Use of sacubitril valsartan substance for the preparation of medicaments for the treatment of neurotoxicity and cognitive impairment

Abstract

This invention relates to the application of sacubitril / valsartan derivatives in the preparation of drugs for neurotoxicity and cognitive impairment. The sacubitril / valsartan derivatives include at least one of sacubitril monomer, sacubitril derivative, pharmacologically acceptable sacubitril salt, valsartan monomer, valsartan derivative, pharmacologically acceptable valsartan salt, and sacubitril / valsartan combination drugs. Compared with existing technologies, the sacubitril / valsartan derivatives of this invention have significant effects in treating cognitive impairment induced by psychotropic drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a new use of sacubitril / valsartan-like substances, specifically the application of sacubitril / valsartan-like substances in the preparation of drugs that cause neurotoxicity and cognitive impairment caused by psychotropic drugs. Background Technology

[0002] Disorders of use of psychotropic drugs can lead to neurotoxicity, which in turn can impair cognitive function, including spatial learning and memory, executive function, social cognition, language / verbal fluency, and attention.

[0003] Take methamphetamine (METH, commonly known as crystal meth) as an example. As an amphetamine-type stimulant, it produces euphoria and suppresses appetite. Long-term use may cause neurotoxicity and cognitive impairment.

[0004] Sacubitril / valsartan is a combination drug consisting of a neprilysin inhibitor (sacubitril) and an angiotensin receptor inhibitor (valsartan), primarily used clinically to treat heart failure and hypertension. For example, [Ye S, et al. FrontCell Dev Biol] and [Menendez JT. Card Fail Rev] reported significant efficacy of sacubitril / valsartan in treating heart failure. [Xu X, et al. Food Chem Toxicol] reported a correlation between angiotensin II and methamphetamine addiction in its pathogenesis.

[0005] The invention patent application filed by the applicant, with patent number 202211034360.4, entitled "Application of Sacubitril / Valsartan in the Preparation of Drugs for Drug Addiction and Relapse" (authorization announcement number CN115317478B), discloses the application of sacubitril / valsartan in the preparation of drugs for drug addiction and relapse, proving that sacubitril / valsartan can treat drug addiction and relapse after administration, and that the drug itself is not addictive.

[0006] The effects of sacubitril / valsartan on neurotoxicity and cognitive impairment caused by psychotropic drugs have not yet been studied. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide an application of sacubitril / valsartan-like substances in the preparation of a therapeutic drug for neurotoxicity and cognitive impairment caused by psychotropic drugs, in light of the current state of the prior art.

[0008] The technical solution adopted by the present invention to solve the above-mentioned technical problems is: the application of sacubitril / valsartan substances in the preparation of neurotoxic and cognitive impairment drugs, wherein the sacubitril / valsartan substances include at least one of sacubitril monomer, sacubitril derivative, pharmacologically acceptable sacubitril salt, valsartan monomer, valsartan derivative, pharmacologically acceptable valsartan salt, and sacubitril / valsartan compound drugs.

[0009] The chemical formula of the sacubitril / valsartan combination drug is as follows, where the left side represents sacubitril monomer and the right side represents valsartan monomer, together forming the sacubitril / valsartan combination drug:

[0010]

[0011] Preferably, the derivative is an acetylation or an esterification.

[0012] Preferably, the pharmacologically acceptable salt is a sodium or potassium salt. The chemical formula of the sodium salt is as follows:

[0013]

[0014] Preferably, the effective dose of the sacubitril / valsartan analogue in mice is 20-200 mg / kg / day.

[0015] Preferably, the effective dose of the sacubitril / valsartan analogue in mice is 60 mg / kg / day.

[0016] In the above embodiments, preferably, the neurotoxicity and cognitive impairment are caused by psychotropic drugs, and the psychotropic drugs include opioids, barbiturates, benzodiazepines or amphetamines.

[0017] Compared with the prior art, the advantages of the present invention are as follows:

[0018] I. In view of the current lack of drugs for treating neurotoxicity and cognitive impairment caused by psychotropic drugs in clinical practice, this invention provides a new application of sacubitril / valsartan-like substances in the preparation of drugs for treating neurotoxicity and cognitive impairment caused by psychotropic drugs.

[0019] II. This invention provides that sacubitril / valsartan significantly improves neurotoxicity and cognitive impairment caused by psychotropic drugs after administration, demonstrating that sacubitril / valsartan has a significant effect in treating cognitive impairment caused by psychotropic drugs.

[0020] III. Sacubitril / valsartan does not cause adverse effects after administration. Attached Figure Description

[0021] Figure 1This is for the establishment of a model of methamphetamine-induced cognitive impairment in Example 1 of the present invention;

[0022] Figure 2 This is for the establishment of a model of methamphetamine-induced cognitive impairment in Example 1 of the present invention;

[0023] Figure 3 This is a diagram illustrating the therapeutic effect of the sacubitril / valsartan combination drug on methamphetamine-induced cognitive impairment in Example 2 of the present invention.

[0024] Figure 4 This is a diagram illustrating the therapeutic effect of the sacubitril / valsartan combination drug on methamphetamine-induced cognitive impairment in Example 2 of the present invention.

[0025] Figure 5 This is a diagram illustrating the therapeutic effect of the sacubitril / valsartan combination drug on neuroblastoma cells induced by methamphetamine treatment in Example 3 of the present invention. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0027] The methamphetamine used in these embodiments is a standard product sourced from the Narcotics Control Detachment of the Ningbo Municipal Public Security Bureau. The sacubitril / valsartan combination drug is from Shanghai Ruihui Chemical Co., Ltd.

[0028] Example 1: Establishment of an experimental model of methamphetamine-induced cognitive impairment

[0029] The new object recognition model is used to evaluate cognitive memory experimental models, while the Y-maze model is used to evaluate spatial learning and memory abilities. Both models are used to assess cognitive impairment caused by psychotropic drugs.

[0030] Sixteen male mice (C57BL / 6J breed, 6-8 weeks old, weighing 22-25g) were housed in an SPF-grade animal facility. After one week of acclimatization, they were randomly divided into a saline group (n=8) and a methamphetamine group (n=8).

[0031] Perform new object recognition and Y-maze testing using the following methods:

[0032] From day 1 to day 5, the methamphetamine group received intraperitoneal injection of methamphetamine (2.5 mg / kg / day), while the saline group received intraperitoneal injection of saline. On day 6, two identical objects A were placed in the device, allowing mice to explore for 10 minutes. The time mice spent on each object was recorded using a camera (AniLab Software Instruments Co., Ltd., Ningbo, China). On day 7, one of the two identical objects A was replaced with object B, which was not used for object A, and the mice were allowed to explore for 10 minutes, recording the time spent on each object. During exploration, each mouse explored the device individually. Before the next mouse explored, the explored object and the device were wiped with alcohol to eliminate odor cues. The primary outcome measures were the preference index for the new object and the exploration time. Preference index = (new object detection time - old object detection time) / (new object detection time + old object detection time) * 100%. In the formula, the new object refers to object B, the old object refers to object A, and the detection time refers to the time the mouse touched the object.

[0033] The Y-shaped maze consists of three equal arms (50cm*18cm*35cm), labeled Arm A, Arm B, and Arm C, arranged in a clockwise or counterclockwise direction. Each arm forms a 120-degree angle with a central movable partition (AniLab Software Instruments Co., Ltd., Ningbo, China). On day 8, mice were placed on one arm (as the starting arm) and allowed 5 minutes to freely explore the three open arms. On day 9, a camera recorded the number of consecutive entries the mouse made into the three arms. Entries arranged in a clockwise or counterclockwise order (e.g., arms ABC, BCA, CAB) were valid; alternating arms BCB, AAC, BAB were invalid. The primary outcome measure was the percentage of alternations, calculated as follows: Percentage of alternations = Number of valid alternations / (Total number of entries - 2) * 100%. During the exploration on days 8 and 9, each mouse explored the Y-shaped maze alone. Before the next mouse could explore, the explored Y-shaped maze was wiped with alcohol to eliminate odor cues.

[0034] like Figure 1 and Figure 2 As shown, in the new object recognition experiment, the preference index for new objects in the methamphetamine group was significantly lower than that in the saline group; simultaneously, in the Y-maze experiment, the percentage of effective alternations in the methamphetamine group was significantly lower than that in the saline group. This indicates that the cognitive function of the methamphetamine group was impaired. Figure 1 , 2 In this context, "physiological saline" refers to the physiological saline group, and "methamphetamine" refers to the methamphetamine group.

[0035] Example 2: Therapeutic effect of sacubitril / valsartan combination drug on methamphetamine-induced cognitive impairment. This application uses the following method to establish a mouse model of cognitive impairment:

[0036] Twenty-one male mice (C57BL / 6J breed, 6-8 weeks old, weighing 22-25g) were housed in an SPF-grade animal facility. After one week of acclimatization, they were randomly divided into a methamphetamine + sacubitril / valsartan group (n=6), a saline group (n=7), and a methamphetamine group (n=8).

[0037] Perform new object recognition and Y-maze testing using the following methods:

[0038] From day 1 to day 9, the methamphetamine + sacubitril / valsartan group received sacubitril / valsartan (60 mg / kg / day) via gavage, while the saline and methamphetamine groups received saline. From day 10 to day 14, the methamphetamine + sacubitril / valsartan group received sacubitril / valsartan pretreatment, followed by intraperitoneal administration of methamphetamine (2.5 mg / kg / day) one hour later. The saline and methamphetamine groups received saline via gavage, followed by intraperitoneal administration of saline one hour later, while the methamphetamine group received methamphetamine (2.5 mg / kg / day) via intraperitoneal administration. On day 15, mice were allowed free movement in a device without objects for 10 minutes. On day 16, two identical objects A were placed in the device, allowing mice to explore for 10 minutes. The time mice spent on each object was recorded using a camera (AniLab Software Instruments Co., Ltd., Ningbo, China). On day 17, one of the two identical objects A in the device was replaced with object B, which is not used for object A. Mice were allowed to explore for 10 minutes, and the time spent on each object was recorded. During the exploration, each mouse explored the device alone. Before the next mouse started exploring, the explored object and the device were wiped with alcohol to eliminate odor cues. The primary outcome measures were the preference index for the new object and the exploration time. Preference index = (new object detection time - old object detection time) / (new object detection time + old object detection time) * 100%. In the formula, the new object refers to object B, the old object refers to object A, and the detection time refers to the time the mouse touched the object.

[0039] The Y-shaped maze consists of three equal arms (50cm*18cm*35cm), labeled Arm A, Arm B, and Arm C, arranged in a clockwise or counterclockwise direction. Each arm forms a 120-degree angle with a central movable partition (AniLab Software Instruments Co., Ltd., Ningbo, China). On day 18, mice were placed on one arm (the starting arm) and allowed 5 minutes to freely explore the three open arms. On day 19, a camera recorded the number of consecutive entries the mouse made into the three arms. Entries arranged in a clockwise or counterclockwise order (e.g., arms ABC, BCA, CAB) were valid; alternating arms BCB, AAC, BAB were invalid. The primary outcome measure was the percentage of alternations, calculated as follows: Percentage of alternations = Number of valid alternations / (Total number of entries - 2) * 100%. During the exploration on days 18 and 19, each mouse explored the Y-shaped maze alone. Before the next mouse could explore, the explored Y-shaped maze was wiped with alcohol to eliminate odor cues.

[0040] like Figure 3 and Figure 4 As shown, there were differences in the preference index for novel objects and the effective alternation ratio between the methamphetamine group and the methamphetamine + sacubitril / valsartan group, indicating that 60 mg / kg / day of sacubitril / valsartan administered orally has a therapeutic effect on methamphetamine-induced cognitive impairment. Figure 3 , 4 In the text, "physiological saline + physiological saline" refers to the physiological saline group, "metabolic amine + sacubitril / valsartan" refers to the methamphetamine + sacubitril / valsartan group, and "physiological saline + methamphetamine" refers to the methamphetamine group.

[0041] Example 3: The therapeutic effect of sacubitril / valsartan combination drug on methamphetamine toxicity in human neuroblastoma cell line SH-SY5Y.

[0042] Human neuroblastoma cells were cultured in F12 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin in a constant temperature CO2 incubator at 37 degrees Celsius. Cell growth was observed and the medium was changed every two days. When the cell density reached about 75%, the cells were passaged for subsequent experiments.

[0043] The protective effect of sacubitril / valsartan against the toxicity of methamphetamine to neuroblastoma cells was investigated using the following methods:

[0044] The therapeutic concentration of sacubitril / valsartan in methamphetamine-treated neuroblastoma cells was determined using the CCK8 assay kit from APExBIO (USA). Neuroblastoma cells were seeded in 96-well plates and pretreated with different concentrations of sacubitril / valsartan for 30 minutes, followed by pretreatment with 2.5 mM METH for 24 hours. The CCK8 solution was diluted with culture medium at a 1:9 ratio, and 100 μL of the mixture was added to each well. The cells were incubated at 37°C for 2–3 hours. The absorbance of each well at λ = 450 nm was measured using a microplate reader.

[0045] like Figure 5 As shown, sacubitril / valsartan can reduce the toxicity of neuroblastoma cells caused by methamphetamine treatment.

[0046] In this invention, the effects of the above embodiments can be achieved when the effective dose of the sacubitril / valsartan combination drug is 20 mg / kg / day, 200 mg / kg / day, or other doses in between. Furthermore, experiments have shown that using at least one of sacubitril monomer, sacubitril acetylated or esterified compounds, sacubitril sodium or potassium salts, valsartan monomer, valsartan acetylated or esterified compounds, or valsartan sodium or potassium salts can also achieve the effects of the above embodiments.

Claims

1. The application of sacubitril / valsartan derivatives in the preparation of drugs to reduce neurotoxicity, wherein the sacubitril / valsartan derivatives are sacubitril / valsartan compound drugs, the neurotoxicity is caused by psychotropic drugs, and the psychotropic drugs are amphetamine drugs; in, The chemical formula of the sacubitril / valsartan combination drug is as follows, where the left side represents sacubitril monomer and the right side represents valsartan monomer, together forming the sacubitril / valsartan combination drug: 。

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