CN114984008A - Application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparation of pharmaceutical preparation for treating Parkinson's disease - Google Patents
Application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparation of pharmaceutical preparation for treating Parkinson's disease Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The invention discloses application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparation of a pharmaceutical preparation for treating Parkinson's disease. The invention has definite effect and provides a new medicinal application for treating the Parkinson's disease.
Description
Technical Field
The invention relates to a pharmaceutical application of 2- (4-tert-butylphenyl) -1H-benzimidazole.
Background
Parkinson's Disease (PD), also known as parkinsonism tremors, is a common degenerative disorder of the nervous system. The elderly are common, and the average age of onset is about 60 years old. Statistically, 1 out of every 800 people worldwide will have parkinson, and by 2030, the prevalence of parkinson will double, with over 900 million patients expected due to the accelerated aging process. Parkinson's disease is characterized by progressive, multiple and occult onset of disease, and mainly manifests as bradykinesia, myotonia, resting tremor and postural instability. The main pathological features of parkinson are mainly represented by the decrease of dopaminergic neuronal cells in the substantia nigra site. The dopamine-producing cells in the brain gradually lose function affecting the nervous system, limiting the ability of the patient to control the muscles. At present, the exact etiology of the pathological changes is still unclear, and genetic factors, environmental factors, oxidative stress, neuroinflammation and the like can all participate in the degenerative death process of PD dopaminergic neurons. Clinically, dopamine replacement therapy is mainly used for the drug treatment of the Parkinson disease. The long-term use of the therapy can cause various adverse reactions, such as insane, insomnia, hallucination and other mental symptoms. Moreover, this therapy only improves symptoms, does not prevent the progression of the disease, and does not cure the disease. The direct medical costs to the patient per year are expected to exceed $ 10,000, placing a heavy burden on the home and society. Therefore, the search for new PD therapeutic drugs has great economic and social benefits.
Disclosure of Invention
The invention aims to provide application of 2- (4-tert-butylphenyl) -1H-benzimidazole with a definite effect in preparing a medicinal preparation for treating Parkinson's disease.
The technical solution of the invention is as follows:
an application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparing a medicinal preparation for treating Parkinson's disease.
The medicinal preparation for treating the Parkinson disease is a medicinal preparation for realizing the treatment of the Parkinson disease by protecting dopaminergic neurons.
The medicinal preparation for treating the Parkinson's disease is a medicinal preparation for treating the Parkinson's disease through the improvement effect of the movement function.
The medicinal preparation for treating the Parkinson disease is a medicinal preparation for treating the Parkinson disease through the improvement effect of olfactory function.
The invention has definite effect and provides a new medicinal application for treating the Parkinson's disease.
Drawings
The invention is further illustrated by the following examples in conjunction with the drawings.
FIG. 1 is a structural formula of 2- (4-tert-butylphenyl) -1H-benzimidazole (i.e., compound ZLN 005).
FIG. 2 is a graph of the effect of ZLN005 on cell viability of rat primary dopaminergic neurons.
Wherein: rat primary dopaminergic neurons cultured in vitro were treated with 50 μ M MPP + and simultaneously added with compound ZLN005 at different concentrations (2.5, 5 and 10 μ M), and cell viability was measured after 24 hours of culture. P <0.05, p <0.01, p <0.001, one-way ANOVA analysis.
FIG. 3 is a schematic representation of compound ZLN005 for alleviating motor and olfactory dysfunction in Parkinson's model mice.
A: animal experiment process; b: rotating a rod for experiment; c, climbing a pole for experiment; and D, olfactory test. P <0.01, p <0.001, one-way ANOVA assay. ZLN005, 005: 2- (4-tert-Butylphenyl) -1H-benzimidazole (2- (4-tert-Butylphenyl) -1H-benzimidazole); MPTP: n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (N-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine).
Detailed Description
An application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparing a medicinal preparation for treating Parkinson's disease.
The medicinal preparation for treating the Parkinson disease is a medicinal preparation for realizing the treatment of the Parkinson disease by protecting dopaminergic neurons.
The medicinal preparation for treating the Parkinson's disease is a medicinal preparation for treating the Parkinson's disease through the improvement effect of the movement function.
The medicinal preparation for treating the Parkinson disease is a medicinal preparation for treating the Parkinson disease through the improvement effect of olfactory function.
Compound ZLN005 is shown in FIG. 1. MPP + (1-methyl-4-phenylpyridine ion) is a neurotoxin, commonly used to induce parkinsonian cell models. To investigate ZLN005 whether it has an effect on combating Parkinson's disease, we used MPP + Rat primary dopaminergic neurons were treated with varying concentrations of ZLN005 for intervention. The cell activity detection result shows that compared with the control group, the MPP + The cell activity of the treated group is obviously reduced; ZLN005 with three action concentrations can relieve MPP + Resulting in a decrease in cell viability (figure 2). The above results show that ZLN005 has the effect of protecting dopaminergic neurons in the parkinsonian cell model, suggesting that ZLN005 may have the effect of combating parkinson's diseaseActivity of (2). To verify this hypothesis, we treated mice with MPTP (N-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine): the mice in the Parkinson model were induced by intraperitoneal injection of MPTP at a dose of 20mg/kg/day for 7 consecutive days. Control mice were injected with the same volume of saline. After successful induction in the Parkinson model mice, the mice were subjected to ZLN005 drug intervention in a gavage manner at a dose of 20mg/kg/day for 7 consecutive days (FIG. 3A). After the treatment is finished, animal behavioural analysis is used for carrying out relevant detection. The result shows that the residence time of the mice in the Parkinson model group in the rotating rod is obviously reduced; ZLN005 treatment significantly increased the residence time of the Parkinson model mice on the rotarod (FIG. 3B). The rod climbing experiment shows that the rod climbing time of the Parkinson model mouse is obviously prolonged; and ZLN005 treatment significantly reduced the time for the parkinson model mice to complete climbing the rods (fig. 3C). The results of olfactory tests show that the time for the mice to find hidden food after MPTP treatment is obviously prolonged; ZLN005 intervention significantly reduced the time to find hidden food in the Parkinson model mice (FIG. 3D), suggesting that ZLN005 treatment improved olfactory function in the Parkinson model mice.
Firstly, experimental steps
1. Rat primary dopaminergic neuron culture
Collecting midbrain ventral region tissue of Sprague Dawley rat fetal rat with SPF grade healthy pregnancy for 14 days, collecting the collected tissue, centrifuging at 1000rpm for 5min, removing supernatant, adding pancreatin 1ml for digestion for 2min, adding complete culture medium to stop digestion, and centrifuging at 1000rpm for 5 min; discarding the supernatant, adding complete culture medium, washing once, and centrifuging at 1000rpm for 5 min; discarding the supernatant, adding 2ml complete culture medium to resuspend the cells, filtering with 400 mesh screen, seeding the cells in 96-well plate or 6-well plate coated with Poly-L-Lysine according to a certain density, culturing for 6-8h, changing to neuron culture medium containing 2% B27, changing the medium every 2 days, and treating the cells about 6-8 days later.
2. Rat primary dopaminergic neuron drug treatment
The cells of the control group were not treated with any drug; PD model group cells plus 50 μ M MPP + (1-methyl-4-phenylpyridinium); drug intervention group cell plus 50μM MPP + At the same time, ZLN005(2.5, 5, 10. mu.M) was added at different concentrations. After 24 hours of treatment, cell viability assays were performed.
3. Rat primary dopaminergic neuron cell viability assay
Cells were seeded at 7000 cells/well in 96-well cell culture plates and cultured overnight. After the cell treatment, the medium was removed, 100. mu.l of MTT working solution (MTT: basal medium: 1: 9) was added to each well, and the mixture was cultured in an incubator for 4 to 6 hours, and then 100. mu.l of 20% SDS solution was added thereto and the incubation was continued for 20 hours, and the whole procedure was carefully protected from light. Finally, absorbance is detected by a microplate reader at a wavelength of 570nm, and the OD value reflects the activity of the cells.
4. Preparation of Parkinson's animal model
12 weeks old C57BL/6J male mice, PD model mice were induced by intraperitoneal injection of neurotoxin MPTP (N-methyl-4-phenyl-l,2,3, 6-tetrahydropyridine). Three days before administration, a series of behavioural training such as rod rotating, rod climbing and the like is performed on the mice every day. Mice with the same motor ability are selected as much as possible, so that the influence caused by individual difference is avoided, and the mice are divided into two groups. One group was saline group, and the other group was MPTP group. Then, MPTP (20mg/kg/day) was intraperitoneally administered for one week, and the behavioral assessment was performed again. Mice with a significant decrease in behavioural performance compared to control mice (injected with an equivalent volume of saline) were considered to be successfully induced PD model mice for subsequent experiments.
5. Mouse drug administration treatment
ZLN005 is dissolved in corn oil. Mice were treated with intragastric administration at a dose of 20mg/kg/day once a day for 7 consecutive days. Control and MPTP alone mice were given equal volumes of corn oil.
6. Mouse rod rotation experiment
The mice were first subjected to a 5min acceleration mode (2-20rpm) with a rotarod training in order to try to achieve the same level of time the mice stay on the rod, 2 times per day for a total of 3 days. After drug treatment, mice were behaviorally tested and the rotarod apparatus started, and time and rotational speed were automatically recorded. The residence time on the rotarod was recorded for each mouse.
7. Pole climbing experiment of mouse
A pole of 1cm diameter, 50cm length and 1.5cm diameter cork pellets fixed at the top was made and gauze was wrapped to increase friction, the pole was placed upright, the mouse was placed on the pellet at the top of the home made climbing pole, then the time from the beginning of the animal's movement to the complete turn to head down until it returned to the bottom of the pole was recorded, 5 minutes apart for each test, 3 tests were averaged. Three days before tail vein injection, the mice are trained by climbing poles at the same time every day, and the mice with larger differences are removed to reduce experimental errors.
8. Olfaction function experiment of mouse
Feeding mouse cheese in advance before olfactory sensation test, fasting for 20 hours before olfactory sensation test, putting the mouse into a cage box with clean padding in the test process, burying the cheese in the middle, at the upper left, at the upper right, at the lower left and at the lower right in sequence 2cm below the padding, and detecting the time when the mouse finds the cheese.
Claims (4)
1. An application of 2- (4-tert-butylphenyl) -1H-benzimidazole in preparing a medicinal preparation for treating Parkinson's disease.
2. Use of 2- (4-tert-butylphenyl) -1H-benzimidazole according to claim 1, for the preparation of a pharmaceutical preparation for the treatment of parkinson's disease, characterized in that: the medicinal preparation for treating the Parkinson disease is a medicinal preparation for realizing the treatment of the Parkinson disease by protecting dopaminergic neurons.
3. Use of 2- (4-tert-butylphenyl) -1H-benzimidazole according to claim 1, for the preparation of a pharmaceutical preparation for the treatment of parkinson's disease, characterized in that: the medicinal preparation for treating the Parkinson's disease is a medicinal preparation for treating the Parkinson's disease through the improvement effect of the movement function.
4. Use of 2- (4-tert-butylphenyl) -1H-benzimidazole according to claim 1, for the preparation of a pharmaceutical preparation for the treatment of parkinson's disease, characterized in that: the medicinal preparation for treating the Parkinson disease is a medicinal preparation for treating the Parkinson disease through the improvement effect of olfactory function.
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| WO2016061190A1 (en) * | 2014-10-14 | 2016-04-21 | The Board Of Trustees Of The Leland Stanford Junior University | Method for treating neurodegenerative diseases |
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| WO2016061190A1 (en) * | 2014-10-14 | 2016-04-21 | The Board Of Trustees Of The Leland Stanford Junior University | Method for treating neurodegenerative diseases |
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