Application of lipoic acid in preventing and treating altitude sickness

Abstract

The present invention discloses the use of lipoic acid in the prevention and treatment of altitude sickness. The present invention constructs a high-altitude hypoxia model in wild-type mice and ALDH2-KO mice, sets up a lipoic acid (α-LA) treatment group and a PBS control group, and evaluates the survival rate, cardiac function, and myocardial apoptosis level of each group. The results show that compared with the PBS control group, the α-LA treatment group has reduced myocardial cell apoptosis, significantly improved cardiac function, and significantly increased survival rate. α-LA can reduce the damage caused by high-altitude hypoxia, protect cardiac function, and improve the survival rate of mice by regulating the activity of ALDH2, and can be used as a clinical drug for the prevention and treatment of altitude sickness.

Description

Technical Field

[0001] The invention relates to application of lipoic acid in preventing and treating altitude sickness, and belongs to the technical field of biomedicine. Background Art

[0002] Altitude sickness (AMS) is a syndrome caused by the body's incomplete or dysfunctional adaptation to the low-oxygen environment when entering high altitude areas from low altitude. The impact of plateau hypoxia (PH) on health is becoming increasingly significant. According to statistics, in my country, the incidence of altitude sickness in the general population at altitudes above 4,200 meters is 38%-76%. Symptoms include headaches, dizziness, palpitations, shortness of breath, fatigue, insomnia, and drowsiness. Severe cases can develop acute and severe AMS, such as high-altitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), and heart failure. Mild cases can lead to loss of ability to work, while severe cases can be life-threatening. Therefore, it is crucial to prioritize the prevention and treatment of AMS. Current treatment and prevention options primarily include medication, physical therapy, and symptomatic treatment. Acetazolamide is considered the best medication for preventing AMS, but its effectiveness remains limited, with some aid workers in Tibet experiencing significant AMS symptoms and even death.

[0003] The aldehyde dehydrogenase 2 (ALDH2) gene, located on human chromosome 12, is one of the most critical ethanol-metabolizing enzymes in humans and has been linked to an increased risk of cardiovascular disease, stroke, and cancer. Three genotypes exist at the ALDH2 rs671 locus: wild-type ALDH2*1 / 1 (GG), heterozygous ALDH2*1 / 2 (GA), and homozygous ALDH2*2 / 2 (AA). Recent studies suggest that ALDH2 likely originated in a specific population and reached a stable frequency within that population through natural selection and evolution. The ALDH2 (Glu504Lys) mutation is present in approximately 30-50% of East Asian populations, but only 4.4% of Tibetans. Furthermore, our results indicate that high-altitude hypoxia significantly reduces systemic ALDH2 activity in mice, leading to mortality, while ALDH2-deficient mice exhibit significantly increased mortality. Therefore, future research is focused on identifying drugs that target ALDH2 activity to prevent and treat altitude sickness.

[0004] Alpha-lipoic acid (α-LA) is a coenzyme present in mitochondria and a cofactor for the pyruvate dehydrogenase complex, the ketoglutarate and amino acid hydrogenase complexes, and belongs to the class of B vitamins. Studies have shown that α-LA has been shown to protect against diabetic cardiomyopathy and acute ischemia-reperfusion injury by restoring ALDH2 activity. Our previous research data further confirm that α-LA plays a positive role in protecting the heart from the adverse effects of chronic pressure overload. However, whether α-LA plays a role in altitude sickness by regulating ALDH2 activity has not been explored. Summary of the Invention

[0005] The purpose of the present invention is to solve the technical problem of poor efficacy of current drugs for treating and preventing altitude sickness. The present invention provides the use of lipoic acid (α-LA) in preventing and treating altitude sickness. By constructing a high-altitude hypoxic mouse model, the present invention clarifies the protective effect of α-LA against high-altitude hypoxic damage, providing a new drug for treating and preventing altitude sickness.

[0006] To achieve the purpose of solving the above problems, the technical solution adopted by the present invention is to provide the use of lipoic acid and / or lipoic acid derivatives as medicinal ingredients in the preparation of drugs for treating and / or preventing altitude sickness.

[0007] Preferably, the lipoic acid derivative includes a salt of lipoic acid (eg, lipoic acid sodium salt).

[0008] Preferably, the dosage form of the drug includes injection, tablet, powder, suspension, capsule, pill or syrup.

[0009] The present invention also provides the use of lipoic acid and / or lipoic acid derivatives as medicinal ingredients in the preparation of medicines for improving cardiac function and myocardial apoptosis caused by altitude sickness.

[0010] Compared with the prior art, the present invention has the following beneficial effects:

[0011] The present invention verifies through experiments on a high-altitude hypoxia mouse model that lipoic acid (α-LA) can significantly improve the survival rate of mice, improve their cardiac function and myocardial apoptosis level, and that α-LA has a protective effect against high-altitude hypoxia damage. The present invention provides a new drug α-LA for the clinical prevention and treatment of altitude sickness, and also opens up a new use of α-LA as a drug, with good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It shows that α-LA can protect mice from plateau hypoxia damage; A: Survival curves of each group of mice under plain conditions; B: Survival curves of each group of mice under plateau hypoxia conditions.

[0013] Figure 2 The results of echocardiography evaluation of the cardiac function of mice in each group are shown; A: echocardiogram; B: heart rate (BPM); C: left ventricular ejection fraction (Ejection Fraction,%);

[0014] Figure 3 The results of myocardial 4-HNE staining are shown;

[0015] Figure 4 The results of myocardial ROS staining are shown;

[0016] Figure 5 The results of myocardial Tunel staining are shown. DETAILED DESCRIPTION

[0017] To make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0018] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; the materials and reagents used are commercially available unless otherwise specified. The α-lipoic acid (α-LA) used in the examples was purchased from Shenlong Pharmaceutical Co., Ltd. (approval number: National Medicine Standard H20059737, specification: 12 ml: 0.3 g) for lipoic acid injection.

[0019] Example

[0020] SPF male ALDH2-deficient (ALDH2-KO) and C57 / B6 mice (purchased from Shanghai JST Laboratory Animal Co., Ltd.), aged 6-8 weeks and weighing 20 g, were used to establish a high-altitude hypoxia injury model (experienced at 6000 meters for 2 weeks). The mice were divided into eight groups. The control group and the drug-treated group received intravenous phosphate buffer saline (PBS) and α-LA at a dose of 0.2% g / g mouse body weight, respectively, for two weeks before and after the intervention. The experimental protocol was approved by the Animal Care and Ethics Committee of Fudan University.

[0021] 1) The survival of mice exposed to an environmental environment at 6,000 meters for two weeks was monitored in real time to investigate the efficacy of α-LA treatment in each group. The results showed that under normal conditions, there was no difference in survival between mice fed α-LA and those fed PBS, with no mouse deaths. However, under simulated high-altitude conditions, the survival rate of ALDH2-deficient mice was significantly lower than that of WT mice. However, α-LA significantly improved the survival of both wild-type and ALDH2-KO mice, indicating that α-LA protects mice from high-altitude hypoxia.

[0022] 2) Echocardiography was used to assess cardiac function in each group of mice. After isoflurane anesthesia, M-mode images were recorded when the heart rate of the mice was maintained at 450-500 beats / minute. Parasternal long axis and apical four-chamber B-Mode images were collected. Parasternal left ventricular short axis images were obtained, 2D ultrasound was used to show the left ventricular short axis, and M-mode ultrasound was used at the level of the papillary muscles to record left ventricular motion. Functional indicators include: heart rate (Heart Rate), left ventricular ejection fraction (Ejection Fraction, %), and left ventricular fractional shortening (Fractional Shortening, %). The changes in cardiac morphology and function of the mice in each group were compared. The results showed that the cardiac function indicators of the mice in the α-LA treatment group were significantly improved.

[0023] 3) Immunofluorescence staining was used to assess myocardial apoptosis (Tunel), 4-HNE, and oxidative stress (ROS) levels in each group of mice. After two weeks of plateau exposure, mice were anesthetized with 2% pentobarbital, and their hearts were removed, embedded in OCT, and fixed for immunofluorescence staining. Tunel, 4-HNE, and ROS staining results indicated that α-LA significantly ameliorated myocardial apoptosis, 4-HNE, and ROS infiltration in both WT and KO groups, protecting them from myocardial damage.

[0024] The above results show that in the plateau hypoxia model, treatment with α-LA can significantly improve the survival rate of mice, improve the cardiac function and myocardial apoptosis level of mice, and α-LA has a protective effect on plateau hypoxia damage, suggesting that α-LA can be used as a drug for the clinical prevention and treatment of altitude sickness.

[0025] The above embodiments are only preferred embodiments of the present invention and are not intended to limit the present invention in any form or substance. It should be noted that ordinary technicians in this technical field can make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. Use of lipoic acid and / or its salts as a pharmaceutical ingredient in the preparation of a drug for treating and / or preventing altitude sickness.

2. The use according to claim 1, wherein the dosage form of the drug includes injection, tablet, powder, suspension, capsule, pill or syrup.

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