CN111803473A - Nortriptyline for the treatment of Parkinson's disease - Google Patents

Abstract

The theory of dopamine channels states that dopamine molecules pass through dopamine functional channels to reach dopamine active cavities to play a dopamine functional role. The science and pathology of Parkinson's disease states that Parkinson's disease occurs when dopamine functional pathways are blocked by fibrin. This is because occlusion of dopamine functional channels results in a decrease in dopamine-functional factors and a decrease in functional dopamine content. The invention discloses a method for controlling Parkinson's disease by applying nortriptyline to treat, wherein nortriptyline is adopted and is a substance capable of blocking dopamine protective channels. Mouse and animal experiments prove that the nortriptyline can block dopamine protection channels, dredge blocked dopamine functional channels and has the effect of treating and controlling the Parkinson's disease.

Description

Nortriptyline for the treatment of Parkinson's disease

1. Technical field

Parkinson's disease has existed since ancient times. This disease is called Parkinson's disease, because in 1817 the British doctor James Parkinson carefully observed and studied the disease and published a paper, and then named the disease (Parkinson's Disease) with the doctor's surname Parkinson. At present, there are about 10 million Parkinson's patients in the world, of which more than 2 million are in China, and the number of young adults in their 30s and 40s is increasing rapidly. Parkinson's disease includes four main symptoms: (1) resting tremor, (2) muscle rigidity, (3) bradykinesia, (4) abnormal gait and postural instability, and many possible complications that make patients life-threatening It is extremely difficult, and often feels that life is worse than death, but it is not easy to die. It is a severe, torturous, and disabling disease.

Parkinson's disease is still considered to be an incurable, uncontrollable, and disabling disease, and it is still recklessly torturing human beings. Obviously, it is closely related to the lack of a comprehensive and in-depth understanding of the nature of Parkinson's disease, and it is obviously related to the failure to correctly target the cause of the disease, the lack of appropriate drugs, and the lack of rational drug use.

The most essential of these is the production and release of dopamine molecules into the intercellular space by substantia nigra dopamine cells, which have long been ignored. No one has studied where the dopamine molecule actually works in its receptors, and no one has studied whether there is a dopamine channel problem in the dopamine receptors. In the intercellular space, there are various other particles, including Na ⁺ , K ⁺ , Ca ²⁺ , H ₂ O. Each of these particles has channels, so why doesn't the dopamine molecule have channels? How can there be no channel? Obviously, the dopamine molecule should have its channel.

Through long-term basic research, with the support of the National Natural Science Foundation of China, we are very fortunate to discover two dopamine molecular channels, one is a "dopamine functional channel" and the other is a "dopamine protective channel" (ActaPhys.-Chim. Sin. 2017, 23, 927; Acta Phys.-Chim. Sin. 2011, 17, 2432). Based on the "dopamine functional channel", we defined the concepts of total dopamine, "functional dopamine" and non-functional dopamine, and established the functional dopamine content formula: G _D = f × T _D , thus establishing the "dopamine channel theory" and found The essence of Parkinson's disease: lack of functional dopamine, "Scientific Pathology of Parkinson's Disease" and "New Pathology of Parkinson's Disease" were proposed. We also scientifically defined Parkinson's disease, named it: "Functional Dopamine Deficiency Syndrome". Based on "Theory of Dopamine Channels" and "Scientific Pathology of Parkinson's Disease", in academic theory, the essential problem of Parkinson's disease is basically solved. Based on the "Scientific Pathology of Parkinson's Disease", through our invention of a series of treatments for the treatment of dopamine function transforming factors and the application of drugs, Parkinson's disease can be transformed from a complex, incurable and uncontrollable disabling disease to a curable or curable disease. The time to control the simple disease and promote the complete control of Parkinson's disease will come soon, for the benefit of mankind. Since Dr. James Parkinson carefully observed the disease in 1817, at least 50 million people around the world have suffered from this disease. At present, the disease is still torturing human beings recklessly. It cannot be stopped. It is time to stop.

2. Background technology

At present, the study of Parkinson's disease generally adopts the "Science of Dopamine Function" and the old pathology of dopamine neuron apoptosis. "Science of Dopamine Function" believes that the dopamine molecules in the living body, by binding to different types of dopamine receptors, regulate the movement and other functions of the living body, and are related to Parkinson's disease. Arvid Carlsson, Paul Greengard and Eric Kandel were awarded the 2000 Nobel Prize in Medicine for their discovery of the signal transduction of the dopamine molecule. In 1960, Hornykliewic examined the remains of a patient who died in the late stages of Parkinson's disease and found that the deceased had severe striatal dopamine deficiency. Combined with the function of dopamine, the old pathology of Parkinson's appears: the irreversible and progressive apoptosis of dopaminergic neurons in the substantia nigra of the midbrain. When the apoptosis of dopamine cells reaches a certain level, Parkinson's disease occurs.

According to the old pathology of apoptosis, the current clinical measures are: (1) Exogenous supplementation to increase dopamine (commonly used drugs include: Medopa and Sine, etc.), (2) To reduce the decrease in dopamine in the body (commonly used drugs include: Selenium) Gillan, rasagiline, safinamide), (3) provide pseudo-dopamine function through agonists, enhance dopamine function (commonly used drugs: semporol, peptide seda, etc.), (4) antagonize acetylcholine receptors Function, reduce the effect of acetylcholine, so that it can balance the function of dopamine (commonly used drugs are: amantadine, antan, etc.). These drugs only solve the problem of total dopamine and enhance the function of total dopamine, and do not involve the problem of dopamine functionalizing factors. The principles and ideas of these therapies are limited to the problem of total dopamine and the problem of enhancing the function of total dopamine, which is based on the old pathology of Parkinson's disease. The principles and ideas of these treatments only regard the essential problem of Parkinson's disease as a "total dopamine" problem, but do not regard the essential problem of Parkinson's disease as a "functional dopamine" problem. Obviously, the anti-Parkinsonian drugs used in these therapies, although they can achieve partial remission for a limited time, gradually fail in the face of Parkinson's disease. As the patient's age increases, the patient's condition always worsens and aggravates, making the condition an uncontrollable and disabling disease.

3. Contents of the invention

Based on our research, the formula of functional dopamine content is established: G _D = f × T _D , it can be seen that the current therapy only solves the problem of total dopamine in the problem of functional dopamine, that is, to solve the problem of total dopamine content and enhance the function of total dopamine, which is the formula The _TD item in the formula does not involve the dopamine functionalizing factor, which is the f item in the formula. The patented technology and medicine of this series of inventions are the technology and medicine for solving the problem of item f in the formula, and the technology and medicine for solving the problem of dopamine functionalization factor. The current clinical measures only solve the problem of total dopamine content and enhance the function of total dopamine, but have not yet dealt with the problem of dopamine functionalization factors. That is to say, the technology to solve the problem of dopamine functionalizing factor is currently a technical blank in clinical practice. The reason is that the basic scientific research in the past has not yet reached the understanding of the essential problem of Parkinson's disease: "lack of functional dopamine", and the problem of "dopamine functionalization factor" has not been scientifically understood and proposed. And we, based on the functional dopamine content formula: G _D = f × T _D , the application of scientific principles such as "Theory of Dopamine Channels" and "Scientific Pathology of Parkinson's Disease", invented a series of technologies and drugs for treating dopamine function conversion factors.

The patented technology of this invention is the invention of the technology of nortriptyline to block the dopamine protective channel, so as to clear the dopamine functional channel blocked by ±-synuclein-like fibrin, and the invention of nortriptyline for the treatment of Parkinson's disease. sick. Injection or oral administration of nortriptyline to treat Parkinson's disease, by blocking the dopamine protective channel, achieves clearing the dopamine functional channel. Nortriptyline blocking the dopamine protective channel can increase the dopamine functionalization factor, increase the functional dopamine content, and achieve the effect of treating and curing Parkinson's disease. In the substantia nigra of the midbrain, the main substance blocking dopamine functional channels is fibrin, including the most important fibrin is alpha (±-) synuclein.

4. Description of drawings

Figure 1. Nortriptyline molecular structure. Nortriptyline (Nortriptyline, alias, noramitriptyline, noramitriptyline), molecular formula is C ₁₉ H ₂₁ N, chemical name: N-methyl-3-[10,11-dihydro- 5H-Dibenzo[a,d]cycloheptatriene-5-ylidene]-1-propanamine.

5. Specific implementation

1) Establishment of Parkinson's disease animals

±-synuclein contains 140 residues and is a fibrin. Dimeric structure has been reported, which is also a fiber state [J Chem Phys, 2018, 148(12), 123322]. At present, many biotechnology companies can express and purify ±-synuclein well, and the obtained samples have a purity greater than 95%. The literature has reported the use of ±-synuclein to generate an experimental mouse model of Parkinson's disease [Nature 2015,522,340]. According to literature reports, about 200 grams of experimental mice were injected with 2 micrograms of ±-synuclein into the substantia nigra of the midbrain, and then the spatial distribution of ±-synuclein over time was observed by protein fluorescence tracking. Standard Parkinson's disease condition, and apoptosis of dopamine neurons was observed in laboratory mice. The Parkinson's disease experimental mice reported in the literature are based on the apoptosis mechanism of dopamine neurons, and are analyzed by the old pathology of Parkinson's disease. The observed Parkinson's disease in laboratory mice is not self-healing and returning to health. The results have proved that ±-synuclein cannot be eliminated by its own mechanism for experimental mice, and it is also well proved that experimental mice cannot rely on themselves to heal apoptotic dopamine neuron cells, thereby restoring health. .

We also used ±-synuclein to produce Parkinson's disease experimental mice, referring to the method of the above literature. However, we injected 5 μg ±-synuclein into the substantia nigra of the midbrain to about 200 grams of experimental mice, which is 2.5 times that reported in the literature. After injecting 5 micrograms ±-synuclein into the substantia nigra of mice, the experimental mice developed Parkinson's disease on the second day, and the Parkinson's disease caused by injection and solution reagents was excluded by blank test. The day after the injection, the mice did not, and could not, experience massive apoptosis of dopamine neurons, but the mice had severe, standard Parkinson's disease symptoms. These Parkinson's symptoms can persist for more than 2 months. Therefore, our experiment proves that ±-synuclein can block the dopamine functional channel of experimental mice, resulting in Parkinson's disease. After the dopamine functional channel is blocked, ±-synuclein can also play other roles, resulting in a large number of dopamine neurons apoptosis. Such experimental mouse Parkinson's disease can be analyzed through "Scientific Pathology of Parkinson's Disease" and "New Pathology of Parkinson's Disease". Therefore, we refer to the literature method to uniquely establish the standard Parkinson's disease condition in laboratory mice.

In addition, it should be pointed out that it cannot be assumed that a large number of apoptosis of dopamine neurons must be required to generate an animal model of Parkinson's disease. This animal model is based on the old pathology of Parkinson's disease. This situation is possible in the later stages of long-term Parkinson's disease patients. However, in the early, early, and middle stages of Parkinson's disease, patients do not experience true apoptosis of large areas of dopamine neurons. Therefore, treating this animal model as a standard Parkinson's disease animal model for studying Parkinson's disease in different situations has greatly misled and seriously endangered the research and treatment of Parkinson's disease. Parkinson's disease is currently defined by four main conditions: (1) resting tremor, (2) muscle rigidity, (3) bradykinesia, (4) abnormal gait and postural instability, and other complications. Therefore, Parkinson's disease is determined according to the symptoms, not according to a specific cause. The massive apoptosis of dopamine neurons is only one cause of Parkinson's disease, and this situation is possible in the later stages of long-term Parkinson's disease patients. The massive apoptosis of dopamine neurons does lead to a decrease in total dopamine content, but the decrease in total dopamine content cannot be regarded as the essence of Parkinson's disease. Decreased total dopamine content as a cause will lead to: decreased functional dopamine, and decreased functional dopamine is the essence of Parkinson's disease. Therefore, use "functional dopamine" as a standard to judge Parkinson's disease and whether there is Parkinson's disease. The content of functional dopamine also includes dopamine functionalizing factors, which are closely related to the unblocked functional dopamine channels. Therefore, the blockage of functional dopamine channels is another cause of Parkinson's disease. It is not that the old pathology of Parkinson's disease will not appear, but to regard the old pathology of Parkinson's disease as an absolute pathology obviously brings a lot of pain and life to many patients with Parkinson's disease. Treating the old pathology of Parkinson's disease as an absolute pathology has obviously greatly misled and seriously endangered the research and treatment of Parkinson's disease, and seriously affected the invention and development of drugs for the treatment of Parkinson's disease.

2) The effect of nortriptyline on the treatment of Parkinson's disease in animals

From our experiments and reports in the literature, the use of ±-synuclein enables the establishment and generation of standard Parkinson's disease laboratory mice. In this way, experimental mice with Parkinson's disease cannot rely on or rely on their own mechanisms (that is, without any external help) to cure and restore their health. In this way, the standard symptoms of Parkinson's disease experimental mice can be maintained for a long time. Because of this disease, the diseased mice cannot eliminate the cause by their own mechanisms. We analyzed that the cause of this was that the functional dopamine channels of experimental mice were blocked by ±-synuclein, and the cause reported in the literature was that the dopamine neurons of experimental mice were apoptotic by ±-synuclein. In fact, apoptotic dopamine neuron cells should be difficult to revive, so it should be difficult to restore the health of experimental mice. Moreover, in our experiment, about 200 grams of experimental mice were injected with 5 micrograms of the above samples in the substantia nigra of mice, and the experimental mice developed Parkinson's disease on the second day. The mice were unlikely to have a large number of dopamine neurons dying the day after the injection, but the mice had severe, standard Parkinson's disease symptoms. These experiments fully proved that the cause is the clogging of the functional dopamine channels in experimental mice by ±-synuclein.

Since the cause of Parkinson's disease is that the functional dopamine channels of the experimental mice are blocked by ±-synuclein, if foreign drugs are used to help the experimental mice to unblock: the functional dopamine channels blocked by ±-synuclein will increase and restore the functional dopamine content, The Parkinson's disease in the laboratory mice should be cured and the health of the laboratory mice can be restored. In another patented technology project, we adopted the technology of dredging functional dopamine channels, and the technology of directly removing ±-synuclein, to clear the functional dopamine channels blocked by ±-synuclein, so as to cure Parkinson’s disease. Effect. This patented technology uses the technology of blocking dopamine protection channels to improve functional factors, increase functional dopamine content, clear the blocked dopamine protection channels, and cure Parkinson's disease. Nortriptyline is a tricyclic molecule that is lipophilic and is enriched at the site of cell bilayer membranes. The dopamine protective channel exits directly into the space of the cell bilayer membrane, which is the space where nortriptyline binds to the target site of dopamine receptors. Nortriptyline and dopamine receptors protect the exit of the channel have two targets. One target is located in the middle of the receptor, and the interaction energy is about 65kJ.mol ^-1 . Another target is located close to the inner part of the receptor, and the interaction energy is about 76kJ.mol ^-1 . These interactions allow nortriptyline molecules to bind stably at the exit of the dopamine protective channel within a certain period of time, and play the effect of blocking the dopamine protective channel.

Based on the above standard Parkinson's disease experimental mice produced with ±-synuclein, we injected 0.3 mg of nortriptyline intraperitoneally into the experimental mice once a day. In about 30 days, the standard Parkinson's disease symptoms of the experimental mice were eliminated, the drug was stopped, and the experimental mice recovered completely. And no longer needed any help, the lab mice continued to maintain normal health. Therefore, through such standard Parkinson's disease mouse experiments, it is fully proved that nortriptyline has the effect of treating and curing Parkinson's disease.

Claims (2)

1. Nortriptyline (Nortriptyline, alias, noramitriptyline) with molecular formula C for treating and controlling Parkinson disease₁₉H₂₁N, chemical name is N-methyl-3- [10, 11-dihydro-5H-dibenzo [ a, d ]]Cycloheptatrien-5-ylidene]-1-propylamine.

2. The nortriptyline is applied to blocking a dopamine protection channel and dredging a dopamine functional channel blocked by fibrin.

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