Has anyone said that to you?
“It seems that your body is shaking all the time.”
“Your movements seem to be slower than before.”
“How did you start taking small steps?”
“It seems a little difficult for you to turn around.”
“You have fallen several times during this time.”
That is because there is a disease called Parkinson’s Disease (PD).
Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease. It is estimated that there are close to 10 million PD patients in the world. The main pathological change of PD is the degeneration and death of dopaminergic (DA) neurons in the dense part of the midbrain substantia nigra, resulting in a significant decrease in striatum dopamine levels. The clinical manifestations are tremor, muscle rigidity, slow movement, and unstable gait and posture. In the past, the main treatment for PD was levodopa/carbidopa, but long-term use of dopamine drugs can cause movement complications such as symptom fluctuations and dyskinesia. At present, drugs for treating PD can only relieve symptoms, and cannot fundamentally prevent degeneration of dopaminergic neurons.
Parkinson’s pathogenesis and pathology Parkinson’s pathogenesis and pathology
Dopamine and acetylcholine are two important neurotransmitters in the striatum, and their functions are antagonistic to each other. Maintaining a balance between the two plays an important role in regulating the activity of the basal ganglia circuit. In Parkinson’s disease, due to the degeneration and loss of dopaminergic neurons in the substantia nigra, the dopamine content in the striatum is significantly reduced, resulting in the relative hyperfunction of the acetylcholine system, resulting in increased muscle tone and decreased exercise. The exact pathogenesis leading to the degeneration and death of nigra dopaminergic neurons is not yet clear. Current studies have shown that oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, glial cell hyperplasia, and inflammatory reactions in the nigra dopaminergic neurons degeneration It plays an important role in death.
The pathological changes of PD are mainly located in the substantia nigra, and the degenerated and shed cells are mainly dopaminergic cells in the dense zone. In addition, pigmented nerve cell populations in the lobe nucleus, dorsal nucleus nucleus, and mesenteric nucleus also have obvious degeneration, and the basal ganglia nucleus also has obvious lesions. Another pathological feature of PD is the Lewy bodies in the cytoplasm of the remaining neurons in the degeneration area, but the significance of Lewy bodies is unknown. The latest research found that α-synuclein mutations in Lewy bodies are related to the etiology of PD, but recent studies have found that Lewy bodies are the normal components of cells-composed of neuronal filaments. Lewy bodies are not unique to PD, and they can also be seen in dementia.
Parkinson’s treatment method
When the patient first appeared symptoms, the patient’s brain dopaminergic neurons decreased by more than 50%, so the existing treatment is to supplement dopamine and try to restore normal dopamine levels in the brain.
Drug therapy is the most important treatment method for Parkinson’s disease, including disease-modifying drugs and symptomatic drugs. The purpose of disease-modifying therapy is to delay the progression of the disease. The current commonly used drugs for disease-modifying effects are monoamine oxidase B type (MAO-B) Inhibitors and dopamine receptor (DR) agonists, etc. In addition to possible disease-modifying effects, disease-modifying therapeutic drugs can also improve symptoms. Symptomatic therapeutic drugs can not only significantly improve symptoms, but also have a certain disease modifying effect.
Anticholinergic drugs: At present, the main domestic application of diphenhydroxide is for patients with tremor, but it is not recommended for patients without tremor. Long-term use of this class of drugs may lead to a decline in cognitive function. It is best not to use it for patients ≥60 years old, and narrow angle glaucoma and prostatic hypertrophy patients are prohibited.
Amantadine: This medicine is effective for stiffness, tremor, and reduced movement. The combination of amantadine and anticholinergic drugs or levodopa has a synergistic effect and is helpful in improving dyskinesia. Patients with renal insufficiency, epilepsy, severe gastric ulcer, and liver disease should be used with caution, and lactating women should not use it. Long-term medication can cause reticular plaques in the lower extremity skin, edema of the ankle and calf.
Dopamine: By supplementing the deficiency of dopamine, the acetylcholine and dopamine system can be rebalanced to improve symptoms.
DR agonists: Most non-ergot DR agonists (Bedil sustained-release tablets (Tesoda sustained-release tablets)) are currently the first-selected drugs, especially for early-stage patients with early-onset Parkinson’s disease. Because, to prevent or reduce the occurrence of sports complications. Start with a small dose and gradually increase the dose until you get a satisfactory effect without side effects. The side effects of DR agonists are similar to compound levodopa, except that its symptom fluctuations and dyskinesia have a low incidence, while postural hypotension, ankle edema and mental abnormalities (illusion, hyperphagia, hypersexuality, etc.) occur. The rate is higher.
Monoamine oxidase-B inhibitor: Take it in the morning and noon, do not use it in the evening or evening to avoid insomnia, or use it with vitamin E 2000U. Use it with caution in patients with gastric ulcers. Forbid use with serotonin reuptake inhibitor (SSRI).
COMT inhibitors: Compound levodopa + COMT inhibitors are preferred in the early stage of the disease, such as entacapone double dopa tablets (combined with entacapone/levodopa/carbidopa), and its drug side effects include diarrhea , Headache, sweating, dry mouth, increased transaminase, abdominal pain, yellow urine, etc. Tocapone may cause liver function damage, and liver function needs to be closely monitored, especially in the first 3 months after medication. <
Deep brain electrical stimulator (English abbreviation DBS, commonly known as brain pacemaker) is the main surgical treatment for Parkinson’s disease. The principle is to implant an electrode with a diameter of 1.27 mm in the abnormally excited area of the patient’s brain. There are four stimulation contacts at the electrode tip to contact the brain tissue. A pulse generator buried under the chest sends out pulsed electrical stimulation, which is transmitted through the subcutaneous extension wire to the The electrode acts on the abnormally excited area of the brain to correct its abnormal discharge, thereby controlling the symptoms of Parkinson’s disease.
Brain pacemakers are considered to be the second milestone in the treatment of Parkinson’s disease after levodopa. Brain pacemakers can significantly relieve tremor, stiffness, and slow movements. They are particularly effective for the complications of dyskinesia caused by drugs, and can reduce the dose of drug therapy. However, surgical treatment has the following disadvantages:
Although the application of rechargeable technology in pulse generators of brain pacemakers greatly prolongs the life of pulse generators and reduces the frequency of replacing pulse generators, the operation cost of implanting brain pacemakers is still relatively expensive.
Limited improvement in some symptoms
Brain pacemakers are similar to medical treatments, mainly to control symptoms. As the course of Parkinson’s disease prolongs, the condition itself will continue to develop. Brain pacemakers have limited improvement in axial symptoms such as balance, posture, gait, swallowing, and speech, especially freezing gait and dysarthria, which are ineffective for medical treatment.
Surgical implants have risks
Although the pacemaker operation is a minimally invasive operation, there is still a risk of surgical complications, but the risk is very low. Complications include cerebral hemorrhage caused by electrode implantation, skin infections and ulcers, and lung infections. Among them, cerebral hemorrhage is the most serious complication, and its incidence is about 1.5%.
Stem cell therapy
In recent years, some researchers have turned Parkinson’s treatment to innovative treatment schemes, in which cell transplantation has attracted the attention of many scientists. The study found that transplanting DA neurons from embryonic cells into the patient’s brain can alleviate the symptoms of Parkinson’s disease. The rise of stem cell technology has made this possible.
Neural precursor cells are cultured using induced pluripotent stem cells, and these precursor cells that can differentiate into neural cells are transplanted into the brains of patients with Parkinson’s disease. Under the treatment of this method, the patient’s hands and feet trembling and other symptoms were significantly improved. The implanted stem cells played a major role in the monkey brain of the patient, and there were no abnormalities within two years after transplantation. At present, stem cell therapy has entered the clinic.
Although the use of stem cell transplantation to treat Parkinson’s disease currently requires more clinical trials to prove its effectiveness, but pre-clinical and some clinical data have given very positive results feedback. Stem cells have the characteristics of pluripotent differentiation potential and secretion of multiple factors, or will become a new hope to delay or even cure degenerative diseases such as Parkinson’s disease.
At present, there is no complete cure for Parkinson’s disease, and drug therapy is still the mainstay. Drugs can relieve the symptoms of Parkinson’s disease. Although its effect is merely relief, it is difficult to fundamentally cure Parkinson’s disease, but we never give up the pace of exploration. We have made great progress in finding and developing new treatments for PD. Several drug candidates are entering clinical research, and they have the potential to change the disease process. Although the pathogenesis of PD has not been fully clarified, with the discovery of better disease biomarkers and targets, the development of better PD therapies has broad prospects.
Medicilon has effective models for evaluating new drugs for the treatment of PD, including MPTP-induced subacute PD model in mice, MPTP+ probenecid-induced chronic PD model in mice, and oxytremor-induced choline-like symptoms model. Rotation bar method, pole climbing method, grip test and other methods to evaluate the improvement of the test substance on the symptoms of PD. Immunohistochemical staining (ICH) method can be used to observe whether the test substance is protected by dopamine neurons (TH staining) Effect, by immunohistochemical staining of α-synuclein, GFAP, Iba-1, etc., to observe the effect of the test substance on the corresponding pathology. We have successfully conducted effective new drug evaluation services for Chinese and foreign customers.
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