I. Overview
Parkinson’s disease is a common neurodegenerative disease in the elderly, with reduced movement, muscle tonus, limb tremor and postural instability as the main clinical symptoms, and the incidence of this disease has a gradually increasing trend with the development of the aging of the social population. In a sample of 63,195 people in Shanghai, Guangzhou, Chengdu, Harbin, Changsha, and Yinchuan, the prevalence rate was 57/100,000, with 92/100,000 in the age group of 50-59, 145/100,000 in the age group of 60-69, and 615/100,000 in the age group of 70 and above. According to the latest estimates, the prevalence of the disease is 100-180 per 100,000 people, with an annual incidence of 4-20 per 100,000 people, and is still increasing. It has been pointed out that dopaminergic neurons in the substantia nigra decrease by 7%-10% for every 10 years of aging, which is related to the loss of dopaminergic neurons associated with natural aging and the reduction of tyrosine lightening enzyme activity, an important enzyme for dopamine synthesis. Lian Xinfu, Department of Brain Diseases, Guangdong Provincial Hospital of Traditional Chinese Medicine
There is no specific cure for Parkinson’s disease, and drug replacement therapy, represented by levodopa preparations, has been dominant in the treatment of PD and is regarded as the “gold standard” for the treatment of PD. Louis E [2], a British scholar, found that the use of levodopa and other drugs could improve the life expectancy of Parkinson’s disease patients in 1988 in a study of Parkinson’s disease patients in northern Manhattan, New York, but the mortality rate was still high. And the occurrence of their side effects is almost inevitable. Common side effects can be broadly classified into two categories [3]: (1) peripheral side effects: they appear early and are mostly manifested as symptoms of gastrointestinal discomfort, such as nausea, vomiting, and poor appetite; they are manifested as symptoms of the cardiovascular system, such as hypertension, arrhythmias and postural hypotension. (2) Central side effects: they appear later, mostly after the application of high-dose levodopa preparations, such as end-of-dose phenomenon, switch phenomenon, isokinetic disorder, sleep disorder and psychiatric symptoms such as anxiety and depression. Amantadine has anticholinergic effects and can improve the efficacy of levodopa, but adverse reactions in the gastrointestinal tract and hematopoietic system can occur. Dopamine receptor agonists can also develop premature beats, tachycardia, atrial fibrillation and other lesions. Surgical stereotactic destruction of the lateral thalamic nucleus and pallidum destruction are rarely used due to poor long-term efficacy and many side effects, while fetal brain nigrostriatal transplantation and genetic engineering treatment are still in the laboratory research stage since the 1980s. The deep brain stimulation therapy introduced in China since 2003 has significantly improved the clinical remission rate of the disease, but there are strict indications and expensive, and the long-term efficacy is still difficult to determine. This provides an entry point for the treatment of TCM. The advantages of TCM in the treatment of this disease are [4]: (1) TCM is a natural medicine with less toxic side effects; (2) it can be taken for a long time with very little drug resistance; (3) the epistemology and methodology of TCM is different from Western medicine, and its holistic concept, whole-body adjustment and individualized treatment according to the person’s needs have the potential to treat the disease at the root. However, its disadvantage lies in the slower improvement of symptoms.
II. The origin of toxicity reduction and potentiation
The concept of toxicity reduction and potentiation emerged from Chinese medical oncology. Over the years, China has made great progress in the research of using Chinese medicine to prevent the toxic side effects of chemotherapy and improve the sensitivity of tumor cells to chemotherapy. Protecting normal tissues from the damage of chemotherapy so as to reduce the toxic side effects and improving the sensitivity of tumor tissues to chemotherapy is undoubtedly an important way to improve the treatment effect of malignant tumors. It has the following two main effects.
1. The prevention or mitigation of toxic side effects of chemotherapy by traditional Chinese medicine is reflected in: (1) slowing down gastrointestinal reactions; (2) improving bone marrow suppression; (3) reducing immunosuppression; (4) preventing multi-organ functional damage.
2. Chinese medicine has a sensitizing effect on chemotherapy drugs, which is reflected in: (1) reversing multidrug resistance of tumor cells; (2) inducing apoptosis of tumor cells by Chinese medicine.
Chinese medicine has made promising achievements in oncology medicine, does it have this role of reducing toxicity and increasing sensitivity in the treatment of other diseases? The Department of Nephrology of Beijing Xiyuan Hospital has used Chinese medicine with hormones to treat a large number of patients with nephrotic syndrome in long-term clinical practice, and has conducted more extensive clinical research on its treatment rules. They believe that hormone with Chinese medicine has a better effect of reducing toxicity and increasing effectiveness. For example, at the early stage of hormone application, combining with Chinese herbal medicines to strengthen the spleen, activate blood circulation and promote water circulation can significantly reduce side effects such as water and sodium retention, hypertension and gastrointestinal reactions caused by hormones. At the middle stage of hormone application, patients will have symptoms such as irritability, insomnia, acne and other symptoms of yin deficiency and heat toxicity, which can be combined with Chinese herbal medicines to nourish yin and clear heat and detoxify toxins in order to reduce the side effects of hormones and thus improve the sensitivity of patients to hormones. During the withdrawal phase of hormone reduction, according to the different reactions of patients, matching with corresponding Chinese herbs is beneficial to the smooth withdrawal of hormones, thus reducing the dependence on hormones. Many patients who are ineffective or partially effective to hormones or are dependent on hormones have improved or recovered after the addition of systematic TCM treatment.
Therefore, it can be considered that Chinese medicine can play the role of reducing toxicity and increasing sensitivity in the combined treatment of Chinese and Western medicine for other diseases.
III. Current status of research on PD sensitization and toxicity reduction
Bao Yangyuan [5] et al. applied 6-OHDA stereotactic injection technique to make a PD rat model. Twenty-four rats were randomly selected and divided into 4 groups (4 rats in each group): model group, Chinese medicine group (anti-shock and antispasmodic capsules: Shou Wu, Fructus Lycii, Fructus Fructus, Radix Angelicae Sinensis, Astragali, Paeonia lactiflora, Gynostemma lucidum, Dilong, Cannabis, Papaya, Atractylodes, Salviae Miltiorrhiza, Scorpion, Crotalus), levodopa (L-dopa) group, Chinese medicine + GSH group, and 6 rats in the normal group. The levels of GSH-Px, MDA and ROS in the substantia nigra were measured after 45 d, and the levels of DA, HVA and MAO-B in the caudate nucleus were measured. It was concluded that the combination of anti-vibration and antispasmodic capsules with GSH could partially improve the rotational behavior of PD model rats, reduce the oxidative stress damage in the nigrostriatal area, decrease MAO-B activity, and regulate the striatal DA content and its metabolism. In addition, there is still a part of Chinese herbal medicine single flavor pharmacological studies at the level of animal experiments have been confirmed to have the effect of alleviating the progression of Parkinson’s disease. For example, and the formula of He Shou Wu, Bai Shao, and Wu Wei Zi as traditional age-delaying drugs have significant antioxidant effects, reducing free radical and lipid peroxide levels and mitigating damage to cell membrane structures [6, 7]. He Shou Wu significantly increased the D2 receptor binding sites and equilibrium dissociation constant values in striatal homogenates of aged rats [8]. Asparagus increases striatal DA content and has a modulating effect on neurotransmitter homeostasis [9]. Also more representative are.
Cao Fei [10] et al. based on the pathogenesis of PD and the basis of the pharmacological action of Ginkgo biloba: scavenging free radicals and orange anti-platelet activating factor (PAF), with the intention of using EGb for PD treatment, through a rat model of Parkinson’s disease, using the TUNEL method, Nissl’s staining, HE staining, and observation of rotational behavior, compared with the control group, to observe the successful model after EGb treatment for 1d, 5d The results showed that the number of apoptotic cells and the number of rotational circles in the substantia nigra were reduced in the EGb group compared with the PD group, and the structure of HE staining was improved. It was concluded that Ginkgo biloba extract could effectively prevent nigrostriatal cell damage in rats with Parkinson’s disease. It has been found that EGb effectively prevented apoptosis of cerebellar granule cells and rat hippocampal cells. While leucogalactone is the main component of anti-apoptosis, this experiment found for the first time that EGb has the effect of preventing apoptosis in rat substantia nigra cells.
Yuan Chonggang et al [11] established an animal model of Parkinson’s disease using ICR pure-line mice to study the inhibitory effect of Shou Wu preparation on the activity of MAO-B in the brain. The results showed that Shou Wu preparation could effectively inhibit the activity of MAO-B in the brain, and the researchers administered Shou Wu preparation to the MPTP-injected mice simultaneously in the experiment, which effectively prevented the MPTP-induced reduction of active activity and the decrease of DA content in the brain. Injecting MPTP into the mice to produce symptoms of Parkinson’s disease and then injecting Shou Wu preparation also improved the active motor state and increased the striatal DA content, and the experimental results demonstrated that Shou Wu preparation has the effect of preventing and treating experimental Parkinson’s disease. Researchers believe that this effect may be related to the inhibition of MAO-B, which inhibits the conversion of MPTP to MPP+, and the inhibition of dopamine catabolism through the inhibition of MAO-B. However, it remains to be further investigated why the Shou Wu preparation has a significant effect on DA content in the striatum compared to other brain regions.
Chen [12] in order to investigate the mechanism of efficacy of Chinese herbal medicines (Lycium barbarum, He Shou Wu, Cistanches) for the treatment of Parkinson’s disease. Forty-eight adult C57BL male mice were randomly divided into six groups, namely, normal group, herbal protection group, herbal test group, methyldopa test group, compound test group, and natural recovery group. The contents of certain monoamine transmitters in the striatum of mice in each group were measured. The levels of DA, DOPAC, NE, MH-PG, 5-HT and 5-HIAA in the striatum of mice in the natural recovery group were all lower than those in the normal group (P<0.05 or P<0.01). The levels of the above indexes in the natural recovery group were lower than those in the herbal protection group, the herbal test group, the methocarbamol test group, and the composite test group (P<0.05 or P<0.01). There was no statistically significant difference between the above indexes in the herbal medicine test group, the methocarbamol test group and the composite test group and the normal group (P>0.05). Conclusion: Chinese herbal medicines to cultivate the liver and kidney can improve the levels of DA, DOPAC, NE, MH-PG, 5-HT, and 5-HIAA in the declining striatum.
He Jiancheng et al [13] in order to investigate the effects of liver and kidney nourishing and detoxifying herbs on oxidative stress in a rat model of experimental Parkinson’s disease. We used 6-hydroxydopamine injected into the right substantia nigra of the brain to cause a lateralized experimental PD model, and nourished liver and kidney, and detoxified herbs (including oral liquid and capsules. The oral solution contained Radix rehmanniae, Radix sanguisorba, Fructus wolfberry, Rhizoma asparagus, Rhizoma gastrodiae, Rhizoma stiffener, Salvia miltiorrhiza, Curcuma longa, Paeonia lactiflora, Radix et Rhizoma nancellus, and the capsule contained Scorpion and Centipede) were used for treatment. Results: The content of reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly lower in the liver and kidney nourishment and detoxification herbs compared with the model group, at (226±59) U mg-1 and (5±3) nmol mg-1, respectively (P< 0.01); the content of GSH, GSH-PX and SOD were significantly higher, at (6.6±2.0) mg g-1, (3.8±0.4) nU g-1 and (6.6±2.0) mg g-1, respectively. The levels of GSH, GSH-PX and SOD were significantly increased to (6.6±2.0) mg・g-1, (3.8±0.4) nU・g-1 and (174±5) nU・mg-1 respectively (P< 0.05 or P< 0.01). It was concluded that herbal medicines nourishing the liver and kidney and detoxifying the ligaments can improve the antioxidant capacity of the body and remove free radicals to protect the body from damage by free radicals.
Cheng Xiaoxin et al [14] investigated the protective effect of regeneryl chlorohydrin (T4) on dopamine (DA) neurons in rats with Parkinson’s disease (PD). The results of the experiment showed that the immunosuppressant T4 had a positive neuroprotective effect in PD rats, and its effect was related to the toxic effect of T4 against the excessive elevation of cytokines in the brain. As a small molecule that can pass through the blood-brain barrier, raffinolactone has a positive neuroprotective and nutritional effect by resisting the toxic effects of excessive elevation of cytokines in the brain and alleviating the death of DA cells at concentrations lower than the toxic effects. Through this experiment, it is also suggested that there is a close relationship between immune abnormalities and PD lesions, and the immunosuppressant T4 can protect neural cells by interfering with the abnormal immune process in PD. Thus, it reveals that T4 has good application prospects for the prevention and treatment of PD and is expected to be a new neuronal protective class of drugs.
The experimental study by Dingfang Cai et al [15] showed that the kidney and liver tonic formula could effectively correct the excessive levels of DA and its metabolites in the nigrostriatal system of PD rats on long-term levodopa, suggesting that the kidney and liver tonic formula neither affected the efficacy of levodopa nor improved the toxic side effects of levodopa on the nigrostriatal system.
IV. Our thinking
A series of studies we conducted in the previous period showed that the herbal treatment we adopted reduced the dose and number of medications taken by patients with Parkinson’s disease to some extent and improved the clinical symptoms and quality of life of patients with Parkinson’s disease [16]. Based on the study of ancient and modern literature, we summarized the current treatment status of Parkinson’s disease, proposed the idea of treating Parkinson’s disease according to the six meridians of syncope, and selected 101 patients with Parkinson’s disease evidence of yin-blood deficiency, tendon loss of moistening type and cold-heat mismatch, syncope wind movement type as the study subjects, and treated Parkinson’s disease with the self-prepared Lianmei Wan plus and minus formula for Parkinson’s disease No. 1 and with Wumei Wan plus and minus formula for Parkinson’s disease No. 3 Parkinson’s disease, a clinical randomized controlled trial was conducted and the following preliminary conclusions were drawn.
(a) The six meridians are the platform for all diseases and are applicable to Parkinson’s disease.
Parkinson’s disease is characterized by limb tremors and muscle constriction and hypermobility, and its pathogenesis involves liver qi and liver blood. The liver has a Yin body and a Yang body. The Yin body refers to the fact that the liver is the main reservoir of blood and has blood as its body; the Yang body refers to the fact that the liver uses Qi as its body and is good at draining it. The liver is the organ of wind and wood, the main drainage, too much drainage, liver wind within the movement of tremors; liver is the main blood collection, moisten the tendons, liver blood deficiency, tendons out of moisten the tendons constricted. These are all liver diseases. The six meridians of the syncope is based on the liver and the heart’s internal organs and meridians, for the two yin crossed the end, a yang first born, there are cold and heat mixed characteristics, “the syncope above the yin, the wind treatment”, the liver is the main blood collection moisten the tendons, the syncope dirty tendons lose moisten the tendons tight: the liver is the main drainage, drainage too much liver wind within the move for tremors, these two main symptoms of PD The two main symptoms of PD are the important pathogenesis of the syncope disease, the deficiency of dirty qi, can not preside over, cold and heat, yin and yang swing and wind up trembling. Moreover, the movement disorders (mostly manifested as dose peak dyskinesia, biphasic dyskinesia, “off” phase dystonia, and erratic movement) and freezing phenomena caused by the use of anti-Parkinson’s disease drugs are still inseparable from the internal movement of liver wind and the blockage of the meridians by phlegm and stagnant blood, resulting in the lack of smooth flow of qi and blood and the loss of nourishment of the tendons [17]. Therefore, the six meridians are the platform for all diseases, not only for typhoid fever, but also for miscellaneous internal injuries.
(2) It is clear that Wu Mei Wan is the main formula for syncopal Yin diseases.
Umei Pill was firstly found in the chapter of “Treating syncope and prolonged diarrhea” in the Treatise on Typhoid Fever. Many later prescription books contain its formula, and its main treatment of symptoms is generally no more than “ascariasis” and “prolonged diarrhea”. Therefore, people gradually regarded this formula as a special agent to expel roundworms and kill worms, which had a profound influence in later times. Ke Yunbo, a doctor of the Qing Dynasty, started from the analysis of the rules of evidence and treatment of syncope and explained the formula of Wu Mei Wan from a new perspective. First of all, he put forward the view that “Wu Mei Wan is the main formula for syncope, not just an agent for ascending syncope”. It is believed that “Zhongjing’s formula, which is originally for all the evidence of syncope, was compiled by Shuhe under the article of vomiting roundworm, so that people do not know that there is a main formula for syncope. The medicine is consistent with the evidence, not only vomiting ascaris a certificate …… syncope fever evidence, the articles do not cubic treatment, when you know that the treatment is not this formula. After that, many doctors advocate this statement. In the clinical evidence, following the principle of treating with evidence, for all kinds of diseases, regardless of which kind, when there is a mixture of cold and heat, deficiency and reality, we can consider using Wu Mei Wan to add or subtract treatment, which is the so-called “treating different diseases together”. Therefore, through long-term clinical observation and exploration, we have achieved certain efficacy in treating PD syncopal Yin cold-heat mixed with wind-movement evidence and syncopal Yin injury deficiency-heat tendons and veins constriction by adding and subtracting Wu Mei Wan, the main formula of syncopal Yin disease in Zhang Zhongjing’s Treatise on Typhoid Fever, and adding and subtracting Lien Mei Tang in Wu Jutong’s Wenzhi Zhuanzhi, respectively.
(C) The study of PD No. 1 and PD No. 3 in reducing toxicity and increasing efficacy.
We treated patients with two subtypes of Parkinson’s disease, rigid hypokinetic type and tremor type, using PAD 1 and PAD 3, respectively, and came to the preliminary conclusion that the difference between the UPDRS scores of each part of the patients in the treatment group and the control group after treatment with PAD 1 group improved by mean comparison, the difference in daily activity score, and the difference in total score, P < 0.05, with significant differences. The difference of mental, behavioral and emotional scores, the difference of motor function scores and the difference of comorbidity treatment scores did not improve, P＞0.05,the difference was not significant. There was no improvement in the difference of the score of complications treatment, P>0.05, and the difference was not significant. It can be seen that Chinese herbal medicine played a certain effect of augmentation, but it was not very effective in reducing complications. When the three groups were compared, the difference in complication treatment points improved, P < 0.05, and the difference was significant. In the analysis of variance of the difference in the components of complications after treatment in the three groups of patients compared by multiple sample means, the difference in the difference in the points of fluctuation phenomenon improved, P < 0.05, and the difference was significant, while the difference in the points of isokinetic disorders and other complications did not improve, P > 0.05, and the difference was not significant. This is consistent with the clinical observation that Chinese medicine can reduce the end-of-dose phenomenon. The sample content should be further expanded for further study.
V. Outlook
First of all, we should standardize clinical research, select the best research plan, and conduct multi-center research. From many reports, many scientific research protocols on TCM treatment of Parkinson’s disease are not rigorous enough. It is suggested that future clinical studies should highlight the characteristics of TCM and achieve complete unity of theory, method, prescription and medicine, as well as strict scientific research trials, follow the principle of randomization, and try to use blinded, multicenter clinical observations and establish a recognized Western control group to confirm the advantages of TCM in the treatment of this disease.
Secondly, we should further strengthen the dosage form reform. In view of the long duration of the disease and the inconvenience of taking tonics, it is difficult for patients to adhere to the treatment, so the research on dosage forms should be strengthened. Should be based on the cream pill, also in line with the characteristics of Chinese medicine treatment of chronic diseases to cream pill. Again, the treatment should be staged. In the process of clinical practice, some patients have achieved promising results with simple Chinese medicine treatment, suggesting that early stage patients can try Chinese medicine treatment; patients in the middle and late stage can be treated with a combination of Chinese and Western medicine, in order to bring into play the efficacy of Chinese medicine to increase efficiency and reduce side effects.