CN116173003A - Use of drug Ji Weisi for treating Alzheimer's disease - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
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- A61P25/00—Drugs for disorders of the nervous system
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of a medicine Ji Weisi in treating Alzheimer disease. According to the invention, ji Weisi is used for treating Alzheimer's disease for the first time, the neuroprotection of Ji Weisi is observed through a behavioral experiment and electrophysiological recording means system, and the result shows that Ji Weisi can improve the autonomous exploration behavior, long-term spatial learning, reference memory capacity and synaptic plasticity injury of an APP/PS1 double-turn mouse, so that Ji Weisi can have an obvious treatment effect on Alzheimer's disease.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a medicine Ji Weisi in treating Alzheimer disease.
Background
Alzheimer's Disease (AD) is a neurodegenerative disease with very hidden onset and slow progression, the most common of the dementia types, whose main clinical manifestations include: decline of memory, decline of life ability, impairment of cognitive function, etc. Since the discovery of AD in 1907, there has been no effective improved method that has a significant impact on the quality of life of patients and relatives, as well as on medical care and social costs.
The brain pathology of AD is mainly characterized by extracellular accumulation of amyloid- β (aβ) in the form of amyloid plaques and the presence of microtubule-associated protein Tau in the intracellular in the form of neurofibrillary tangles (Neurofibrillary tangles, NTF). The pathogenesis of AD is extremely complex, the pathogenesis is not clear, the main clinically mainstream medicines are mainly cholinesterase inhibitors and NMDA receptor antagonists, and the symptoms are only temporarily relieved, and the progress of AD cannot be prevented or the cognitive impairment can not be reversed.
Ji Weisi he is a histone deacetylase inhibitor with anti-inflammatory properties at low nanomolar concentrations. Phase I safety and pharmacokinetic experiments showed that healthy men with repeated doses of 50, 100 and 200mg Ji Weisi for 7 consecutive days had almost the same kinetics without serious adverse reactions (AEs) and without organ toxicity.
However, there is no report on the novel medical use of Ji Weisi for treating Alzheimer's disease.
Disclosure of Invention
Based on the background, the invention predicts the new application of Ji Weisi in treating Alzheimer disease by using a drug repositioning technology.
In order to achieve the above purpose, the present invention is realized by the following technical scheme:
ji Weisi for use in the manufacture of a product for the treatment of Alzheimer's disease.
Further, the product is a tablet, a hard capsule, a soft capsule, a granule, a pill, an oral liquid or an injection.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, ji Weisi is used for treating Alzheimer's disease for the first time, ji Weisi neuroprotection is systematically observed through a behavioral experiment and an electrophysiological recording means, and Ji Weisi can improve learning and memory functions and enhance the synaptic plasticity of the sea horse of an APP/PS1-AD model mouse, so that Ji Weisi can have an obvious treatment effect on Alzheimer's disease.
Drawings
FIG. 1 is a histogram of total distance walked within 5min of an open field experimental mouse of the present invention;
FIG. 2 is a graph showing the percent residence time in the central area of the field test mice of the present invention;
FIG. 3 is a diagram of a typical original walking trajectory of an open field laboratory mouse of the present invention;
FIG. 4 is a plot of average escape latency for a mouse finding platform for the Morris water maze positioning voyage test of the present invention;
FIG. 5 is a graph of average swimming speed lines of Morris water maze test mice of the present invention;
FIG. 6 is a histogram of the percent of swimming time in the target quadrant of mice after the platform is removed in the Morris water maze space exploration experiment of the present invention;
FIG. 7 is a time histogram of the mouse swimming to the platform for the Morris water maze visual platform test of the present invention;
FIG. 8 is a diagram of an original swimming track of a typical mouse for a Morris water maze positioning navigation experiment of the present invention;
FIG. 9 is a diagram of an original swimming track of a typical mouse in a Morris water maze space exploration experiment of the present invention;
FIG. 10 is a plot of the increase in magnitude of mouse fEPSP as a function of stimulus current intensity recorded in vivo hippocampal field potential, i.e., I-O curve, in accordance with the present invention;
FIG. 11 is a scatter plot of the percent slope of the hippocampal fEPSP versus time for mice before and after HFS in vivo hippocampal field potential recordings in accordance with the present invention;
FIG. 12 is a histogram of the percentage slope of hippocampal fEPSP of a mice recorded in vivo on hippocampal field potential at different times before and after high frequency stimulation in accordance with the present invention;
FIG. 13 is a statistical histogram of in vivo hippocampal field potential record mouse dipulse facilitation (PPF) of the present invention;
FIG. 14 is a diagram of the raw waveform of fEPSP of the present invention typical of mice recorded in the body hippocampal field potential before high frequency stimulation (solid line) and 60min after high frequency stimulation (lower dashed line indicates LTP maintenance).
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Examples
APP/PS1 mice are recognized genetically mutated mice, can well simulate the pathological features of AD, and are ideal AD animal models.
The invention adopts a system of behavioral experiments and electrophysiological recording means to observe the neuroprotection of Ji Weisi. The study is mainly divided into the following two parts: (1) The action of Ji Weisi on the movement capacity and the spatial learning memory capacity of the 9-month-old APP/PS1-AD model mouse is intuitively detected through a behavioral experiment; (2) After the end of the behavioural study, ji Weisi was investigated for his effect on the synaptic plasticity of the hippocampal mice in the APP/PS1-AD model using in vivo hippocampal field potential LTP recording experiments, and dosing intervention was maintained throughout the course of the experiment.
The specific experimental method is as follows:
APP/PS1 transgenic mice (B6C 3-Tg (appwe, PS1d E) and control wild-type (WT) mice were randomly divided into four groups: normal control group (wt+saline), normal administration group (wt+ Ji Weisi he), AD control group (APP/ps1+saline), AD administration group (APP/ps1+ Ji Weisi he). The administration of the drug Ji Weisi to the abdominal cavity or an equal volume of physiological saline was started one month prior to the behavioural test at a dose of 10mg/kg, and remained administered throughout the entire experimental period.
In the open field experiment, the length, width and height of the open field are 40cm respectively, a quarter area at the center of the bottom surface is defined as a central area, and each mouse is placed in the open field in the same central position direction and is free to explore for 5min. Recording a walking track by using a camera, and analyzing the total walking path of the mouse in the open field and the residence time ratio of the central area of the open field by using Smart 3.0 software; the Morris water maze experiment is preceded by five days of positioning navigation experiment to induce each group of mice to learn and memorize the position of the underwater platform, the underwater platform is removed for space exploration in the sixth day, the ratio of the escape latency time of each group of mice in the positioning navigation stage to the total time of the space exploration stage in the target quadrant is detected and counted, and the long-term space learning and memorizing capability of the mice is reflected; after behavioural experiments, the mice were anesthetized and fixed, after positioning the hippocampal Schaffer collateral-CA 1 region pathway of the neurite transmission, the skull was drilled open and stimulation electrodes and recording electrodes were inserted in parallel, the field excitatory postsynaptic potential (field excitatory postsynaptic potential, fEPSP) was recorded for 30min, then 3 pairs of paired pulse stimuli induced bipulsate dissimilarisation (PPF), followed by high frequency stimuli (high frequency stimulation, HFS) induced long-term potentiation (long-term potentiation, LTP), recorded for 60min; finally, the percentage change of the fEPSP slope before and after each group of high-frequency stimulation is counted.
The results of the open field experiments are shown in fig. 1 to 3: the total movement distances of the WT+normal saline group, the WT+ Ji Weisi group, the APP/PS1+normal saline group and the APP/PS1+ Ji Weisi group mice in the open field are 1779.18 +/-120.66 cm, 1942.12 +/-102.97 cm, 1677.53 +/-104.15 cm and 1826.49 +/-177.07 cm respectively, and the total movement distances of the four groups of mice in the open field have no statistical difference (P > 0.05), which indicates that Ji Weisi does not influence the movement ability of the mice. But the percentage of retention time in the central area was 3.41.+ -. 0.19% for the APP/PS1+ saline group mice significantly lower than 8.66.+ -. 1.39% for the WT+ saline group (P < 0.05). After Ji Weisi he was treated, the percentage of APP/PS1 mice stay in the central area of the open field increased to 8.38±1.09% (P < 0.05). In conclusion, the phenomenon that the 9-month-old APP/PS1 mouse has autonomous behavior and the exploring behavior is similar to depression with weakening can be found, the exploring desire of the APP/PS1 mouse in the unfamiliar environment is enhanced through Ji Weisi treatment, the ability of adapting to the new environment is enhanced, and Ji Weisi shows that the autonomous exploring behavior of the APP/PS1 double-rotation mouse can be improved.
The water maze test results are shown in fig. 4 to 9: the escape latency at the 1-5 day position voyage stage showed that the escape latency of all four groups of mice was shortened with the increase of the training days. Among them, APP/PS1+ saline group mice had a significant difference in escape latency between the fourth day (48.06±3.33s, p < 0.05) and the fifth day (44.487 ±2.27s, p < 0.001) over wt+ saline group (fourth day: 28.07±2.19s; fifth day: 19.14±1.44 s), whereas APP/PS1 mice after drug Ji Weisi had been dry had a significantly shortened escape latency (fourth day: 30.99±2.05s, p <0.05; fifth day: 27.31±1.67s, p < 0.01). Space exploration experiments on day 6, wt+normal saline, wt+ Ji Weisi, APP/ps1+normal saline and APP/ps1+ Ji Weisi were 40±4%, 37.5±2.4%, 25±1.2% and 36.1±1.8%, respectively, with APP/ps1+normal saline groups having significantly lower target quadrant residence time percentages than wt+normal saline groups (P < 0.01), while APP/ps1+ Ji Weisi groups had an elevated duty cycle (P < 0.05), indicating that Ji Weisi post-treatment APP/PS1 mice were better able to remember plateau positions. Finally, the swimming speeds of the mice in each group within six days were counted, and the four groups of mice were not different (P > 0.05), indicating that the escape latency period of the mice was not affected by the swimming speed. Meanwhile, in the visual platform experiment, all groups of mice directly swim to the platform and have no difference (P > 0.05) in use, so that the normal vision of the mice is proved. In conclusion, it is demonstrated that under the conditions of motor ability and normal vision of the mice in the water maze, ji Weisi he can improve the long-term spatial learning and reference memory ability of the APP/PS1 mice.
The experimental results of field potential recordings of the CA1 region of the hippocampus in vivo are shown in fig. 10 to 14: IO curves show the magnitude change of fEPSP under different current stimulus intensities, and the magnitude of fEPSP of four groups of mice under the same current stimulus intensity has no statistical difference (P > 0.05), which indicates that the synaptic transmission mechanism of the basis of the four groups of mice is not influenced by genotype and medicine. There was no statistical difference in fEPSP slope (P > 0.05) for the four groups of mice within 30min prior to high frequency stimulation, and the four groups of mice induced LTP after high frequency stimulation, but were on a decreasing trend with recording time. After high frequency stimulation, the four groups of mice had no difference in the percentage of fEPSP slope (P > 0.05); at 30min, there was a significant decrease in fEPSP of 123+ -4.9% in APP/PS1+ saline group (P < 0.001) compared to 173.3+ -4% in WT+ saline group, while 165.1+ -3.2% recovery (P < 0.001) in APP/PS1 group after Ji Weisi he had been treated; also at 60min, 107.9+ -4.4% of APP/PS1+ saline group was significantly reduced (P < 0.001) compared to 159+ -5.5% of WT+ saline group, while 138.9+ -4.6% of APP/PS1+ Ji Weisi group was significantly improved (P < 0.01) compared to APP/PS1+ saline group. Furthermore, the administration of dipulse stimulation prior to high frequency stimulation induced dipulse facilitation (PPF), and there was no statistical difference in PPF (P > 0.05) in the four groups of mice, suggesting that Ji Weisi he reversed the mechanism of post-synaptic rather than release of presynaptic transmitters associated with LTP depression in APP/PS1 mice. Taken together, the results indicate that Ji Weisi he was able to ameliorate synaptic plasticity lesions in APP/PS1 mouse LTP.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (2)
1. Ji Weisi for use in the manufacture of a product for the treatment of Alzheimer's disease.
2. Use according to claim 1, characterized in that: the product is tablet, hard capsule, soft capsule, granule, pill, oral liquid or injection.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113368044A (en) * | 2015-11-03 | 2021-09-10 | 意大发马克股份公司 | Physically and chemically stable oral suspensions of gevinostat |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113368044A (en) * | 2015-11-03 | 2021-09-10 | 意大发马克股份公司 | Physically and chemically stable oral suspensions of gevinostat |
Non-Patent Citations (3)
| Title |
|---|
| ELIF KAYA-TILKI等: "Neuroprotective effects of some epigenetic modifying drugs’ on Chlamydia pneumoniaeinduced neuroinflammation: A novel model", PLOS ONE, 30 November 2021 (2021-11-30), pages 1 - 27 * |
| RAMO´N CACABELOS等: "Epigenetic drug discovery for Alzheimer’s disease", EXPERT OPIN. DRUG DISCOV, 31 December 2014 (2014-12-31), pages 1 - 28 * |
| SURABHI SHUKLA等: "Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation", FRONTIERS IN PHARMACOLOGY, vol. 11, 30 April 2020 (2020-04-30), pages 1 - 20 * |
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