World Parkinson’s Day 2019: World Parkinson’s
Day is celebrated on April 11.
April
11 is observed as World Parkinson's Day. This day is meant to raise awareness
about Parkinson's disease (PD). Lack of awareness about Parkinson's disease may result in the disease
becoming a major healthcare challenge in the near future.
Parkinson’s
is the second most common neurodegenerative and movement disorder among the aging
population after Alzheimer disease (Those who read Chinese please check out my WeChat post). Progressive
loss of controlled muscle activity, which leads to trembling of the limbs and
head while at rest, stiffness, slowness, and impaired balance are some of the
characteristics of the disease. Along
with the largely aging population in the world, the incidence is increasing
year by year, which imposes the negative impacts on patients, their families
and the whole society. Hence,
on World Parkinson's Day 2019, let's take a look at the traditional and safe
medicine (although mostly from micro-level Western medicine views) for
prevention or mitigation of Parkinson's disease.
Clinically in the conventional Western medicine
world, the PD patients are usually treated with levodopa, dopamine receptor
agonist, monoamine oxidase B inhibitors and other types of drugs. The clinical
symptoms of the disease are mitigated by supplementing dopamine or reducing the
degradation of it. However, the pathogenesis of PD is still not very clear, so
that the efficacy of these drugs is not ideal and the unpleasant side effects
are apparent after long-term administration such as the motor complications
(Stocchi and Marconi, 2010),
nausea, constipation, headache, and sleep disorder, etc. (Borovac, 2016)
which would negatively influence the quality of life of the patients (Kum et
al., 2011;
Qin and Wu, 2016).
Considering the long-term side effects of western
medicines, many patients are searching for a more safe and effective
alternative treatment for PD. TCM has been used for thousands of years to treat
diseases such as the tremor of head and hands, which is different but similar
to the modern PD. Traditional Chinese medicine (TCM) has a positive
prospect for the prevention and cure of PD due to its advantages of less side
effects and multi-target effects. One
of the many examples I found on YouTube and shared with our “health and
medical information sharing” WeChat group is about the pleasant surprise of complete
healing or dramatic improvement TCM intervention within half year. Sadly, most
patients are either not aware of TCM treatment effectiveness or have not found
quality providers until years later. At those stages after two years, any
methods become less effective, yet some still see improvement that’s not achievable
through conventional Western medicine standard treatment.
Central nervous system activity
The inhibition of oxidative
stress
At present, the pathogenesis of PD is not yet
fully discovered, but it has been generally acknowledged that the improvement
of oxidative stress is one of the most important pathophysiological mechanisms
(Avila et al., 2009; Chen
et al., 2009;
Sanyal et al., 2009). PD
patients are in a state of oxidative stress. In the substantia nigra of PD
patients, the elevated concentration of ferric ion, weaken mitochondrial
function and anomaly protection system of antioxidant (Such as low molecular
free radical scavenger glutathione (GSH) and free radical scavenging enzyme
SOD, GSH-Px) have contributed to the acceleration of oxidative stress and
excessive generation of oxygen free radicals. Thereby, large amount of lipid
peroxide, such as Malondialdehyde (MDA), hydroxyl, carbonyl, etc., will cause
cell death, which leads to neuronal apoptosis ultimately (Wu et al., 2009; Wang
et al., 2012).
A Taiwanese TCM doctor named Haixia NI, who helped many patients with PD cases improve
quality of life spoke and wrote in Chinese many times that, he suspected that
the side effects of synthetic drugs created by modern Western medicine contributed
to the development of PD.
According to the theories of traditional Chinese
medicine, Parkinson's disease is characterized by deficiency in the Ben (root)
and excess in the Biao (branch). The Ben (root) is insufficiency of liver and
kidney and deficiency of qi and blood; and the Biao (branch) is wind, fire,
phlegm and stasis. Good therapeutic effects have been obtained by treatment
based on syndrome differentiation, treatment with specific prescriptions and
acupuncture.
We will briefly quote the mechanisms of TCM
underlying the prevention and treatment of PD with regards to the inhibition of
oxidative stress, the regulation of mitochondrial dysfunction, the reduction of
toxic excitatory amino acids (EAA), the inhibition of neuroinflammation, the
inhibition of neuronal apoptosis, and the inhibition of abnormal protein
aggregation.
Since oxidative stress plays a crucial role in
the occurrence and deterioration of PD, we can achieve the purpose of
prevention and treatment against it by resisting oxidative stress. Many TCM or
its effective components may act as a potential antioxidant. Therefore, the
idea of screening TCM to delay the progression of PD has attracted the
attention from many researchers. An overview of the improvement of oxidative
stress is described in detail below, and the additional information is shown in
Table 1.
Effect of TCM on Oxidative Stress Responses in
the Model of PD.
A Chinese herbal medicine could be effective in
treating Parkinson's disease and the side effects of Western treatments used in
fighting it, a university study has found. Parkinson's patients are usually
treated with drugs such as levodopa to relieve symptoms such as stiffness and
poor muscle control, but the drugs cause nausea and hallucinations. In the
research, the patients continued treatment with levodopa but took gambir vine stem
simultaneously. By taking the herb the patients were able to reduce the drug
dosage and thus the side effects.
Back
in 2011, a clinical
study re-confirmed findings that
suggest that a Chinese herbal medicine formula (Jia Wei Liu Jun Zi
Tang: JWLJZT)
can relieve some non-motor complications of
conventional therapy and improve the communication ability in patients with idiopathic
Parkinson's disease.
The regulation of mitochondrial
dysfunction
Abnormal morphology and dysfunction of mitochondrial
are one of the important pathological mechanisms of PD. Mitochondria, as the “power plant” and “energy
conversion station” of cells, regulates the process of gene expression and
apoptosis. Recent reports have suggested that mitochondrial dysfunction is
closely related to a variety of neurodegenerative diseases including PD (Exner
et al., 2012;
Liu et al., 2012; Feng
and Wu, 2014).
In a study, locomotor activity, pole and rotarod
test were used to evaluate the effects of Qianzheng San extract to the
dyskinesia induced by MPTP. Compared with the model group, the MPTP-treated
mice laid out a significant reduction in locomotor activity and ultrastructure
of substantia nigra neuron was obviously harmed. However, Qianzheng San extract
treatment largely increased autonomic activities, prolonged incubation period
and shortened the pole-climbing time (P < 0.05), and reduced the
impairment of ultrastructure of substantia nigra neurons. On the other hand,
electron microscopy showed that the ultrastructure of substantia nigra neurons
was ameliorated effectively and the high degree of mitochondrial damage was
alleviated remarkedly by treatment of Qianzheng San extract. All these
experimental results reveal that Qianzheng San extract may play a
neuroprotective role through improving mitochondrial functions (Li et
al., 2015).
Catalpol, which is relatively abundant in the TCM such as Radix Rehmanniae and
Radix Scrophulariae, is a small molecule compound of iridoids. It also showed
that it has protective effects on mice brain mitochondrial damage induced by
rotenone, partly through enhancing the activities of complex I, increasing the
content of GSH, lowering the loss of mitochondrial membrane potential and
restraining the release of LDH (Shi et al., 2012).
Baicalein, a well-known flavonoid compound
isolated from dried roots of Scutellaria baicalensis, has been applied
extensively as an antioxidant and anti-inflammatory agent (Ge et al., 2017). In
recent years, with continuous studies on its mechanisms, it has been found that
baicalein has some effect on the improvement of clinical symptoms and neuroprotection
in neurodegenerative diseases such as PD. The protective effect of baicalein on
mitochondria may be one of the pharmacological targets of neuroprotection
against PD. The study confirmed that exposure of PC12 cells to 0.15 mM H2O2 for
20 min resulted in mitochondrial damage and cell apoptosis. And pre-treatment
of PC12 cells with different concentrations of baicalein greatly cut down the
cell viability loss. The protective effect of baicalein on mitochondrial
function was related to inhibition of ROS production and the regulation of
Bcl-2 family members first, and these regulations might adjust the
mitochondrial membrane permeability, attenuate cytochrome c release to cytosol
(Zhang et al., 2010).
The reduction of toxic EAA
In pathological conditions, glutamate (Glu) can
produce the effects of excitotoxicity on nerve cells. The relationship between
neurotoxicity of Glu and pathogenesis of PD has received elevating attention.
At present, the treatment of PD with Glu release inhibitor has become one of
the hottest spots in the research.
In recent years, a growing number of evidences
suggests that in addition to dopamine (DA) and acetylcholine (Ach), there are
also many other neurotransmitters such as Glu, gamma-aminobutyric acid (GABA)
and enkephalin etc., and they can interact with each other in the substantia
nigra and striatum (Papa and Chase, 1996).
Under normal conditions, Glu creates excitatory effect on nerve cells, but it
demonstrates toxic effects when DA neurons are fully or partially degenerated
(Vital et al., 2003). The
concentration of Glu in normal brain cells is close to 10 μmol/L, while the
extracellular concentration is about 0.6 μmol/L. When the extracellular Glu
concentration reaches 25 μmol/L, it can damage the cerebral cortex and hippocampus
(Caragine et al., 1998; Zhou
et al., 2003).
The toxicity of EAA (Glu, aspartate) is mainly reflected in the activation of
the corresponding receptor (NMDA-R, AMPA-R, KA-R) which mediate acute osmotic
swelling or delayed injury of nerve cells. It was found that local and systemic
application of EAA receptor antagonists could lower or prevent motor symptoms
of the PD model rats induced by 6-OHDA, and postpone its the process of
neurodegenerative (Hallett and Standaert, 2004). It
was separately reported that low dose of NMDA receptor antagonist MK-801
combined with levodopa could enhance the efficacy and prolong its duration of
action. Clinically, motor fluctuations and dyskinesia, caused by long term use
of levodopa, can be effectively treated by MK-801. Anticholinergics are one of
NMDA receptor non-competitive antagonists. Amantadine, a drug that has been
used for years to moderately intervene symptoms of PD, has also been shown to
be an NMDA receptor antagonist (Strugstad and Sager, 1998;
Blesa and Przedborski, 2014).
Tetrandrine (Tet), a class of
bisbenzylisoquinoline extracted from the roots of Radix stephania tetrandrae,
(Wong et al., 2017) is a
new type of reversible inhibitor of P-glycoprotein. The level of L-dopa in the
brain can be increased by reversible P-glycoprotein inhibitors, which is
conductive to clinical efficacy of neurodegenerative diseases, including PD
(Schinkel, 1999). The
researchers used Tet combined with GSH and L-dopa to explore the therapeutic
mechanism of PD rats induced by 6-OHDA. By detecting the aspartate (Asp) and
Glu in the affected side of striatum, it was evident that compared with the
model group, the concentration of Asp was dramatically downgraded in the GSH
treatment group; The level of Glu in the GSH + Tet treatment group was much
lower than that in the GSH treatment group; The concentration of Glu and Asp in
the L-dopa treatment group was notably higher than that in the model group; The
concentration of Glu and Asp in the GSH + L-dopa + Tet treatment group was
considerably lower than the model group. The above results show that Tet, by
the means of increasing the concentration of anti-PD drugs in the brain, can
protect the brain neuron from the toxic effect of EAA (Jin and Bao, 2010). In
a separate study, Glu treatment largely increased LDH release and produced a
great deal of NO in primary cultured rat brain neurons. While Baicalein, at 3.5
μmol·L−1, could exert neuroprotective effects against Glu
stimulation by reducing the generation of LDH and NO (Yu et al., 2012).
Puerarin, a kind of flavonoid compound, was extracted from Puerariae Radix. It
stated neuroprotective effects on a variety of brain damage by sharply reducing
the content of EAA. The results demonstrated that puerarin can promote the
expression of Glu decarboxylase mRNA in rats with cerebral ischemia and increase
the contents of cerebral GABA to antagonize the toxic effect of EAA (Huang and
Wang, 2015).
The inhibition of
neuroinflammation
Neuroinflammation is a common and important pathological
mechanism in nervous system diseases and different neurological diseases are
involved in neuroinflammation at some stage. At present, it is believed that
neuroinflammation was involved in an important cascade reaction in neuronal
degeneration of PD (Niranjan, 2014).
In recent years, some progress has been made in
the research of anti-inflammatory TCM in the treatment of PD. The protective
effect of triptolide on dopaminergic neurons in MPP+-induced
hemiparkinsonian rats may be concerned to the inhibition of microglial cell
activation (Hirsch et al., 2005; Gao
et al., 2008).
Curcumin can effectively antagonize the loss of dopaminergic neurons in the
parkinsonian mouse model caused by MPTP. Its mechanism is associated with the
decrease of the active oxygen content of dopaminergic neuron and inhibition of
inflammation (Pan et al., 2007).
Through the antioxidant and anti-inflammatory effects, celastrol also can
efficiently prevent or delay the progression of PD (Faust et al., 2009;
Zhang et al., 2012). In
the study of Polygona-Polysaccharose on PD, it was found that the expression of
Peroxisome proliferator-activated receptor-γ (PPAR-γ) was up-regulated in treatment
group as compared with model group. PPAR-γ is a class of ligand-activated type
2 nuclear transcription factor belonging to the nuclear receptor superfamily.
It has neuroprotective effects and attenuate the neuronal damages from
neurodegenerative diseases such as Alzheimer's disease, PD, cerebral ischemia
and multiple sclerosis. Meanwhile, the study results about
Polygona-Polysaccharose also revealed that the mechanism might be related to
the up-regulation of PPAR-γ expression, thereby inhibiting the inflammatory
reaction and promoting the regeneration of dopaminergic neurons (Chen et
al., 2010).
Polyphenols from toona sinensis seeds (PTSS) can exert the protective effect to
DA neurons of substantia nigra of PD rats by reducing the number of microglia
and astrocytes in the substantia nigra and down-regulating expression levels of
protein and mRNA of inflammatory factors COX-2 and TNF-α (Li X. J. et
al., 2016).
Parthenolide, as an active ingredient obtained from Chinese herbs tansy,
possesses extensive biological functions, such as anti-inflammation, antioxidation
et al., and it also has apparent protective effects against the damage of DA
neurons induced by MPTP in substantia nigra. The research showed that compared
with the mice in control group, the model mice represented the typical symptoms
of PD. The numbers of COX-2, PGE2 and iNOS positive cells were reduced
noticeably (P < 0.01), the number of TH-positive neurons in
substantia nigra was decreased from 58 to 27% after the intervention with
parthenolide. Taken together, the protective effect of parthenolide for
dopaminergic neurons may be related to its activity as an anti-inflammatory in
the expression of COX-2, PGE2, and iNOS in substantia nigra of PD mice model
(Zhang H. et al., 2015).
The inhibition of neuronal
apoptosis
With the in-depth study, the researchers find
that another way of loss of dopaminergic neurons is abnormal apoptosis (Golpich
et al., 2015).
Apoptosis may be one of the most important factors in the death of dopamine
neurons, and accelerate the occurrence and progression of PD (Valdeolivas et
al., 2013).
Energy consumption of normal activities of brain cells are derived directly
from aerobic energy, and there is little energy storage. Once the brain damage
occurs, it will cause nerve cell apoptosis or death (Kermer et al., 1999; Li
R. et al., 2013).
Apoptosis, which is an active programmed cell death, is the terminal phenomenon
of gene-induced biological cascade reaction under the stimulation of both in
vitroand in vivo. The Bcl-2 family is a kind of important
apoptosis-regulatory genes. It is divided into two categories: anti-apoptosis
gene (such as Bcl-2, Bcl-xL, Bcl-w, Bcl-1, etc.) and pro-apoptosis gene (such
as Bax, Bak, Bad, Bid, etc.). Bcl-2, located in the outer mitochondrial
membrane primarily, can counter pro-apoptotic factor. The early phase of the
apoptotic cascade depends mainly on the balance between the pro- and
anti-apoptotic proteins of the Bcl-2 family, while the Bcl-2/Bax ratio is
regarded as a better predictor of apoptosis than the expression of either Bcl-2
or Bax alone (Sa et al., 2015; Wu
et al., 2015).
Studies have shown that the overexpression of bcl-2 can break off the apoptosis
of various nerve cell, can also restrain the toxic effects of MPTP and 6-OHDA
on dopaminergic neurons, thus reducing the apoptosis of dopaminergic neurons in
substantia nigra (Burke, 2011; Chen
et al., 2015b).
Studies indicated that Guiling pa'an Wan (Chinese
patent medicine) could improve pathology and behavior of the PD model rats
induced by 6-OHDA. Based on this background, the mechanism of action was
further studied. After treatment with Guiling pa'an Wan, the expression of
Bcl-2 and Bcl-2/Bax ratio was increased while Bax and Caspase-3 expression were
dropped in substantia nigra neurons, which showed that Guiling pa'an could
provide protection for dopaminergic neurons by reducing the apoptosis of nerve
cells in PD rats (Meng et al., 2014b;
Zhang H. Z. et al., 2016).
Some flavonoids have good effect on the prevention and treatment of PD. … Geniposide,
an iridoid glycoside compound extracted from the TCM Gardenia jasminoides Ellis
fruit, exerts neuroprotective effects by alleviating inflammation responses and
oxidative damages (Zhao et al., 2016). The
behavioral experiment including rotarod and swimming trials indicated that the
Geniposide could substantially improve the abnormal behavior caused by MPTP.
Meanwhile, the number of TH positive neuron sharply increased (P <
0.001) and the apoptotic neurons fell (P < 0.001) after
treatment with Geniposide. Thereby suggesting that Geniposide has protective
effect on dopaminergic neurons in substantia nigra of PD mice model induced by
MPTP, and its mechanism may be related to the inhibition of neuronal apoptosis
(Chen et al., 2015a).
The inhibition of abnormal
protein aggregation
Currently, impaired degradation of misfolded and
aggregated proteins has been proposed to play a key role in the pathogenesis of
PD (Le and Chen, 2009). The
abnormal deposition of protein in brain tissue is characteristic of several
age-related neurodegenerative diseases, such as PD. Although, the composition
and position (i.e., intra- or extracellular) of protein aggregates are
different from disease to disease, this common characteristic shows that
protein deposition per se, or some related event, is toxic to
neurons (Dauer and Przedborski, 2003).
The pathological changes of PD are characterized
by degeneration of DA neurons in the substantia nigra and formation of Lewy
body (LB) in neurons (Scherfler et al., 2007).
Many proteins, including α-synuclein (α-syn), ubiquitin and its related
enzymes, aregathered in LB. The study showed that the death of nerve cells in
the brain was caused by the α-synprotein conformational change, the formation
of amyloid filaments and abnormal accumulation (Dekundy et al., 2015).
α-syn is the main component of LB, which is the firstly identified as a protein
with gene mutation associated with PD. The abnormal aggregation of the protein
is closely related to the pathogenesis of PD (Lubbe and Morris, 2014;
Zhang X. et al., 2016).
The ubiquitin proteasome system (UPS), a new protein degradation pathway, is
regarded as the major pathway of non-lysosomal protein degradation in
eukaryotic cells. The study confirmed that the activity of the proteasome
dropped substantially in substantia nigra of patients with PD, which weakened
the effect of the substantia nigra on the degradation of α-syn and other
proteins (Masliah et al., 2005). The
overexpression and mutation of α-syn can accelerate mitochondrial disorder,
enhance the sensitivity to oxidative stress and promote cell death due to its
cytotoxicity mediated by DAT (Alberio et al., 2012).
In a study, rotenone was used to stimulate PC12
cells to develop a cell model of PD with over expression of α-syn. After
treatment with bilobalide, the oligomer of α-syn were effectively restrained,
cell activity was intensified, and apoptosis was decreased accordingly. Before
that, some scholars found that the bilobalide could regulate the metabolism of
the amyloid precursor protein (APP), increase the proportion of soluble APP
alpha, reduce the formation of β-amyloid protein (Shi et al., 2011). The
similar experimental results were presented that bilobalide could inhibit the
formation of abnormal aggregation of different protein by some common mechanism
and alleviate the toxic effects of abnormal proteins on cells. Therefore, it
acts as a neuroprotective role in this kind of “protein folding diseases” (Zeng
et al., 2013).
In another open study, to produce the symptoms of
PD, researchers injected the trace amounts of the proteasome inhibitor
lactacystin into the substantia nigra pars compacta (SNC) and ventral tegmental
area (VTA) in the brain of SD rats. Compared with the model control, the
aggregation of α-syn and the apoptosis of substantia nigra were obviously
inhibited in rats with PD after treatment with the Anchanling (Chinese patent
medicine), which presented that the mechanism of Anchanling might be related to
the improvement of UPS function. When the damaged UPS function was improved,
the UPS raised up the degradation of α-syn, thereby reducing the accumulation
of intracellular proteins and the formation of inclusion bodies. So, the
improving the function of UPS may be of great significance for the prevention
and treatment of PD (Gao, 2007; Wu
et al., 2009).
Some studies have proved that baicalein can protect nerve cells by inhibiting
fibrosis procedure of α-syn protein. 12.5 mol·L−1 baicalein can
significantly inhibit the oligomerization of α-syn and its cytotoxic effect on
SH-SY5Y cells (Lu et al., 2011).
Clinically, Bushen Huoxue Granule was proved to be effective in treating PD for
many years, a Chinese herbal compound granule (Li et al., 2012). The
therapeutic mechanisms of Bushen Huoxue Granule against PD might be related
with up-regulation of the TrkB expression that could strengthen the effect of
repairing nerve injury factors and down-regulation of the Tau expression that
could contribute to reduce the condensed expression of proteins in the cells
(Yu et al., 2016).
Conclusion
In summary,
PD is regarded as a complex disease caused by interaction among multiple
factors (environmental factors, genetic factors) and various mechanisms.
Considering curative effect and symptom control, in short term, western medicine
seems superior to TCM -- not considering the bias of most folks seek western medicine cure during the time window that it is best managed. However, the long-term effect of treatment is debilitated,
and a series of side effects will be produced. In contrast, TCM has become a
research hotspot in recent years due to its great advantages of multiple
components and holistic regulation. In particular, some progress has been made
in the study of inhibition of oxidative stress, improvement of mitochondrial
energy metabolism, resistance to EAA toxicity and suppression of cell
apoptosis. A range of TCM is summarized in Table Table2,2,
which exhibits neuroprotective effects on dopamine neurons in substantia nigra
or shows beneficial improvements on PD symptoms through one or more biological interventions.
Although TCM has the glorious history in the treatment of PD, the experimental
studies have only been carried out in recent years, especially for the adoption
of the PD model.
PD is a result of the interaction of many
neuroendocrine factors in the aging state. The
use of TCM alone can effectively control the early signs of PD, avoid toxic
side effects of western medicine and enhance the compliance of patients with
medication greatly. Although TCM have showed the magic effect for the
disease, conventional Western trained researchers usually find it difficult for them to
understand the composition and the mechanism of TCM action, let alone
understanding invisible synergy, energy, holography, and so on -- a completely different system where TCM practices are based on and a field in which most conventional Western practitioners and even some low-quality acupuncturists are not trained.
Abbreviations
TCM Traditional Chinese medicine
PD Parkinson's disease
References:
倪海厦谈帕金森病起因 --中国自古以来根本不存在的病
倪海厦医生论帕金森病的治疗方法原则
The Mechanisms of Traditional Chinese Medicine
Underlying the Prevention and Treatment of Parkinson's Disease
Therapeutic History of Parkinson's Disease in
Chinese Medical Treatises
Parkinson's patients find hope in herbs | South
China Morning Post https://www.scmp.com/article/974070/parkinsons-patients-find-hope-herbs
This World Parkinson's Day, Know If You Are At Risk
Of Parkinson's Disease And How You Can Prevent It
Treatment of Idiopathic Parkinson's Disease with Traditional
Chinese Herbal Medicine: A Randomized Placebo-Controlled Pilot Clinical Study
World Parkinson’s Day 2019: Useful tips to help
fight Parkinson’s disease
倪海厦演讲：为什么中医可以从感冒一直治到癌症
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