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.
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).
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.
TCM Traditional Chinese medicine
PD Parkinson's disease
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
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