阅读说明：本技术 一种治疗由神经细胞损伤造成的认知功能损害的靶向药物及应用 (Targeted medicine for treating cognitive function damage caused by nerve cell damage and application ) 是由 蔡晓红 邱雪浩 陈逸峰 许丹芬 涂昀嘉 李媛媛 马春艳 于 2021-07-05 设计创作，主要内容包括：一种治疗由神经细胞损伤造成的认知功能损害的靶向药物及其应用,通过Nrf2这一靶点保护CIH和SF导致神经细胞损伤造成的认知功能损害,可有效应用于阻塞性睡眠呼吸暂停低通气综合征动物模型中出现的认知功能损害的治疗。(A target medicine for treating cognitive function damage caused by nerve cell damage and application thereof are disclosed, wherein the cognitive function damage caused by nerve cell damage caused by CIH and SF is protected by using a target Nrf2, and the target medicine can be effectively applied to treatment of the cognitive function damage in an obstructive sleep apnea hypopnea syndrome animal model.)

1. A targeted drug for treating cognitive impairment caused by nerve cell injury is characterized in that a target point of the targeted drug for treating cognitive impairment is a nuclear factor E2-related factor (Nrf 2).

2. The targeted agent of claim 1, wherein the agent comprises an agonist of nuclear factor E2-related factor (Nrf 2).

3. The targeted drug of claim 1, wherein the agonist of nuclear factor E2-related factor (Nrf2) is Sulforaphane (SFN).

4. The targeted agent of claim 1, wherein the cognitive impairment caused by neuronal cell damage comprises cognitive impairment caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

5. The application of an agonist of a factor related to nuclear factor E2 in preparing a targeted medicament for treating cognitive function impairment caused by nerve cell injury.

6. The use of claim 5, wherein said agonist of factor E2-related factor is sulforaphane.

7. The use of claim 5, wherein the cognitive impairment caused by neuronal cell damage is cognitive impairment caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

Technical Field

The invention relates to the technical field of obstructive sleep apnea hypopnea syndrome, in particular to a targeted medicine for treating cognitive function damage caused by nerve cell injury and application thereof.

Background

Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) is a sleep breathing disorder characterized by repeated collapse of the upper airway during sleep, accompanied by apnea and/or superficial breathing, with concomitant decrease in blood oxygen saturation. Mainly manifested by snoring, mouth breathing, sleep disorder, daytime sleepiness, attention disturbance, etc. The major pathophysiological mechanisms of OSAHS are Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF). A large number of studies indicate that chronic intermittent hypoxia may damage the blood brain barrier maintaining the homeostasis of the central nervous system, and the damage of the blood brain barrier affects synaptic plasticity, and at the same time, the brain microenvironment changes, ultimately damaging the nervous system. Chronic sleep fragmentation on the one hand prevents the central nervous system from clearing neurotoxic by-products and on the other hand increases the energy demand of the central nervous system, creating mental stress, causing some degree of neurological damage.

Disclosure of Invention

In order to solve the technical defects in the prior art, the invention provides a targeted medicine for treating cognitive function damage caused by nerve cell damage and application thereof, and the cognitive function damage caused by nerve cell damage is protected by a target Nrf2 (cytokine induced killer) to protect CIH (cytokine induced killer) and SF (SF).

The technical solution adopted by the invention is as follows: a targeted drug for treating cognitive impairment caused by nerve cell injury is targeted on a nuclear factor E2-related factor (Nrf 2).

The targeted drug comprises an agonist of a nuclear factor E2 related factor (Nrf 2).

The agonist of the nuclear factor E2 related factor (Nrf2) is Sulforaphane (SFN).

The cognitive function impairment caused by nerve cell damage comprises cognitive function impairment caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

The application of an agonist of a factor related to nuclear factor E2 in preparing a targeted medicament for treating cognitive function impairment caused by nerve cell injury.

The agonist of the nuclear factor E2 related factor is sulforaphane.

The cognitive function damage caused by nerve cell damage is cognitive function damage caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

The invention has the beneficial effects that: the invention provides a targeted medicine for treating cognitive function damage caused by nerve cell damage and application thereof, and the targeted medicine protects the cognitive function damage caused by nerve cell damage caused by CIH and SF through a target Nrf2, and can be effectively applied to treatment of the cognitive function damage in an obstructive sleep apnea hypopnea syndrome animal model.

Drawings

FIG. 1 shows the eight arm maze test for groups of mice WME, RWE, TE.

FIG. 2 shows the Neisseria staining (light mirror. times.400, scale 25 μm) of the hippocampus of each group of mice.

FIG. 3 shows the TUNEL-DAB visualization of hippocampus of each group of mice (light microscope X400, scale 20 μm).

Detailed Description

The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

A targeted medicine for treating cognitive function damage caused by nerve cell damage and application thereof protect the cognitive function damage caused by the nerve cell damage caused by CIH and SF through a target Nrf 2.

The technical solution adopted by the invention is as follows: a targeted drug for treating cognitive impairment caused by nerve cell injury is targeted on a nuclear factor E2-related factor (Nrf 2).

The targeted drug comprises an agonist of a nuclear factor E2 related factor (Nrf 2).

The agonist of the nuclear factor E2 related factor (Nrf2) is Sulforaphane (SFN).

The cognitive function impairment caused by nerve cell damage comprises cognitive function impairment caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

The application of an agonist of a factor related to nuclear factor E2 in preparing a targeted medicament for treating cognitive function impairment caused by nerve cell injury.

The agonist of the nuclear factor E2 related factor is sulforaphane.

The cognitive function damage caused by nerve cell damage is cognitive function damage caused by Chronic Intermittent Hypoxia (CIH) and Sleep Fragmentation (SF).

Assay analysis

1) Grouping experimental animals: healthy, clean-grade male C57BL/6 mice, 4 weeks of age, 18-22g in weight, 32 in total, were randomly divided into 4 groups using a digital table method: a blank control group (C), a chronic intermittent hypoxia + sleep fragmentation model group (CIH + SF), a CIH + SF + dimethyl sulfoxide solvent control group (CIH + SF + DMSO), and a CIH + SF + agonist group (CIH + SF + SFN), wherein 8 mice are used in each group. 10 Nrf2 knockout (knock-out type, KO) 4-week-old C57BL/6 mice after successful gene knockout are taken, and 8 of the 10 mice are randomly taken out according to a random number table method to form a CIH + SF + Nrf2 gene knockout group (CIH + SF + Nrf 2-KO). All experimental procedures followed ethical standards for experimental animals.

2) Molding: placing CIH + SF, CIH + SF + DMSO, CIH + SF + SFN, and CIH + SF + Nrf2-KO on sleep fragmentation instrument in intermittent oxygen chamber, placing SF group on sleep fragmentation instrument outside the same indoor oxygen chamber, and feeding group C outside the same indoor oxygen chamber. At other times, all groups of mice are raised in the same room, the model is built for 7 hours every day, and the whole model building stage is maintained for 4 weeks. SFN (1mg/kg) and 1% DMSO (equivalent to the drug) were intraperitoneally injected 30 minutes before entering the oxygen chamber every day in the CIH + SF + SFN group and the CIH + SF + DMSO group, respectively. Then, the eight-arm maze cognitive ethology test and the brain tissue pathological detection are carried out.

(1) And (3) behavioral detection: the eight-arm maze behavioural test detects Working Memory Errors (WME), Reference Memory Errors (RME) and Total memory errors (TE) of mice in each group, compared with the group C, the WME, the RME and the TE of the group CIH + SF are increased, the difference has statistical significance (P is less than 0.05), and the comparison difference between the group CIH + SF + DMSO and the group CIH + SF has no statistical significance (P is more than 0.05); compared with the CIH + SF group, the WME, RME and TE of the CIH + SF + SFN group are reduced, the difference has statistical significance (P is less than 0.05), the WME, RME and TE of the CIH + SF + Nrf2-KO group are increased, and the difference has statistical significance (P is less than 0.05). As shown in table 1 below:

TABLE 1 comparison of WME, RME, TE in groups of mice

*P＜0.05vs C；#P＜0.05vs CIH+SF

(2) And (3) Nie dyeing: under a light microscope, the hippocampal neurons of the group C are neatly and tightly arranged, the structure is clear and complete, and the number of the niscidium bodies in the neurons is rich. The CIH + SF group can see a large number of disordered hippocampal neuron arrangement, the cell swelling degree is deepened, the number of Nissner corpuscles is obviously reduced, and the neuron forms and the number of Nissner corpuscles between the CIH + SF + DMSO group and the CIH + SF group have no obvious difference; the reduction in nisome counts was improved in the CIH + SF + SFN group compared to the CIH + SF group. In the group CIH + SF + Nrf2-KO, a large amount of hippocampal cells were found to shrink, the number of nissl bodies was greatly reduced, staining became lighter, and the shape was blurred.

(3) TUNEL-DAB detection: under the light microscope, the hippocampal neurons in group C are normal and have no apoptosis positive cells; compared with the group C, the apoptosis positive cells of the group CIH + SF and the group CIH + SF + DMSO are remarkably increased; compared with the group of CIH + SF, the apoptosis positive cells in the CA3-CA1 area of the hippocampus of the mice in the group of CIH + SF + SFN are obviously reduced, and the apoptosis positive cells in the group of CIH + SF + Nrf2-KO are increased.

Conclusion

According to the invention, the pathophysiological characteristics of OSAHS are simulated by establishing CIH and SF mouse models, the Nrf2 agonist Sulforaphane (SFN) and Nrf2 gene knockout (Nrf2-KO) are utilized to establish Nrf2 activated and deleted mouse models, the behavioral change of each model mouse, the mouse hippocampal nerve cell morphology and the apoptosis degree are observed, and the SFN can protect the cognitive function damage caused by nerve cell damage through the target point of Nrf 2.

The skilled person should understand that: although the invention has been described in terms of the above specific embodiments, the inventive concept is not limited thereto and any modification applying the inventive concept is intended to be included within the scope of the patent claims.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.