAChR
protects cells against oxidative stress and thus play a neuroprotective
role. After inhibiting α7nAChR gene, the oxidative stress level is
significantly enhanced. Therefore, effective regulation of CAP in ALI is
beneficial to the control of inflammation.
CHM prescriptions . Liang-Ge-San is published in ”Taiping Huimin
Heji Ju Fang”, which is a famous prescription for clearing away heat and
reducing fire. Its anti-inflammatory mechanism is mediated through the
NF-κB, MAPK, JAK-STAT pathways, adjusting the 1 / 2 T helper cells ratio
to regulate immunity. It is commonly used for ALI, pharyngitis and
tonsillitis in clinical practice. It significantly inhibited IL-6 and
TNF-α production, the degradation and phosphorylation of IκBα, and
nuclear translocation of NF-κB p65 in RAW 264.7 macrophages stimulated
with LPS. After activating α7nAChR, selective inhibitor
methyllycaconitine (MLA) or α7nAChR siRNA blocked α7nAChR, and the
inhibitory effects of Liang-Ge-San were all weakened (J. S. Liu et al.,
2016). Therefore, Liang-Ge-San can prevent ALI induced by LPS through
CAP.
Single herb . Scutellariae Radix is a dried root ofScutellaria baicalensis Georgi, which is widely used in acute
infections treatment. It has anti-inflammatory, antipyretic,
antiendotoxin and other pharmacological effects, which are associated
with inhibition of NF-κB pathway. Scutellariae Radix significantly
reduced the wet-dry mass ratio of lung tissue in LPS-induced ALI rats,
decreased body temperature, lowered serum TNF-α and NO levels, increased
ACh levels, and improved lung tissue inflammatory lesions. Its effect on
CAP may play an anti-inflammatory effect on indirect transient release
promotion, which has nothing to do with biosynthesis (Cui, Meng, Wang,
Li, & Yu, 2012). Coptidis Rhizoma is the dried root of Coptis
chinensis Franch., Coptis deltoidei C.Y.Cheng et Hsiao,Coptis teeta Wall. It is commonly used in the treatment of upper
respiratory tract infection, cough, jaundice, pneumonia, dysentery,
hypertension, etc. It has anti-inflammatory, antiviral, and
antihypertensive effects, it is also related to the NF-κB pathway.
Coptidis Rhizoma significantly reduced the wet-dry mass ratio of lung
tissue, enhanced lung tissue activity, and reduced serum TNF-α and NO
levels, but had no significant effect on ACh and enzyme activity.
High-dose Coptidis Rhizoma increased ChAT and ACh levels in brain tissue
homogenate and improved inflammatory lesions in lung and brain tissue.
Based on the protective mechanism of CAP in ALI rats, the central and
peripheral mechanisms of action are different. In central nervous
system, Coptidis Rhizoma may reduce the inflammation of brain tissue by
indirectly promoting the release of the body, which has nothing to do
with biosynthesis. In peripheral tissue, it may play an
anti-inflammatory role by increasing the activity of rat lung tissue and
promoting synthesis (Cui, 2012).
Extracts . Litchi pit is the dried mature seed of Litchi
chinensis Sonn. It is often used clinically for pains such as cold
hernia, abdominal pain, testicular swelling, and epigastric pain. Its
total flavonoids and total saponins are effective parts, which have the
effects of lowering blood sugar, anti-tumor, anti-virus,
anti-inflammatory, and anti-liver injury. Studies have found that total
flavonoids of litchi also has a certain effect on ALI, which decreased
the wet-dry weight of lung tissues, IL-1β, NO, TNF-α, and NF-κB levels,
increased ACh levels and activity of ChAT and AChE in ALI rats. It
showed that it could regulate the CAP, inhibit the development of
inflammatory response, and protect the damaged lung tissue (J. Chen,
Lin, & Zheng, 2016).
Component . Andrographis paniculate is the dried above-ground
part of Andrographis paniculata (Burm. f.) Nees. It is commonly
used in the treatment of respiratory diseases such as colds, coughs,
sore throat and other symptoms. It has antipyretic, anti-inflammatory,
immune enhancement, cardiovascular protection, and anti-tumor effects.
It is commonly used in respiratory disease treatment, and
3-Dehydroandrographolide (3-DA) is an important active ingredient of it.
The study has revealed that 3-DA attenuated the release of
proinflammatory cytokines IL-6 and TNF-α in LPS-stimulated RAW 264.7,
inhibited the degradation and phosphorylation of IκBα, and inhibited the
nuclear translocation of NF-κB p65 and Akt Ser473 phosphorylation,
increased α7nAChR expression level and could bind to α7nAChR. MLA and
α7nAChR siRNA counteracted the anti-inflammatory effect of 3-DA. In
LPS-induced ALI mice, 3-DA reduced inflammatory cytokines and lung water
content, which were related to the inhibition of neutrophil and
macrophage infiltration and activation of the NF-κB/Akt pathway, which
was weakened by MLA (Lu et al., 2018). Therefore, 3-DA can exert
anti-inflammatory effects on ALI through CAP, and α7nAChR seems to be a
potential target.
4.2 | Sepsis
Sepsis is an infection of the systemic inflammatory response syndrome.
The serious mortality rate is as high as 30%-50%, which is related to
the lack of hemodynamic stability, abnormal platelets, multiple organ
dysfunction and disseminated intravascular coagulation (Angus & Wax,
2001). In recent years, sepsis has been redefined as a life-threatening
organ dysfunction caused by the dysregulation of the host’s response to
infection (Singer et al., 2016). It has been an important cause of the
death of major diseases worldwide, and it is closely related to
cytokines dysregulation. Bacteria or LPS activates TLR4 to induce
macrophages to release pro-inflammatory factors (cytokines, chemokines)
and participate in neutrophils recruitment, but excessive systemic
inflammation is the reason for the migration of neutrophils into the
infection focus, thereby infiltrating organs and causing failure. The
efferent vagus nerve activates ACh and stimulates the splenic nerve to
release NE, which in turn interacts with β2AR expressed in T
lymphocytes. Furthermore, ACh activates α7nAChR in macrophages, inhibits
NF-κB nuclear translocation, and inhibits inflammatory mediators release
(Kanashiro et al., 2017). Pavlov (Pavlov & Tracey, 2006) found that the
transmission of certain signals through vagus nerve in brain reduced the
pro-inflammatory cytokines production and improved the survival rate of
sepsis models. It is also an earlier report that the CAP may be involved
in the improvement of sepsis. In the early stage of sepsis, CAP is
stimulated mainly by stimulating the mAChR receptors of monocytes
(stimulating peripheral α7nAChR and central mAChR). Therefore, CAP plays
an anti-inflammatory role in sepsis, and α7nAChR mRNA level in
peripheral blood monocytes can also be detected as clinically relevant
markers in patients with sepsis. That is, the higher the α7nAChR
expression, the better the inflammation control and prognosis (Cedillo
et al., 2015).
CHM prescriptions. Huang-Lian-Jie-Du-Decoction has
anti-inflammatory, antibacterial, antihypertensive, and anti-cerebral
ischemia effects. It is commonly used to treat sepsis, pneumonia,
urinary system infection, dysentery, Japanese encephalitis, etc., which
has been used more than 1700 years. It is commonly used to treat sepsis,
its therapeutic effect on cecal ligation and puncture (CLP), and the
efficacy of four variants of prescription (original prescription removes
one herb respectively). The results showed that the original
prescription had the best effect, mainly through enhancing CAP and
inhibiting HMGB-1/TLR4/NF-κB pathway (D. Xu, Lv, Wang, Yang, & Kong,
2017). Shenfu injection is derived from the ancient prescription ”Shenfu
Decoction”, which is commonly used in clinical emergency medicine. It is
a traditional CHM preparation made from Ginseng Radix Et Rhizoma Rubra
and Aconiti Lateralis Radix Praeparata. Ginsenosides and aconitum
alkaloids are important active ingredients. The injection has
pharmacological activities such as immune regulation, anti-heart
failure, anti-shock, protection of ischemia-reperfusion injury,
regulation of blood coagulation system, etc., and is mainly used for
shock, sepsis, heart failure, and acute pancreatitis. Shenfu injection
has effects on NF-κB, MAPK and AKT pathways. Shenfu injection
significantly reduced serum ALT and AST, liver TNF-α levels in
LPS-induced sepsis rats, increased liver ACh level and ChAT activity,
reduced pathological liver cell edema, inflammatory cell infiltration,
necrosis, and so on. It indicates that it may be achieved by affecting
CAP, that is, increasing the activity of ChAT to increase ACh content,
inhibiting TNF-α expression and thus exerting a protective effect on
sepsis (Hong, 2016).
Rheum palmatum is the dried roots and rhizomes of Rheum palmatumL, Rheum tanguticum Maxim. Et Balf, and Rheum officinaleBaill., which contains active ingredients such as rhein, emodin, and
aloe-emodin. It is effective against ALI, acute severe hepatitis and
multiple organ dysfunction caused by endotoxin. The combination of Rheum
palmatum and Scutellariae Radix is an important basis for many
heat-clearing compounds and has a good therapeutic effect on sepsis. Li
studied the impact of drug pair Rheum palmatum-Scutellariae Radix on
CAP. Rheum palmatum and drug pair significantly inhibited the increase
of body temperature and serum NO in endotoxemia model rats, and the
effect of drug pair was stronger than that of Rheum palmatum, while the
antipyretic effect of Scutellariae Radix and NO level reduction were not
significant. They all significantly increased the vitality of lung ChAT
and AChE in endotoxemia model rats. Rheum palmatum and Scutellariae
Radix had similar strengths to improve lung ChAT activity and were
stronger than drug pair; Scutellariae Radix had a higher effect on lung
AChE than in Rheum palmatum and drug pair. The serum ACh level
improvement of Rheum palmatum was stronger than Scutellariae Radix, and
Scutellariae Radix was stronger than the drug pair. Therefore, after
compatibility application of two herbs, it can increase the absorption
of rhein and baicalin in endotoxin rats, but the effect on CAP is
relatively weak (Fanfan Li, 2013). Due to the low dose of drugs used in
this experiment, its specific mechanism of action does not exclude the
relationship with CAP, its research still needed.
Extracts . Astragalus polysaccharide is an effective component
of Astmgali Radix (the root of Astragalus propinquus Schischkin).
Astmgali Radix has the functions of regulating immunity, anti-oxidation,
anti-virus, enhancing myocardial function, protecting liver,
anti-cancer, etc. It is often used clinically for pulmonary heart
disease, coronary heart disease, tuberculosis, cerebral infarction,
tumors, etc. Astragalus polysaccharide has antiviral, antibacterial and
immune function enhancement effects. It combined with ibuprofen in the
treatment of CLP septic rats, significantly reduced the production of
TNF-α and IL-6, and increased α7nAChR mRNA expression and the release of
serum ACh. Which indicating that it is through α7nAChR-mediated CAP to
suppress sepsis (L. Liu, Chen, Xu, Hou, & Mo, 2017).
Component . Sepsis can also cause brain damage during systemic
infections (H. Xu, Turnquist, Hoffman, & Billiar, 2017). Emodin is an
important active ingredient of Polygonaceae plant Rheum palmatum,
Polygoni cuspidati rhizome et radix, etc. It has anti-inflammatory,
antibacterial, immune regulation, and vasodilator effects. And it is
widely used in clinical applications, such as Japanese encephalitis,
mumps, urinary tract infection, pneumonia, and otitis media. Emodin has
obvious anti-inflammatory effects, reduce tissue and organ damage, and
excessive inflammation caused by LPS (X. Dong et al., 2016). It is also
revealed that have neuroprotective effects on acute brain injury caused
by sepsis. That is, emodin significantly reduced the degree of brain
damage, reduced the levels of S100β, IL-6, TNF-α, nerve-specific enolase
in plasma, and reduced the levels of lactic acid and AChE in brain (Y.
Dong, Liu, Zhang, & Tang, 2019). The mechanism may be involved in CAP
activation and inhibition of inflammation.
4.3 | Inflammatory diseases of
brain
4.3.1 | AD
Among brain diseases, the incidence of dementia is getting higher and
higher, and it is also related to CAP. The incidence of AD has increased
in recent years. AD is a degenerative disease of the central nervous
system. In addition to β-amyloid plaque deposition, cholinergic nervous
system function damage, oxidative damage, and inflammation are also
essential features of AD brain pathology. The study has found that the
functions of ChAT and AChE in the cerebrospinal fluid and brain tissue
of patients, as well as the synthesis, release, and uptake of ACh
decreased (Tohgi, Abe, Hashiguchi, Saheki, & Takahashi, 1994), and BChE
activity increased (Perry, 1986). Decreased activity of the cholinergic
system, especially projection abnormalities caused by progressive
degeneration of cholinergic basal forebrain neurons, and decreased
levels of ACh and ChAT in brain are important causes of AD, the early
stage of AD has been significantly reduced (Pappas, Bayley, Bui, Hansen,
& Thal, 2000). mAChR increases the α-secretase pathway of amyloid
precursor protein (APP) and exacerbates APP’s non-β amyloid peptide (Aβ)
pathway metabolism (Nitsch, Slack, Wurtman, & Growdon, 1992), while
nAChR also increases APP expression and decreases Aβ (Mousavi &
Hellström-Lindahl, 2009). In the
early stage of AD, a low concentration of Aβ activates hippocampal
astrocytes to protect nerves. While in the middle and late stages, it
accumulates too much to form a vicious circle, and a large amount of Aβ
is deposited in a feedback manner (Qi Wang & Zhou, 2011).
Aβ and α7nAChR have high affinity
and combine to form a complex, thereby blocking neurotransmitter
transmission and signal transmission, causing nerve cell death. α7nAChR
in astrocytes can regulate cell proliferation activation and
inflammatory response, and its specific agonists and antagonists resist
the combination of Aβ and α7nAChR, thereby alleviating AD-like lesions
(H. Y. Wang et al., 2010). For example, PNU-282987 activates α7nAChR,
attenuates Aβ-induced apoptosis and Aβ deposition, increases the
expression of synapse-related proteins and maintains the synapse
morphology, which is related to the pathway that activates calmodulin
(CaM)-calmodulin-dependent protein kinase II (CalMKI1)-cAMP response
element binding protein (X. L. Wang et al., 2020). Therefore, the
treatment of AD by activating CAP, on the one hand, it regulates the
release of neurotransmitters by nAChR in presynaptic membrane to improve
learning and memory, and nAChR excitatory neurons in the post-synaptic
membrane maintain normal responses (Dajas-Bailador & Wonnacott, 2004).
Whereas, cholinergic receptors play an anti-inflammatory role through
NF-κB, MAPK and JAK/STAT pathway to reduce the chronic inflammation of
AD brain. Among the currently approved treatments for AD, cholinesterase
inhibitors (ChEI) are the most used, which is beneficial to restore the
synaptic concentration of ACh and alleviate AD symptoms without causing
too many side effects. The application and excavation of CHM in AD is
also the direction of many scholars in recent years, and more drugs are
showing potential therapeutic (Figure 3).
In addition, mAChR in central nervous system is also related to AD. The
decreased coupling of M1 mAChR and G protein is the cause of a cognitive
decline in AD patients. Activation of M1, M3 mAChR, or its downstream
protein kinase C (PKC) molecules can significantly increase APP
secretion and reduce Aβ (Tsang et al., 2006).
Both α7nAChR activation and M1
mAChR activation down-regulate GSK3β and reduce the hyperphosphorylation
of tau protein (Figure 4) (Bitner et al., 2009; Caccamo et al.,
2006), thereby reducing
neurofibrillary tangles. Among them, tau protein is a key driver of AD
neurodegeneration and predict late brain atrophy (La Joie et al., 2020).
CHMprescriptions. Mailuoning
injection is a preparation developed on the basis of ”Simiao Yongan
Decoction”, which has the effects of anticoagulation, thrombolysis,
spasmolysis, expansion of blood vessels, and improvement of
microcirculation. It is used to treat thrombotic occlusive diseases.
Mailuoning significantly increased the mRNA expressions of α7nAChR,
M3mAChR, ERα, and NMDAR1 in the temporal cortex of early AD rats, which
had no significant effect on M1mAChR mRNA expression, and protected
nerves (Tian, 2009). Naoling Decoction could delay the disease
development and improve life quality in AD treatment. It has a certain
effect on memory ability and hemodynamic changes. Researchers have found
that it inhibited the expression of TNF-α, IL-1β and IL-6 by inhibiting
the NF-κB pathway and ASC-dependent inflammasome in hippocampus,
normalized chromogranin A level in hippocampus and attenuated the
activation of microglia and astrocytes induced by Aβ1-42(Xia et al., 2017). Simultaneously, Naoling decoction dramatically
up-regulated the expression of α7nAChR and α4nAChR on cell membrane of
hippocampal CA3 area of AD model rats induced by Aβ1-42,
inhibited Aβ deposition, improved learning memory and cognitive ability.
In addition, CA3 area is the central area of learning and memory.
Naoling decoction can reduce the pyknosis of pyramidal cells in CA3 area
(W. Jin, 2010). Among them, α4nAChR is the main subtype of α42β. There
is a loss of α42β neurons in hippocampus, frontal lobe, temporal cortex,
and subcortex of AD patients. Stimulation of α4nAChR can affect
inducible nitric oxide synthase formation, reduce apoptosis and
inflammation caused by NO synthesis, and thus protect nerve cells
(Takada-Takatori et al., 2009). Tianshen Yizhi recipe is a preparation
developed according to AD that has the functions of invigorating the
spleen and “Qi ”, soothing the nerves, calming liver and
eliminating wind, promoting blood circulation and removing blood stasis,
and resuscitating. It against Aβ-induced decrease in α3nAChR and α7nAChR
protein levels and low expression of α7nAChR mRNA, weakened cell damage
and increased lipid peroxidation caused by Aβ25-35 (Gu
et al., 2007). Liuwei Dihuang Decoction regulates immune system,
regulates hippocampus and ability of learning and memory,
corticosteroid-like effects, and lower blood lipids. It is widely used
in clinical practice. It is a decoction of Liuwei Dihuang Pills, which
is often used for cardiovascular and cerebrovascular diseases,
menopause, Lumbocrural pain. Liuwei Dihuang Decoction-containing
cerebrospinal fluid improved Aβ1-40 induced PC12 cell
growth and cell activity, increased α7nAChR protein expression and
inhibited the neurotoxic effect of Aβ1-40 (Ma, Ma, Miao,
Ma, & Tian, 2008). Daicong solution is a preparation from affiliated
hospital of Weifang medical college for the clinical treatment of AD. It
can improve APP gene expression, lymphocyte proliferation and brain
tissue structure in AD. Further research found Daicong solution
increased M1, M3mAChR mRNA levels in brain and improved the learning and
memory functions in AD rats (H. Wang et al., 2007).
There are also some prescriptions through a similar mechanism to AChE
inhibitors in AD treatment. For example, Naosuikang (H. Dong et al.,
2019) and Nao Yikang (Geng et al., 2008) (all are hospital preparations)
used clinically for cerebral arteriosclerosis, sequelae of stroke,
cerebral infarction, cerebral atrophy, senile dementia, etc. They
regulate the cholinergic system (promoting ChAT expression, reducing
AChE activity, increasing Ach synthesis) and increase neurotrophic
factors levels (NGF, BDNF) in the brain, thereby improving the spatial
memory ability in rats with vascular cognitive impairment model.
Dangshen Yuanzhi powder is a modified prescription of Yuanzhi powder
(clinical treatment of dementia and amnesia). The main herbs in
prescription, Polygalae Radix, Codonopsis Radix and Acori Tatarinowii
Rhizome all could improve learning and memory. Dangshen Yuanzhi powder
exerts an anti-AD effect by up-regulating ChAT expression and inhibiting
AChE expression in the CA1 region and cortex of mouse hippocampus (L.
Yang, Zhao, Wang, Wang, & Wang, 2020). Rhizoma Polygonati and Earth
Worm mixtures increased ACh level and ChAT, SOD, GSH-Px activity in
brain, reduced MDA level and AChE activity, and exerted
anti-inflammatory and antioxidant effects through CAP (Y. Xiao, Zeng,
Ouyang, Cheng, & Chen, 2013).
Extracts. Polygalae Radix is the dried root of Polygala
tenuifolie willd. It is often used clinically for neurological
disorders, senile dementia, and concussion syndrome. Polygalae Radix
reduce AChE activity and improve the learning and memory function in AD
rats (Mu & Li, 2007). Tenuigenin (active saponins of Polygalae Radix)
increased α7nAChR expression in hippocampal CA1 region of AD rats (D.
Zhao et al., 2012), reduced AChE activity, increased ACh level of brain,
thereby improving the learning, memory and cognitive ability in aging
model mice (Q. Chen, Cao, & Zhang, 2002; Zeng, Deng, Yan, Liu, & Tang,
2009). Lycii Fructus is one of the most common traditional Chinese
medicine health products in daily life. It has immune enhancement,
anti-fatty liver, and cholinergic effects, and is clinically used for
tumors, diabetes, hyperlipidemia, etc. Studies have found that it
improved cognitive function in AD, up-regulated α7nAChR expression in
aging mice, increased serum SOD activity, reduced MDA level, and
improved cognitive memory function (Sun, Miao, Wang, Qin, & Chen,
2010). Its main component, lycium barbarum polysaccharides, reduced
Aβ1-40-induced astrocytes TNF-α, IL-6 levels increase
and α7nAChR high expression. While its effect is similar to nicotine,
and astrocytes proliferation activity is still significantly increased
(Ren et al., 2016).
Component . Tripterygium wilfordii (the root ofTripterygium wilfordii Hook. f.) has anti-inflammatory,
immune-regulating, anti-tumor, and neuroprotective effects. It is
clinically used for nephropathy, autoimmune diseases, rheumatoid
arthritis, AD, etc. Triptolide is the epoxyditerpene lactone with the
highest activity of Tripterygium wilfordii. It is also one of the most
important anti-inflammatory and immunosuppressive components. It can
regulate the expression of cytokines and NF-κB, and inhibit the
proliferation reaction of T and B lymphocytes. Triptolide inhibited
Aβ-induced activation of astrocytes, reduced inflammatory mediators
release, reduced cholinergic fibers damage, and improved
neurodegenerative diseases such as AD (Huang, 2010). Bilobalide is an
important component of Ginkgo biloba, a sesquiterpene lactone and a drug
for nervous system and psychosis. It has a curious effect on stupidness
caused by old age. Bilobalide is also commonly used for neuropathy,
encephalopathy, and myelopathy. It has a protective effect on the
cognitive impairment of AD rats induced by Aβ1-40, which
regulated the expression of cholinergic neurotransmitters, reduced the
level of oxidative stress and anti-inflammatory (X. Jin, Wang, Xie,
Zhang, & Liu, 2019).
AChEI .
According
to cholinergic deficiency theory of AD, neural ACh is responsible for
learning and cognition. AChE is a key enzyme that affects ACh and has
become a significant target in AD drug development. There are four AChEI
drugs in five AD drugs approved by the FDA, namely Tacrine, Donepezil,
Rivastigmine and Galantamine. CHM prescriptions, single herb and
components are critical sources of AChEI, and many active ingredients
are considered as potential therapeutic drugs for AD because of their
inhibitory effect on AChE. This review sorts out CHM and its ingredients
with IC50 less than 0.05μmol/mL (Table 2, Chinese medicines that only
detect the inhibition rate are not included). Galantamine and Huperzine
A (H. Y. Zhang, Liang, Tang, He, & Bai, 2002) (already listed in China)
are important AChEI extracted and developed from CHM. Galantamine is a
phenanthridine alkaloid extracted from Amaryllidaceae plants. In
addition to interfering with APP metabolic process, it reduces the
production of Aβ. It is also the reversibility of the second-generation
AChEI, as allosteric enhancement ligands, can activate nAChR, promote
the release of ACh from cholinergic terminals, and protect the survival
and function of neurons (Anand & Singh, 2013; Samochocki et al., 2003).
Catechins in green tea have been revealed to exert anti-AD effects
through antioxidant, anti-inflammatory, affecting PKC and
neurotransmission-related properties (Ide, Matsuoka, Yamada, Furushima,
& Kawakami, 2018). Meanwhile, Epigallocatechin Gallate and
Epigallocatechin in green tea inhibit AChE and BuChE, and different
catechins synergistically inhibit AChE. These two enzymes regulate
cholinergic neurotransmission. BuChE is responsible for most of ACh
metabolism in late stage of AD. Although their inhibition rate is not as
high as that of galantamine, they have relatively fewer side effects
(Okello & Mather, 2020). In addition, through experiments on AChE
inhibition and molecular docking studies, it was revealed that the
following components have a certain inhibitory effect on AChE:
Huanglianjiedu decoction (J. Song, Wang, Si, & Bian, 2010), aqueous
extract of Cortex Phellodendri, aqueous extract of Magnoliae Officmalis
Cortex (Shi, Wang, & Liu, 2011), volatile oil of Radix Peucedani (Yamin
Liu, Song, Li, Jiang, & Pan, 2012), polycyclic-meroterpenoid of
Ganoderma (Peng et al., 2014), lanostane-type triterpene of Ganoderma
(Lee et al., 2011), berberine (Xiang, Yu, Yang, Yang, & Ding, 2009),
columbamine, dauricine, jatrorrhizine (P. Li et al., 2019), palmatine
(H. Zhao et al., 2016), carinatumin A and B (Choo et al., 2007),
geissoschizine methyl ether (Z. D. Yang et al., 2012), stenine A and B
(Lai et al., 2013), volvalerenal acid K (H. W. Chen et al., 2016),
leoheteronin A, leopersin G (Hung, Luan, Vinh, Cuong, & Min, 2011),
icariin (Xin, Euikyung, Tian, Lin, & Guo, 2001), tOMe-byakangelicin,
byakangelicol (Seo et al., 2013), demethoxycurcumin,
bisdemethoxycurcumin (Ahmed & Gilani, 2009), ginsenoside (Choi et al.,
2016). These active ingredients are mainly flavonoids, alkaloids,
phenols, terpenes, saponins, etc., which has the potential to treat AD.
Since the screening of various ingredients is limited to in vitro
experiments and molecular docking, complex conditions in vivo may have
low bioavailability, difficulty in penetrating the blood-brain barrier,
and poor drug-forming properties. These ingredients need to be further
screened. In addition, many drug researches have limited the mechanism
of AChEI treatment of AD to the role of ACh in learning and cognition,
and there are relatively little research and discussion on the
anti-inflammatory effects of cholinergic.
4.3.2 | Vascular
dementia
Vascular dementia (VD) is different from AD. It is a severe cognitive
dysfunction syndrome caused by ischemic stroke, hemorrhagic stroke, and
cerebrovascular diseases that cause hypoperfusion of brain regions, such
as memory, cognition, and behavior. Immunity and inflammation are also
involved in the pathogenesis of VD, and the inflammatory response
induced by cerebral ischemia is an important factor leading to cerebral
ischemic injury. The relationship between VD and CAP is mainly related
to the role of ACh, AChE activity, synaptic changes in the central
cholinergic system, and inflammation regulation.
The clinical application of Bushen Xingnao decoction has proved to be
effective in VD treatment. It is the clinical experience formula of
Professor Feng Yinman, a national outstanding contribution expert. It
works by improving free radical metabolism, amino acid neurotransmitter
content, and inhibiting cell apoptosis. Animal experiments have shown
that it significantly reduced the level of VEGF, TNF-α and IL-1β in VD
rat brain, and the level of anti-inflammatory cytokines IL-10 and TGF-β,
down-regulated NF-κB expression, increased ChAT activity, and reduced
AChE activity (J. Hu, He, Zhang, & Zhao, 2011). It may alleviate vagal
nerve suppression, promote increased ACh synthesis, reduce inflammation
and reduce brain damage. Besides, the drug reduced brain adhesion
factors ICAM-1, VCAM-1, E-selectin, P-selectin to reduce
ischemia-reperfusion injury. Therefore, Bushen Xingnao decoction
activates CAP, blocks NF-κB pathway, and regulates the expression of
inflammatory cytokines and adhesion factors (J. Hu, 2011). Bushen
Jiannao Recipe is an improved recipe of Dihuangyinzi. It can improve
learning and memory ability, change the content of amino acid
neurotransmitters, and inhibit cell apoptosis in VD treatment. It
increased ACh level in the cortex and hippocampus, and promoted the
expression of ERK1 and ERK2 in hippocampal CA1 area, regulate CAP to
reduce inflammation (Yonghui Liu, Li, & Zheng, 2012). Dihuangyinzi is
often used for chronic diseases such as AD, VD, advanced hypertension,
cerebral arteriosclerosis, stroke sequelae, and myelitis. Dihuangyinzi
could treat VD and AD caused by chronic cerebral hypoperfusion, increase
the activity of total antioxidant capacity in hippocampus, reduce the
apoptosis rate, and significantly reduce hippocampal AChE activity and
increase ChAT activity (L. Bai, Zhang, Wu, & Yang, 2011). Modified Yiqi
Congming decoction (X. Bai, Peng, Tang, Yang, & Zhang, 2016) and total
flavone of Hawthorn leaf (Mao, Miao, Wu, & Chen, 2014) increased ACh
level in rats hippocampus, reduced AChE level, and improved learning and
memory function of VD rats. Pueraria is an isoflavones derivative in
Puerariae Lobatae Racix (Pueraria lobata (Willd) Ohwi). It has
the effects of reducing fever, calming, increasing coronary blood flow,
and improving immunity. It is clinically used for hypertension, coronary
heart disease, angina, etc. Puerarin relieved neurological damage in
rats with cerebral ischemia-reperfusion injury, improved the
infiltration of inflammatory cells in brain hippocampus, reduced the
level of IL-1β, IL-6, and TNF-α in brain, and increased the level of
IL-10. α-bungarotoxin can block its anti-inflammatory effects,
indicating that it may activate CAP (M. Wang, Mei, Zeng, & Liu, 2012).
4.3.3 | Traumatic brain
injury
Inflammation and apoptosis are pathological features of secondary brain
mechanical injury (TBI), overexpression of inflammatory cytokines such
as IL-6 and TNF-α can induce apoptosis and death. The focus of modern
therapy is to control and reduce secondary injury (Zhai et al., 2015).Arctium lappa L. is a diuretic, anti-inflammatory and detoxifying
CHM. Its active ingredient arctiin has anti-inflammatory and
anti-apoptotic effects. Its effect on neuroprotection is mainly related
to microgliosis and pro-inflammatory cytokine production, active
apoptotic cytokine production, caspase-3 activity and neuronal cell
death significantly reduced. Arctiin reduced levels of TNF-α, IL-6 and
the number of TUNEL+ apoptotic cells surrounding scratches, increased
IL-10 levels, up-regulated the levels of miRNA-16 and miRNA-199a.
Thereby it reducing the upstream IKKα and IKKβ protein expression and
inhibiting the activity of NF-κB pathway. In addition, it caused
increased miRNA-199a to inhibit AChE and enhanced cholinergic signal
(Swarup, Ghosh, Mishra, & Basu, 2008).
4.4 | Cardiovascular
diseases
4.4.1 | Atrial
fibrillation
Atrial fibrillation (AF) is also associated with inflammation, and
inflammatory cytokines may be related to fibrosis and the expression of
current channel subunits that promote AF-related electrical remodeling
(Guo, Lip, & Apostolakis, 2012; Y. F. Hu, Chen, Lin, & Chen, 2015;
Shang et al., 2008). Sensong Yangxin capsule is clinically used for
arrhythmia, coronary heart disease, ventricular premature beats,
paroxysmal atrial fibrillation, and the effect on action potential
duration and atrial conduction capacity is related to the effect on
autonomic nerve (Feng et al., 2009). The study revealed that it
inhibited the effective atrial refractory period of dogs with long-term
intermittent atrial pacing-induced by implantation of a cardiac
pacemaker, and inhibited the increase of sympathetic nerves and the
up-regulation of TNF-α and IL-6 expression. In addition, it inhibited
the long-term intermittent atrial pacing-induced reduction of ACh and
α7nAChR proteins, indicating that it may be related to the imbalance of
autonomic nerve activity and CAP (H. Y. Zhao et al., 2017).
4.4.2 | Myocardial ischemia reperfusion
injury
CAP inhibits NF-κB pathway and NF-κB is a regulatory protein that is
involved in the earlier process of myocardial ischemia reperfusion
injury (MIRI). It regulates the gene transcription process of various
cytokines, inflammatory mediators, and adhesion molecules to control its
biosynthesis. Breviscapine is a flavonoid component in Erigeron
breviscapus, which is commonly used in coronary heart disease, angina
pectoris, and acute myocardial infarction. Its intervention
substantially increased the expression of NF-κB p65 and α7nAChR protein
in MIRI rats and reduced IκB-α expression (Ding et al., 2018). NF-κB
resists apoptosis by regulating a series of gene transcription and
expression, so breviscapine effectively inhibits cardiomyocyte apoptosis
through CAP-mediated NF-κB pathway.
4.4.3 | Obesity-related
hypertension
The expression of SOCS3 and protein tyrosine phosphatase 1B (PTP1B)
inhibitors was upregulated by active IKKβ/NF-κB signaling in
hypothalamus and increased proinflammatory cytokines. As negative
regulators of leptin signaling, both SOCS3 and PTP1B induce central
leptin resistance by disrupting JAK2/STAT3 phosphorylation. Leptin
cannot effectively regulate energy homeostasis while maintaining its
ability to stimulate the cardiovascular/renal sympathetic nervous
system, leading to sympathetic nerve-mediated hypertension (de Git &
Adan, 2015; Mark, 2013; X. Wang et al., 2012). Therefore, low levels of
pro-inflammatory state and leptin resistance are potential mechanisms
resulting in obesity-induced hypertension. Astragaloside IV is one of
the main active ingredients in Astragalus mongholicus, it has the
effects of enhancing immunity, anti-virus, anti-stress, and improving
heart and lung function. Which inhibited the production of
pro-inflammatory cytokines in the central nervous system and the
activation of the IKKβ/NF-KB pathway, enhanced leptin sensitivity, and
improved metabolic disorders. It alleviated leptin resistance by
increasing p-STAT3, LepRb mRNA and POMC mRNA and decreasing p-PI3K,
SOCS3 mRNA, and PTP1B mRNA, up-regulating α7nAchR in hypothalamus and
adipose, inhibiting IKKβ/NF-KB signaling and proinflammatory cytokines.
So that Astragaloside IV prevents obesity-induced hypertension is
associated with increased α7nAChR expression (P. Jiang et al., 2018).
4.4.4 | Shock
The body’s response to the decrease in effective circulating blood
volume is a pathological process of metabolism and cell damage caused by
insufficient tissue perfusion and various neuro-humoral factors are
involved in the occurrence and development of shock. Whether it is
septic shock or hemorrhagic shock, the body will be damaged by pathogens
or ischemia and cause organ damage, resulting in an inflammatory
response, so the treatment of shock by CAP is also possible. Anisodamine
is a belladonna alkaloid extracted from Scopolia tangutica Maxim.
It is a mAChR antagonist and is usually improve circulatory diseases
such as shock, hypertensive encephalopathy, lung disease, acute
nephritis and heart failure, etc., and its strength is similar to that
of atropine. It blocks mAChR, causing ACh to return to α7nAChR,
resulting in ACh-mediated α7nAChR activation and an increase in CAP
activity (T. Zhao, Li, Liu, Su, & Shen, 2011).
4.5 | Arthritis
Rheumatoid arthritis (RA) is a common autoimmune disease. Existing
research indicates that CAP may be an important treatment for RA. The
patient’s joint synovium expresses various inflammatory mediators such
as TNF-α, IL-1β. After NF-κB activation, it enhances the gene
transcription level of the inflammatory mediators, so that the
inflammatory response continues (Makarov, 2001). And initiate the
transcription of genes such as Bcl-2, NOS, and apoptosis inhibitory
protein, causing abnormal apoptosis of fibroblast-like synoviocytes
(FLS). FLS accumulates in cartilage and bone adhesion to secrete MMP and
pro-inflammatory factors, which promote immune inflammation and lead to
bone destruction (S. Bai et al., 2004; Feldmann et al., 2002).
Therefore, FLS is the pathological center of RA, which respond to
inflammation and stimulate inflammation to destroy articular cartilage
and bone. In the collagen-induced arthritis rat model, α7nAChR
expression level in joints and spleen was the highest, which proved that
CAP is involved in the occurrence and development of RA inflammation (Z.
Li et al., 2019). JAK/STAT pathway is also an important mechanism of an
inflammatory response and immune response in the pathogenesis of RA. In
RA inflammatory response, a large amount of ACh is released after vagus
nerve excites, the catalytic activity of the intracellular domain is
activated, a large amount of JAK2 is accumulated around α7nAChR. Maanen
(van Maanen et al., 2009) found that cutting off vagus nerve worsen RA
condition. However, after intraperitoneal injection of the α7nAChR
selective agonist AR-R17779 or nicotine, the release of TNF-α in mice
synovial was significantly reduced, which delay progression and reduce
joint bone destruction. Activating α7nAChR with nicotine reduces joint
degradation caused by monosodium iodoacetate. By inhibiting p38,
extracellular regulation of MIA or IL-1β-induced p65-activated Erk1/2
and JNK-activated MAPK phosphorylation and NF-κB Phosphorylation, and
these effects are also reversed by selective antagonist MLA, suggesting
that activation of α7nAChR may treat arthritis (Y. Liu et al., 2015).
CHM prescriptions. Hebi Recipe is a clinical prescription for
early RA, which improves patients’ joint swelling, pain, rheumatoid,
etc., and reduces synovial membrane thickening and improves the symptoms
of malaise related to the autonomic nervous system. It up-regulated
α7nACh expression to activate CAP, activated JAK2/STAT3 signaling
pathway, reduced TNF-α, IL-6, IL-17 levels, and reduced joint swelling
(Xing et al., 2018).
Extracts. Tripterygium wilfordii is widely used in the
treatment of RA. Wilforlide A, triptolide and celastrol are active
ingredients for anti-inflammatory and immunomodulation. Tripterygium
wilfordii polyglucoside is a compound preparation of multiple
components. It reduced the expression of IL-17 and HMGB1, participated
in regulating CAP activation, and inhibited the activation of downstream
NF-κB and JAK2/STAT3 pathway, reduced NF-κB p65 expression (W. Liu &
Zhang, 2019).
Components. Sinomenine is the principal active ingredient of
Caulis Sinomenii in anti-rheumatical CHM, has anti-inflammatory and
immunomodulatory effects, and is commonly used in RA treatment (Q. Wang
& Li, 2011). It inhibited pro-inflammatory cytokines production and
TLR4/MyD88/NF-κB pathway, and prevented IL-1β-induced inflammation of
human fibroblast-like synoviocytes (Yao, Zhao, Zhao, & Cai, 2017). The
knockout of α7nAChR and α7nAChR antagonist eliminated the effect of
sinomenine on TNF-α and IL-6 production and NF-κB activation stimulated
by LPS in macrophages (Yi et al., 2015). It mainly inhibited macrophage
CD14/TLR4 expression and intracellular free calcium levels through
α7nAChR, activated JAK2/STAT3 pathway to suppress inflammation (Zhu et
al., 2019). It was further revealed that sinomenine has improved the
systemic inflammation of collagen-induced arthritis (CIA) rats, which
significantly reduced the effects of vagotomy or nAChR antagonists, and
may bind to α7nAChR through the interaction of residues Tyr184 and
Tyr191, while mAChR antagonist had no effect. It showed that it mainly
enhanced vasoactive intestinal polypeptide (VIP) production in the
intestine and neuron-like cells in CIA rats by activating the
α7nAChR-PI3K/AKT/mTOR pathway. VIP also plays a key role in the
anti-arthritis effect of sinomenine (Yue et al., 2018). Moreover, its
mechanism was also related to the inhibition of FLS proliferation by
regulating α7nAChR expression through ERK/Egr-1 pathway (Yi et al.,
2018). Therefore, sinomenine plays an anti-arthritis role through
α7nAChR-mediated JAK2/STAT3, NF-κB, MAPK, and PI3K/AKT pathways.
4.6 | Diabetes
Diabetes is called ”Xiao Ke” in traditional Chinese medicine, type 2
diabetes mellitus (T2DM) is a chronic metabolic disease. Insulin
resistance decreases in the efficiency of insulin in promoting glucose
uptake and utilization and often causes T2DM. Insulin resistance is
related to oxidative stress, mitochondrial disorders, endoplasmic
reticulum stress, etc (Hafizi Abu Bakar et al., 2015; Y. X. Li et al.,
2015). The inflammatory response also plays a significant role. Before
T2DM occurs, IL-1β and IL-6 in blood circulation increase, and people
with high inflammatory cytokines levels are more susceptible to T2DM
(Spranger et al., 2003). The relationship between insulin resistance and
inflammation may be attributed to the activation of JNK or IKKβ by
inflammatory cytokines and NF-κB activation. The phosphorylation of
insulin receptor substrate 1 serine 307 inhibits PI3K-Akt, leading to
the inhibition of glucose transporter synthesis, glycogen synthesis and
degradation (de Luca & Olefsky, 2008). Furthermore, CAP activation has
an effect on insulin resistance caused by obesity and diabetes, and will
be worsened after α7nAChR knockout (Marrero et al., 2010). It is even
more conjecture that CAP activated by α7nAChR may influence insulin
resistance. In addition, type 1 diabetes mellitus (T1DM) is an
autoimmune disease driven by T cells, which leads to pancreatic β-cells
death and insulin production loss. Specific AChEI prevents the
development of hyperglycemia in C57BL/6 mice caused by MLD-STZ, which is
associated with inhibition of Th17 cell infiltration into islets and
reduction of IL-1β, IL-6, IL-17 (George et al., 2016). It was further
found that mAChRs are necessary for the protective effect of cholinergic
stimulation in autoimmune diabetes (Fernández-Cabezudo et al., 2019).
Berberine is mainly present in Coptis chinensis, Phellodendron chinense,
etc. It is an effective component of Coptis chinensis to lower blood
sugar. Previous studies have concluded that it inhibits inflammation and
improves insulin resistance(Lou et al., 2011). In addition, studies on
AChE inhibiting the activity of benzylisoquinoline alkaloids indicate
that berberine may be an inhibitor of AChE (D. K. Kim et al., 2004).
Berberine up-regulated the expression of α7nAChR mRNA and protein in
3T3-L1 cells, significantly inhibited the secretion of inflammatory
cytokines TNF-α, IL-1β, IL-6, increased glucose uptake, inhibited AChE
activity, and reduced pIKKβ Ser181/IKKβ, NF-κB p65 expression and IL-6
levels. It indicates that it may enhance glucose uptake in HepG2 cells
and reduce inflammation and insulin resistance by inhibiting CAP and
AChE, (F. Li et al., 2016; X. Zhou et al., 2015).
4.7 | Gastrointestinal
disease
4.7.1 | Postoperative ileus
Postoperative ileus (POI) is a temporary intestinal coordinating
movement disorder resulting from intestinal contents that cannot be
effectively emptied and/or cannot tolerate oral feeding after surgery
(Artinyan et al., 2008). Fuan granule is a compound of Yinchenhao
Decoction and Dachengqi Decoction. It can effectively inhibit the
occurrence of POI and reduce the length of hospital stay. In POI model
rat, Fuan (3mL, enema) significantly inhibited the release of TNF-α and
MCP-1 after surgery, and significantly improved small intestine
propulsion rate and reduced gastric residual rate, showed a significant
improvement effect on POI. The effect of applying Fuan granules after
vagotomy is better than that when used alone, indicating that it may
compete with ACh for receptors on CAP, which needs to be further
verified (W. Chen, 2013). Dajianzhong Decoction comes from ”Synopsis of
the Golden Chamber”, which is often used for digestive system diseases
such as abdominal pain, bloating, and gastric motility disorders. The
mechanism of Dajianzhong decoction, Ginseng radix, Zingiberis rhizome
and Zanthoxylum fructus on POI is studied. The experiment revealed that
they all significantly inhibited neutrophil infiltration, and Zingiberis
rhizome significantly reduced neutrophil infiltration in 5-HT4R knockout
mice, but not in α7nAChR knockout mice. In addition, Zingiberis rhizome
improved the effect of transient receptor potential anchor protein 1
(TRPA1) and mAChR antagonists on neutrophils inhibition. Therefore, the
inhibitory effect of Dajianzhong Decoction on inflammation depends
partly on the function of Zingiberis rhizome, which mainly released 5-HT
by activating the TRPA1 channel of intestinal collateral cells, and
released ACh by 5-HT4R acting on intermuscular plexus neurons (Endo et
al., 2017; Endo et al., 2018). Meanwhile, α7nAChR was activated to
inhibit macrophage infiltration, and activate mAChR to inhibit
neutrophil infiltration.
4.7.2 | Acute
pancreatitis
Uncontrolled synthesis and release of cytokines is an important cause of
tissue damage. CAP anti-inflammatory signals can regulate the
inflammation of acute pancreatitis. Chaiqin Chengqi Decoction (CQCQD)
has a definite effect on the treatment of acute pancreatitis and POI in
West China Hospital of Sichuan University, the mechanisms are related to
remove gastrointestinal stagnation, bacteria and endotoxins, and protect
the mechanical and immune barriers. In severe acute pancreatitis model
rats, vagus nerve was suppressed, ACh synthesis was reduced, and the
inflammatory response was severe. CQCQD treatment reduced serum IL-6,
TNF-α and other inflammatory cytokines, reduced AChE, and increased
serum ChAT, suggesting that it may be activated by CAP (Xue et al.,
2006). At the same time, CQCQD was also found to activate CAP in
patients with acute pancreatitis, reduced inflammatory mediators level,
and reduced inflammatory response (You, 2007).
4.7.3 | Stress gastric
ulcer
Pathogenic factors are multi-sourced, and autonomic dysfunction plays an
important role in stress gastric ulcer. ChAT is a marker enzyme of the
cholinergic nerve. Ulcer formation is one of the outcomes of acute
inflammation, so inflammation is also importantly associated with
gastric ulcers. Banxiaxiexin Decoction is derived from the clinical
experience of treating spleen and stomach diseases in ”Treatise on
Febrile Diseases”. It is often used for acute gastroenteritis, chronic
gastritis, dyspepsia, and incomplete gastric pyloric obstruction.
Banxiaxiexin Decoction and its decomposed formulas treated stress
gastric ulcer in rats, reduced gastric mucosal bleeding, and the
expression of ChAT on rat brain and gastric mucosa, indicating that
Banxiaxiexin decoction may be improved by the anti-inflammatory effect
of CAP (Z. Zhang, Si, Wu, Xu, & Bai, 2005).