Along with the increasing aging of the population, Parkinson’s disease has become one of the important diseases that seriously affect human health. Despite the rapid development of neuroscience in recent times, especially in molecular biology, molecular genetics and molecular pathology have made remarkable achievements, especially in recent years there are breakthroughs in the research methods and theories of neural stem cells, coupled with the use of advanced diagnostic techniques and medical equipment, have made remarkable achievements in the basic research and clinical treatment of Parkinson’s disease; nevertheless, the treatment of Parkinson’s disease still has a long way to go. The treatment of Parkinson’s disease is still a long way to go.
I. Pharmacological treatment of Parkinson’s disease
Drug therapy for Parkinson’s disease continues to be based on the following principles.
1) The choice of anti-Parkinson’s disease drugs is individualized according to the condition, e.g., for resting tremor, choose Senfro and Antan anticholinergic drugs, but use with caution for those older than 70 years old, which may induce the possibility of Alzheimer’s disease.
2) Drug dose to produce satisfactory efficacy of the minimum dose shall prevail, and if necessary, slowly increase the dose according to the condition.
3) Prefer a single drug, if necessary, a combination of drugs; generally should not be suddenly discontinued.
Clinical treatment of Parkinson’s disease has so far developed to the fourth generation of drugs, the first generation of anticholinergic drugs and amantadine, the second generation of levodopa class, the third generation of agonists and enhancers of dopamine receptors, the fourth generation of MAO-B selective inhibitors and catecholamine oxygen site methyltransferase (COMT) inhibitors. The first generation anticholinergic drugs correct the dopamine imbalance effect by inhibiting the action of acetylcholine and correspondingly increasing the dopamine effect, and these drugs are effective in tremor. Second-generation levodopa drugs achieve therapeutic effects by replenishing dopamine transmitters in the brain, and are effective for tremor, rigidity and reduced movement. Some short-term gastrointestinal symptoms such as nausea, vomiting, abdominal pain, anorexia and cardiovascular symptoms such as tachycardia and tachycardia. The third generation of drugs for Parkinson’s disease are agonists and enhancers of dopamine receptors, represented by bromocriptine and pergolide.
Clinically applied agonists almost all act on D2 or D2/D3 receptors, and in recent years D1 receptor agonists have also begun to be used clinically. The most successful fourth-generation MAO-B selective inhibitor is selagiline, and selective combination with antan and other drugs is effective for early PD. Catecholamine oxygen-site methyltransferase (COMT) inhibitors, on the other hand, are represented by entacapone. The most effective method is generally considered to be levodopa replacement therapy, but it is still not effective in stopping or slowing down the progression of the disease. Therefore, monoamine oxidase B inhibitors and catechol 2 oxygen 2 methyltransferase inhibitors are also used clinically as adjunctive therapy.
The most popular drugs are entacapone, selagiline and dextromorphone hydrochloride.
Entacapone (Comtan) is a specific catecholamine O-methyltransferase (COMT) inhibitor, which is a new class of drugs developed and produced by Novartis, and was approved by the FDA in October 1999 for the adjuvant treatment of PD. It can be used in combination with levodopa to treat the end-of-dose phenomenon in Parkinson’s disease patients, increasing the time patients are “on” and decreasing the time they are “off”. Clinical studies have shown that most patients tolerate entacapone well, and Ent is used as an adjunct to levodopa for the treatment of “end-of-dose deterioration” in PD patients with significant efficacy and high safety. With the aging population in China, the number of PD patients is also increasing year by year, and Ent can significantly improve the quality of survival of patients, providing a new development direction for PD treatment. At present, foreign countries have produced the compound formulation of this product, which is composed of Ent levodopa and carbidopa 3 drugs in different proportions. Taking 1 capsule daily can greatly improve the patient’s compliance and significantly improve the efficacy and reduce the complications such as dyskinesia due to the unstable plasma concentration of levodopa.
Selgilone is a highly effective and selective inhibitor of MAO-B, which has been used in clinical treatment of PD since 1986. It can inhibit the production of free radicals in dopamine metabolism and counteract the toxic effects of neurotoxins such as 6-hydroxydopamine (6-OHDA) and toluene tetrahydropyridine on dopaminergic nerves. In addition, its metabolite amphetamine also has antidepressant effect. In the past, sellegran was mostly recommended as an adjunct to levodopa, mainly used in patients with mid- to late-stage PD. Most clinical trials have shown that the combination of sellegran and levodopa can reduce the dose of the latter, improve patients’ symptoms, and control adverse effects such as “switching” phenomenon and allodynia relatively effectively. In recent years, some foreign PD research groups have treated early-stage PD patients who have never received dopamine replacement therapy with sregiline alone or in combination with vitamin E. They have reached positive conclusions that sregiline improves the treatment satisfaction of PD patients and prolongs the time to start levodopa.
R-apomorphine hydrochloride (APH), known by its trade name Apokyn, was developed by Mylan bertek Pharmaceuticals, Inc. and approved for marketing by the FDA in April 2004, making APH the first drug to be used in the treatment of patients with acute exacerbations of severe PD. Indications: APH is approved for the acute, intermittent treatment of the “off” interval associated with hypermobility in advanced PD, where the “on/off” interval is not predicted to be the primary disease symptom in patients with advanced PD, and where motor behavior is characterized by frequent “On/off” fluctuations. APH can shorten the “off” interval by 50% and can rapidly restore movement or prevent the onset of the off phase.
With the rapid development of genetic pharmacology and the continuous updating of PD models, new compounds for PD treatment will emerge, and high-throughput screening compounds will be available.
As patients with Parkinson’s disease will experience a gradual decrease in drug efficacy, “on/off” fluctuations, and the appearance of anomalous evidence; therefore, for patients who are no longer taking drugs or have intolerable side effects, surgical treatment should be chosen.
Surgical treatment of Parkinson’s disease
At present, the surgical treatment of PD has basically formed a pattern of nucleus deep brain stimulation (DBS) treatment mainly supplemented by radiofrequency destruction treatment. Stereotactic technique for PD can be traced back to 1950 when Irving Cooper discovered that ligation of the anterior choroidal artery could relieve the symptoms of stiffness and tremor in the contralateral limb of PD, which led to the application of pallidum destruction method. The more established method is the destruction of the ventral lateral nucleus of the thalamus (Vim) and the medial part of the pallidum (Gpi). Gpi destruction is effective in most Parkinson’s diseases, whereas Vim destruction can only be used to treat tremor-based PD, which is easy to perform, technically mature, and inexpensive. The disadvantage is that it can only be performed unilaterally, while bilateral destruction is prone to complications, such as aphasia and coma in severe cases, and the side effects are irreversible once the nucleus is destroyed. In addition, the side effects of nucleus disruption are irreversible. Because it cannot be regulated according to the development of the disease, “relapse” is often inevitable after 3-5 years.
Compared to disruption, DBS treatment does not extensively destroy the intrinsic nuclei of the brain, thus reducing the direct side effects of the procedure, and can be adjusted in vitro and in accordance with the progress of the disease; while maximizing its therapeutic effect, it avoids as much as possible the adverse effects of electrical stimulation. The electrodes can also be removed if severe non-modifiable adverse symptoms occur. In some cases, when delayed stimulation side effects occur after surgery, the stimulation electrode position can be surgically adjusted again and still achieve good results. This also indicates that the placement of deep electrodes does not directly cause serious irreversible damage to brain tissue; at the same time, it suggests that accurate electrode placement during surgery is fundamental to good outcomes.
In terms of surgical target localization, most scholars believe that anatomical localization of imaging and functional localization of microelectrodes are equally important; the former is the foundation, without accurate anatomical localization there is no way to talk about the next step of functional localization; and the application of microelectrode recording in the target area identified by CT or MRI to get the location of abnormal discharge cells associated with movement, i.e., to perform functional localization; at the same time, it is also an affirmation or correction.
As with other stereotactic procedures, DBS implanted electrodes are subject to the possibility of complications such as intracerebral hemorrhage, convulsions and infection. The incidence of these complications is about 3-4%, and they do not usually cause serious disability. Side effects such as tingling or muscle weakness in the arms and face, slurred pronunciation, dizziness or reduced motor coordination, and a feeling of shock may also occur during the postoperative stimulation procedure. These side effects are usually mild and disappear with the absence of stimulation, and can be minimized by timely and appropriate adjustment of the stimulation parameters.
The recovery of motor function was more pronounced in patients with bilateral STN-DBS, probably due to the simultaneous relief of PD symptoms in both limbs and mid-axis, which facilitated the patient to reach the balance point faster and to coordinate the limb activities during motor training.
It has been found that the reduced function of striatal dopaminergic neurons leads to excessive discharge of hypothalamic neurons, and the excessive electrical activity causes enhanced inhibitory output in the medial part of the pallidum, which in turn causes enhanced inhibition of thalamus, thalamocortical neurons and pedunculopontine and pontine nuclei, resulting in decreased motor coordination and clinical symptoms of Parkinson’s disease. It has been reported that the modulation of dopaminergic neurotransmitters does not play a critical role in the mechanism of action of STN-DBS, and the mechanism of action may be related to the fact that the frequency of DBS stimulation is higher than the excitation frequency of the target STN cells, which inhibits the activity of neurons in the STN or thalamic Vim nucleus, and that the depolarization of electrical stimulation of the STN partially eliminates the inhibition of the thalamic easy effect by the medial nucleus of the pallidum and the substantia nigra reticularis, thus The treatment objective of reducing tremor and relieving muscle tone is achieved by weakening the intensity of stimulation of the thalamus-cortex-spinal motor branch-muscle receptor pathway.
Although STN can improve PD symptoms in general and has been shown to reduce dopamine dosage in postoperative patients in a large number of cases, most scholars believe that it is too early to conclude that GPi is not the best target, firstly, the GPi nucleus is larger than STN, which makes localization easier and its location relatively safe; especially in non-tremoric patients with significant drug anisotropy. PD patients with non-tremor and significant drug allodynia are still often used.
It has been suggested that DBS of the STN can delay the progression of PD because of the inhibition of STN hyperactivity, i.e., it is beneficial for improving progressive nigrostriatal atrophy. However, it has been recently demonstrated with PET functional images that PD patients who had bilateral DBS STN installed and clinically effective still had persistently reduced dopaminergic function, which was not significantly different from PD patients without DBS surgery, and therefore the neuroprotective properties of STN-targeted DBS surgery cannot be confirmed yet. Due to the high controllability and safety of the DBS technique, as well as its definite and long-lasting efficacy, it has been accepted by an increasing number of patients with Parkinson’s disease and is now a routine surgical treatment for Parkinson’s disease.
III. Gamma knife treatment of Parkinson’s disease
Gamma knife is a new technology that has emerged with the development of stereotactic radiosurgery in recent years. Gamma knife is a multi-60Co source radiation device. The 201 radiation sources of about 1mm in diameter and 20mm in length are placed in a helmet-like shield, and the target is destroyed by the principle of stereotactic radiosurgery to achieve the treatment purpose. The indications are the same as those for stereotactic surgery, especially for elderly patients with important organ dysfunction who do not want to undergo open stereotactic surgery. However, the postoperative period is prone to radioactive cerebral edema, and the therapeutic foci of the nucleus are irreversible once the side effects occur, as in the case of radiofrequency destruction. At present, stereotactic radiosurgery for Parkinson’s disease is still in the stage of clinical experience accumulation.
IV. Neural stem cell transplantation and fetal brain transplantation
Neural stem cells are multifunctional stem cells derived from the nervous system and can be differentiated into neurons, oligodendrocytes and astrocytes. Recent studies have shown that they exist not only in developing embryonic tissues but also in the nervous system of adult animals. The discovery of neural stem cell brain tissues, which have the possibility of self-repair after injury, and the discovery of basic research fields that they can be directed to differentiate into neural tissues through other tissues, have been applied from the laboratory to the clinical stage. The autologous bone marrow cultured stromal stem cells carried out by Professor Xu Ruxiang of the Department of Neurosurgery, Zhujiang Hospital, Guangzhou, have entered the basal nucleus cluster in the brain through stereotactic technology, and have relieved the symptoms of stiffness and tremor to a certain extent. Professor Zhang Shizhong successfully implanted neural stem cells in the lateral ventricle and striatum in the laboratory and achieved good results, which is a good demonstration for clinical transplantation of stem cells through lumbar puncture stem cells. Medical doctors in the United States have achieved therapeutic results by transplanting fetal brains into Parkinson’s patients. As the technology of stem cell research further matures and deepens, it is expected that Parkinson’s disease can be treated in the future, and the former has more application prospect because it is easy to take the material, extract the autologous bone marrow, induce differentiation by in vitro orientation, and cultivate biblical stem cells regardless of the physical and moral issues, and there is no immune rejection reaction.
V. Gene therapy
Gene therapy for Parkinson’s is a method of treating the disease by exogenous target genes to target cells that express antisense genes to shut down harmful genes. In essence, gene therapy aims to treat and improve symptoms by increasing dopamine levels at the molecular and genetic levels. Current gene therapy focuses on pouring enzymes involved in dopamine synthesis into the striatal system to replenish dopamine production and expressing neurotrophic factors to protect and repair dopamine-functioning neurons that have been damaged. The latter will be the main direction of gene therapy for Parkinson’s in the future. Due to the rapid advances in molecular biology and the specificity of the pathological alterations in Parkinson’s, treatment from gene therapy will be highly promising.
VI. Outlook
There is no absolute model for the treatment of PD, because the clinical symptoms will vary from patient to patient. The main clinical measures available in the near future are still pharmacological and surgical treatment, emphasizing the integrated treatment of various methods and individualized treatment to effectively improve the survival rate and quality of life of patients. It is foreseeable that more new drugs will enter the clinic in the future, but it is still the direction of future development to stop the progression of the disease and protective measures, and the further promotion of surgical DBS surgery will serve human beings more.