Application of Gabapentin in improvement of cognitive impairment of Alzheimer's disease

Abstract

The invention discloses application of Gabapentin in improvement of cognitive impairment of Alzheimer's disease. An application model is an APP / PS1 Alzheimer's disease animal model, a control group is a wild type mouse, Gabapentin granules are dissolved with normal saline and used in an intraperitoneal injection mode, the dosage of single administration is 50 mg / kg, administration is performed for 7 days each month, and then behavioral detection is performed. By detecting and analyzing the actual application result, the effect description of the Gabapentin on the improvement of the AD scene memory is obtained. When the medicine is subjected to intraperitoneal injection and administration, the excessive excitability of neurons can be reduced, the scene memory function of AD mice can be improved, a new use method of Gabapentin is expanded, and a new thought is provided for treatment of AD.

Description

Technical Field

[0001] The present invention belongs to the field of medical application technology, and in particular relates to the application of Gabapentin in improving cognitive impairment of Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease with the main clinical symptoms of gradual memory loss. In the early stage, it is short-term memory impairment, and as the disease worsens, it leads to long-term memory damage. It may be accompanied by mental and behavioral abnormalities. It is an age-related neuropsychiatric disease. There is currently no cure, and the drugs that have been marketed can only have a certain improvement effect. In AD animal models, there are spontaneous epileptic symptoms. There is evidence that AD manifests itself in the early stage of PV neurons. The imbalance of neuronal excitability and inhibition in the course of AD is one of the main causes of memory damage.

[0003] Gabapentin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and was first approved for use in the United States in 1993. It is clinically used to treat epilepsy, restless legs syndrome, and neuralgia. Compared with other anti-epileptic drugs, it has a relatively benign adverse reaction profile and a wide therapeutic index, making it less likely to interact with other drugs and affect the metabolism and effects of the drug in the body.

[0004] Currently, there are no studies reporting the use of gabapentin in the early treatment of Alzheimer's disease, where gabapentin can inhibit the excessive excitability of neurons during the course of Alzheimer's disease and improve cognitive impairment. Summary of the invention

[0005] The purpose of the present invention is to provide an application of Gabapentin to improve cognitive impairment in Alzheimer's disease, aiming to solve the problems existing in the background technology. To achieve the above purpose, the technical solution adopted by the present invention is:

[0006] Application of Gabapentin in improving cognitive impairment in Alzheimer's disease. Taking APP / PS1 mice (APPswe, PSEN1dE9 human double transgenic), a model animal for Alzheimer's disease, as the research object, and wild-type (C57B6 / C3) mice of the same age as the control group. Gabapentin is a white powdery crystal, dissolved in physiological saline, and administered by intraperitoneal injection: including two dose groups of 50 mg / kg and 100 mg / kg, administered 7 days per month, once a day, and taking a 21-day rest as a course of treatment. Using the APP / PS1 mice treated with physiological saline and the wild-type mice treated with physiological saline matched by age as controls respectively. Continuously intervene from 2-month-old mice (equivalent to the preclinical stage of AD) to 7-8-month-old mice (equivalent to the mid-late stage of the AD course), and detect the learning and memory abilities before and after the intervention to evaluate the improvement effect of early intervention with Gabapentin on cognitive ability during the AD course.

[0007] The present invention discloses the preventive and therapeutic effect of Gabapentin on AD cognitive impairment. Data show that applying the anti-epileptic drug Gabapentin from the preclinical stage of AD can improve the emotional response, motor ability, and learning and memory function of AD mice, providing effective data for the application of the anti-epileptic drug Gabapentin in neurodegenerative diseases with cognitive impairment. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Schematic diagram of the pre-drug background fear memory experiment for mice at 11 to 12 months of age provided for the implementation of the present invention; Figure 2 Schematic diagram of the fear box experiment for mice one month after drug administration (12 - 13 months of age) provided for the implementation of the present invention; Figure 3 Schematic diagram of the fear box experiment for mice two months after drug administration (13 - 14 months of age) provided for the implementation of the present invention; Figure 4 Schematic diagram showing that Gapapendin intervention until 7 - 8 months of age reduces the anxiety-like emotions of AD mice; Figure 5 Schematic diagram showing the detection by the fear memory paradigm provided for the implementation of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0008] To facilitate the understanding of the present invention, the present invention will be described more comprehensively with reference to the relevant embodiments below. The preferred embodiments of the present invention are given in the embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0010] The technical solutions of this patent will be further described in detail below in conjunction with specific embodiments.

[0011] The embodiments of the present invention provide an experiment on the improvement of AD episodic memory by Gabapentin

[0012] Animal grouping:

[0013] Taking APP / PS1 mice, an AD model animal, and age-matched wild-type mice (WT) as research objects, with half males and half females, a total of 4 groups:

[0014] 2-month-old WT-saline control group;

[0015] 2-month-old APP / PS1-saline control group;

[0016] 2-month-old APP / PS1-50 mg / kg Gabapentin treatment group;

[0017] 2-month-old APP / PS1-100 mg / kg Gabapentin treatment group.

[0018] Experimental procedures:

[0019] Gabapentin was dissolved by mixing and shaking with 0.9% saline, including two dose groups of 50 mg / kg and 100 mg / kg. The administration volume was 100 μl / 10 g body weight, and the drug was prepared immediately before use.

[0020] Before and after drug administration, emotional responses, motor abilities, and learning and memory abilities were measured, mainly using the open field test and contextual fear memory behavioral paradigm.

[0021] The data were statistically analyzed using Graphpad Prisim software.

[0022] Contextual fear memory experiment:

[0023] Experiment introduction

[0024] Open field test (OFT): To detect the free movement ability and neuropsychiatric status of mice, place the mice in the central area of the experimental box and then immediately leave. Use analysis software to automatically record the activities of the animals in the box for 30 minutes, and calculate the proportion of the time the mice spend in the central area in the total test time.

[0025] The conditioned fear experiment system (context fear system) is used for environmental-related conditioned fear experiment research on small rodents (rats and mice). Rodents will show a characteristic immobile state (Freezing) when they are afraid, and animals tend to maintain a static defensive posture in this situation. During the experiment, the experimental subjects are given a sound signal (conditioned stimulus), and then an electric shock (unconditioned) stimulus is given. This training is called conditioned training. After the training, the experimental animals undergo sound signal or environmental associative experiments. Generally, rodents will show obvious conditioned fear responses, such as immobility, to the corresponding environment and the same sound signal in different environments. This test can be carried out immediately or several days after the training to provide information on short-term and long-term memory under the influence of conditioned signals.

[0026] The training device is mainly a box of 30x24x21 cm 3 , with 18 stainless steel round rods with a diameter of 4 mm at the bottom, generating a certain current under set conditions: there is a camera on the box door, connected to a computer, and software can be used to record and analyze the electric shock response and analyze the immobile time (MED-Associates St Albans.VT).

[0027] The fear memory test includes three parts:

[0028] ① Adaptation: That is, the prior exposure to the context. Place the test mice in the test box to move freely for 5 minutes to exclude the influence brought by the novel environment.

[0029] ② Training: 24 hours after the adaptation ends, place the mice in the same test box for training. Each training lasts for a total of 12 minutes, with an electric shock every 2 minutes. There is a continuous 30-second sound stimulus before the electric shock, and each electric shock lasts for 2 seconds with an intensity of 0.8 mA. There are a total of 5 electric shocks. After each electric shock, the system records the immobile time as an index for detecting fear memory.

[0030] ③ Test: 1.5 hours later, place the mice in the same test box again. After moving freely for 180 seconds, give 180 seconds of continuous sound stimulus to test their fear level of the sound, and record the immobile time of the mice at the end.

[0031] Statistical method Figure 1 Paired T-test for parameters, Figure 2 andFigure 3 One-way ANOVA was used, and Tukey's multiple comparisons test was used for statistical analysis between groups.

[0032] Figure 1 For the fear box experiment before drug administration in 10 WT mice aged 11 to 12 months and 20 APP / PS1 mice aged 11 to 12 months, the left figure shows the grouping of mice. The values of pre, 1, 2, 3, 4, 5 in the training stage are the rounded values of the percentage of the freezing time of the mice in this group accounting for 120 s. AV is the average value, and SEM is the standard error of the mean. The training stage is to detect the learning ability of the mice. 2 h, 24 h, and 72 h in the test stage are different memory detection stages. 2 h is to detect short-term memory, and 24 h and 72 h are to detect long-term memory. The corresponding values of 2 h, 24 h, and 72 h are the rounded values of the percentage of the freezing time of the mice in this group accounting for 360 s. AV is the average value, and SEM is the standard error of the mean. The test stage detects the memory retrieval stage. In the right figure, the memory of AD mice at 72 h shows memory impairment compared with WT, and the paired T test of statistical parameters shows that p < 0.05, indicating a significant difference between the two groups.

[0033] Figure 2 For the results of the fear box experiment in three groups of 12 - 13-month-old mice after one month of drug administration, in the memory retrieval stage of the experiment, the long-term and short-term memories of the AD Gabapentin administration group of mice have been close to those of the WT saline group, proving that the memory of the experimental group is close to that of the WT group after one month of drug administration, and the drug has played a certain role.

[0034] Figure 3 For the results of the fear box experiment in three groups of 13 - 14-month-old mice after one month of drug administration, in the memory retrieval stage (Test) of the experiment, in the AD Gabapentin administration group, that is, the medium-dose group of AD in the figure, the long-term memories at 24 h and 72 h are improved compared with the AD saline group, that is, the AD solvent control. The number of mice is sufficient. Although there is no significant difference statistically, the trend is very obvious. Compared with other groups, Gabapentin can indeed improve the episodic memory ability after intraperitoneal injection.

[0035] Figure 4 After Gapapendin intervention until 7 - 8 months of age, it reduced the anxiety-like emotions of AD mice, manifested as an increase in the time of mice in the central area (Figure A). And it improved the motor ability of AD mice, manifested as an increase in the movement distance (Figure B).

[0036] Figure 5 Detection by the background fear memory paradigm showed that after Gapapendin intervention until 7 - 8 months of age, the short - term and long - term memory retrieval abilities at 1 hour and 72 hours were improved, and the cognitive impairment in AD mice was ameliorated.

[0037] The above - mentioned embodiments are only used to illustrate the present invention and are not intended to limit the present invention. Those of ordinary skill in the relevant technical field can also make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, all equivalent technical solutions also fall within the scope of the present invention, and the patent protection scope of the present invention shall be defined by the claims.

Claims

1. Application of gabapentin in improving cognitive impairment in Alzheimer's disease.

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