CN110464834B - Application of ceruloplasmin and donepezil combined - Google Patents
Application of ceruloplasmin and donepezil combined Download PDFInfo
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The invention belongs to the application field of biological medicines, and relates to an application of ceruloplasmin and donepezil in preparation of a medicine for preventing or/and improving or/and treating Alzheimer's disease; or/and the application in preparing intelligence-benefiting supplements or medicines. The ceruloplasmin participating in the regulation of the balance of metal ions in vivo in the blood plasma can improve the self-care ability, learning and memory ability of donepezil for treating animal dementia models, and can play a role in enhancing memory and improving cognitive function. The inventor finds that ceruloplasmin and donepezil are combined to obviously improve the learning and memory ability of the dementia animal model. The nesting experiment result shows that the ceruloplasmin and the donepezil are combined to improve the nesting capacity of the dementia animal model and prompt that the self-care capacity of the dementia animal is improved. The result of the water maze experiment shows that the ceruloplasmin can improve the learning and memory ability of the dementia animal model.
Description
Technical Field
The invention belongs to the application field of biological medicines, and relates to an application of ceruloplasmin and donepezil in preparation of a medicine for preventing or/and improving or/and treating Alzheimer's disease; or/and application in preparing intelligence-benefiting supplements or medicines.
Background
Alzheimer's Disease (AD), also known as senile dementia, is a degenerative disease of the central nervous system of the brain caused by neuronal loss, with a prevalence rate of about 4% to 8% in elderly people. In 1906, a german neuropathologist, alzheimer's, first reported a 51 year old female patient with progressive memory decline. In 1910, the psychiatrist Emil Kraepelin, known to name and classify brain disease, proposed to name this disease as alzheimer's disease. The common clinical manifestations of the disease are progressive hypomnesis and cognition, language disorder, psychomotor abnormality, etc., which cause serious impact on the normal life of the patient and bring heavy burden to family and society. In 2010, the WHO reported 3500 ten thousand global dementia patients and 540 thousand Chinese patients. Since 2010, the general population for dementia worldwide doubles every 20 years. The world 2015 report of alzheimer's disease states that by 2050, the number of patients with AD worldwide will increase to 1.3 billion. The pathogenesis of AD is complex, including amyloid deposition, metal ion homeostasis in the brain, neurotransmitter depletion due to mitochondrial dysfunction, and neuronal apoptosis, involving a variety of molecular signaling pathways.
Donepezil is the main drug for clinically treating AD, mainly delays the progression of early symptoms in AD and improves the clinical symptoms of early AD by inhibiting cholinesterase to increase the level of acetylcholine, and no effective drug for reversing or stopping the progression of the disease exists so far.
In recent years, repeated injections of plasma from young mice into older mice have been studied and found that plasma can improve memory function by modulating the classical molecular pathways involved in hippocampal cognition. Plasma is extremely complex in composition, including proteins, lipids, inorganic salts, sugars, amino acids, metabolic waste products, and large amounts of water.
Therefore, in the current research and practice, the components in the blood plasma for improving the learning and memory ability and treating the senile dementia need to be found and combined with the first-line medicine.
Disclosure of Invention
The invention aims to provide combined application of ceruloplasmin and donepezil.
The purpose of the invention is realized by the following technical scheme:
the application of the ceruloplasmin and the donepezil in preparing the medicines for preventing or/and improving or/and treating dementia and/or cognitive dysfunction; or/and application in preparing intelligence-benefiting supplements or medicines.
In a preferred embodiment, the ceruloplasmin is derived from a mammal.
In a preferred embodiment, the ceruloplasmin is from a healthy human.
In a preferred embodiment, the raw material for preparing ceruloplasmin includes human serum.
In a preferred embodiment, the dementia and/or cognitive dysfunction is alzheimer's disease or mild cognitive impairment.
A combination for the prevention or/and amelioration or/and treatment of dementia and/or cognitive dysfunction, comprising: a prophylactically or/and improving or/and therapeutically effective amount of ceruloplasmin, and a prophylactically or/and improving or/and therapeutically effective amount of donepezil.
In a preferred embodiment, the ceruloplasmin and the donepezil are used separately; preferably, the ceruloplasmin is administered intravenously and the donepezil is administered orally.
Compared with the prior art, the invention has the following beneficial effects:
the ceruloplasmin participating in the regulation of the balance of metal ions in vivo in the blood plasma can improve the self-care ability, learning and memory ability of donepezil for treating animal dementia models, and can play a role in enhancing memory and improving cognitive function. The inventor finds that the ceruloplasmin and the donepezil are combined to remarkably improve the learning and memory capacity of the dementia animal model. The nesting experiment result shows that the ceruloplasmin and the donepezil are combined to improve the nesting capacity of the dementia animal model and prompt that the self-care capacity of the dementia animal is improved. The result of the water maze experiment shows that the ceruloplasmin can improve the learning and memory ability of the dementia animal model.
Drawings
FIG. 1: test example 1 nesting behavior test the score of nesting behavior before and after the mice are treated with ceruloplasmin and donepezil in combination (ceruloplasmin activity is 1.02 unit/mg). ({ p <0.0001vs. WT _PBS + PBS, + p <0.05vs. TG \ PBS +, # p <0.01vs. TG _PBS + PBS, + P <0.0001vs. TG _PBS + PBS)
FIG. 2 is a schematic diagram: the water maze behavioural experiment in test example 1 was performed to examine the memory improvement of mice treated with ceruloplasmin and donepezil in combination (ceruloplasmin activity was 1.02 unit/mg). Wherein, part A is the time for the mouse to ascend in the hidden platform training stage, and part B is the percentage of the time for the mouse to stay in the target quadrant in the testing stage. ({ p <0.0001vs. WT _PBS + PBS, + p <0.05vs. TG _PBS + PBS, # # p <0.001vs. TG _PBS + PBS)
FIG. 3: experimental timeline schematic in example 1.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments for better illustrating the technical features and effects of the present invention, but the present invention is not limited thereto.
The invention provides an application of ceruloplasmin and donepezil in preparation of a medicament for preventing or/and improving or/and treating Alzheimer's disease; or/and ceruloplasmin can be used for preparing intelligence-improving supplements or medicines.
The raw materials for preparing the ceruloplasmin comprise healthy human serum.
The inventor detects the memory improvement condition of the combination of ceruloplasmin and donepezil on 5XFAD transgenic (APP) mice from animal test level, and the result shows that the ceruloplasmin obviously improves the memory improvement effect of donepezil on dementia model mice.
The ceruloplasmin used in the invention is prepared from human serum as a raw material by a method described in paper separation and purification of ceruloplasmin and research on properties and functional groups of ceruloplasmin (paperbok, 2006). The obtained ceruloplasmin activity was 1.02unit/mg.
The preparation, identification and use of ceruloplasmin according to the invention are illustrated by the following examples. The molecular biological procedures referred to in the following examples are, for example, those not described in the specific test conditions and methods, see the eds of SambrookJ et al, science publishers, 2017, molecular cloning protocols (fourth edition) or the instructions for the corresponding products. The primary hippocampal cells used in the following examples were cultured according to the following references: guo, W., Y.Ji, et al (2014), "neural activity instruments BDNF-TrkB signaling kinetics and downstream functions," J Cell Sci 127 (Pt 10): 2249-2260.
Example 1
Ceruloplasmin in this example was obtained by the method described in the above-mentioned paper, pages 17-32, by replacing 3.1.5.1 of porcine serum with serum from a healthy person to obtain a dialysate; then, the dialyzate was subjected to DEAE-Sepharose (method described in 3.1.5.2), hydroxyapatite adsorption chromatography (method described in 3.1.5.3), and Superdex-200 gel filtration chromatography (method described in 3.1.5.4) to obtain a fraction having the highest specific activity as a purified ceruloplasmin. And filtering and sterilizing the pure ceruloplasmin product by adopting a filter membrane which is a PVDF membrane with low protein adsorption of 0.22 mu m and the pressure of 5bar to obtain the sterilized ceruloplasmin.
This example is the testing of the nesting ability and learning and memory ability of 5xFAD model mice by the combined application of sterilized ceruloplasmin (CP solution) and Donepezil (DPZ).
The grouping and administration of this example is as follows:
wherein the PBS injection amounts of the groups 1-3 are all 5ml/kg.
The time axis of this example is shown in fig. 3, where the nesting experiment was performed 2 times in total, the first time is before the start of the experiment, the effect is mainly to set a baseline to observe whether there is improvement before and after administration, the second time is 23-24 days, and each group is performed the experiment; experiment the water maze experiment was performed on days 25-30.
Detection 1: and (3) nesting behavior experiment detection:
(1) The kitchen paper is cut into thin strips and crumpled, sawdust padding with the height of about 1cm is added into an empty cage, 3-4g of cut kitchen paper is uniformly scattered on the padding, and a 5XFAD transgenic (APP) mouse or a Wild Type (WT) control mouse is placed.
(2) Nesting was observed after 48 hours and scored. The scoring criteria were as follows:
0 minute: the mice did not move past the nesting material, which remained intact when placed.
1 minute: although the nesting material was mobilized by the mouse, there were no obvious sites in the cage where the nesting material was dispersed.
And 2, dividing: the position of the nest is obvious, the nest is flat, and no obvious dent is formed in the middle.
And 3, dividing: the position of the nest is obvious, the middle of the nest is slightly sunken, and the height of the nest is 1/2 lower than that of the back of the mouse after the back of the mouse is arched.
And 4, dividing: the position of the nest is obvious, a depression is arranged in the middle of the nest, and the height is 1/2 of the height of the back of the mouse which is arched.
And 5, dividing: the position of the nest is obvious, a depression is arranged in the middle of the nest, and the height of the depression is 1/2 higher than that of the back of the mouse after the back of the mouse is arched.
The test results are shown in FIG. 1. Group 1 (WT _ PBS + PBS) scored 4.32 + -0.22, group 2 (TG _ PBS + PBS) scored 0.57 + -0.21, group 3 (TG _ PBS +15mg/kg CP) scored 1.58 + -0.43, group 4 (TG _0.1mg/kg DPZ + PBS) scored 0.55 + -0.17, group 5 (TG _0.3mg/kg DPZ + PBS) scored 0.83 + -0.35, group 6 (TG _1mg/kg DPZ + PBS) scored 1.69 + -0.33, group 7 (TG _0.1mg/kg DPZ +15mg/kg CP) scored 1.67 + -0.23, group 8 (TG _0.3mg/kg DPZ +15mg/kg CP) scored 1.84 + -0.29, group 9 (WT _1mg/kg DPZ +15mg/kg CP) scored a significant improvement in the ability of injected Alzheimer's disease from the blue-testis protein model, 26.23, and the ability of injected Alzheimer's disease was evaluated in mice; similarly, the results of the simultaneous injection of 1mg/kg donepezil and ceruloplasmin were also better than the injection of ceruloplasmin alone.
The transformation of the nesting capacity of the mouse to human refers to the self-care capacity of human beings on daily life, so that the injection of ceruloplasmin can obviously improve the improvement effect of donepezil on the self-care capacity of the daily life of the mouse model of Alzheimer's disease.
And (3) detection 2: morris Water maze test (Experimental test on Water maze behavior).
(1) The length of the incubation period recorded in the water maze experiment determined the spatial discrimination ability of the mice. The water maze device consists of a circular water pool with the diameter of 120cm and the height of 50cm and a movable platform with the diameter of 10cm, a camera is arranged above the water pool and is connected with a computer automatic recorder, and the water temperature is kept at (22 +/-3) DEG C.
(2) The training on the 1 st to 5 th days is hidden platform training, the platform is placed at a fixed position and is 1cm lower than the water surface, titanium dioxide is added to make the platform invisible, the heads of mice are gently and randomly placed into one of 4 quadrants in a water pool towards the pool wall, each mouse swims for 60s in each test, and the mouse finds the platform in the water and stays for 5s; if the mice failed to find a platform after entering the water, the time was recorded as 60s and manually placed on the platform for 20s, with each mouse repeating the test 4 times a day.
(3) And (3) withdrawing the platform 24h after the last positioning navigation experiment is finished, putting the mouse into the movement track of the underwater tracker for 60s, testing the movement track and the latency of the mouse in 60s, and taking the number of times of passing through the position quadrant of the original placement platform and the time of passing through the position quadrant of the original placement platform as space memory forming indexes, and performing comparison among groups.
Note that: the indoor environment consistency such as light, article placement in the laboratory and the like is kept in the whole test process so as to eliminate the interference of the environment.
The test results are shown in FIG. 2. Wherein, the part A is the time for the mouse to ascend in the hidden platform training stage, and the part B is the percentage of the time for the mouse to stay in the target quadrant in the testing stage.
In section A, in the hidden platform training stage, compared with WT _ PBS + PBS group, TG _ PBS + PBS and TG _0.1mg/ml DPZ + PBS and TG _0.3mg/ml DPZ + PBS group study curves (escape latency), the difference is significant at day 2,3 and 4, and the later is consistent, and WT _ PBS + PBS group and WT _ PBS +15mg/kg CP and each dose DPZ + CP group study curves (escape latency) are close. All mice learned to remember the location of the hidden platform prior to testing.
In part B, the percentage of time that each group is in the target quadrant is in turn: 32.1. + -. 0.26 for group 1 (WT _ PBS + PBS), 18.8. + -. 3.1 for group 2 (TG _ PBS + PBS), 27.9. + -. 1.3 for group 3 (TG _ PBS +15mg/kg CP), 18.9. + -. 3.8 for group 4 (TG _0.1mg/kg DPZ + PBS), 21.6. + -. 3.1 for group 5 (TG _0.3mg/kg DPZ + PBS), 26.9. + -. 2.1 for group 6 (TG _1mg/kg DPZ + PBS), 26.7. + -. 2.4 for group 7 (TG _0.1mg/kg DPZ +15mg/kg CP), 27.4. + -. 0.21 for group 8 (TG _0.3mg/kg DPZ +15mg/kg CP), 33.3. + -. 2.3 g/kg P + 3.2.05 for group 9 (TG _1mg/kg DPZ +15mg/kg CP) and < 3.05. + -. 2.05 for group 9 (TG _1mg/kg DPZ +15mg/kg CP). It can be seen that for the mouse model of alzheimer's disease, the treatment of injecting donepezil in combination with ceruloplasmin can improve the time of the 5 × FAD transgenic (APP) mouse in the target quadrant when donepezil is used alone and ceruloplasmin is used alone; especially, the combination of CP and low-dose DPZ enhances the DPZ effect, and the combination of CP and high-dose DPZ respectively and obviously enhances the DPZ and CP effects.
From this, it is found that the effect of donepezil is improved by the combined use of ceruloplasmin in improving the cognitive level in the alzheimer model mouse.
Claims (4)
1. The application of the ceruloplasmin combined with donepezil in the preparation of the drugs for preventing or/and improving or/and treating dementia and/or cognitive dysfunction, wherein the ceruloplasmin comes from healthy people, and the raw materials for preparing the ceruloplasmin comprise the serum of the healthy people; the dementia and/or cognitive dysfunction is alzheimer's disease.
2. A combination for the prevention or/and amelioration or/and treatment of dementia and/or cognitive dysfunction, comprising: the ceruloplasmin is obtained from healthy people, raw materials for preparing the ceruloplasmin comprise healthy human serum, and the dementia and/or cognitive dysfunction are Alzheimer's disease.
3. The combination according to claim 2, wherein ceruloplasmin and donepezil are administered separately.
4. The combination according to claim 2, wherein the ceruloplasmin is administered intravenously and the donepezil is administered orally.
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