Application of Fibroin in the preparation of anti-hypoxia drugs

Abstract

This invention discloses the application of berberine in the preparation of anti-hypoxia drugs, and relates to the field of pharmaceutical technology. Experimental results simulating high-altitude hypoxia show that berberine possesses significant anti-high-altitude hypoxia activity, prolonging the tolerance time to closed-loop hypoxia in mice and increasing the survival rate of mice subjected to acute decompression hypoxia. It also exhibits significant protective effects against tissue damage induced by high-altitude hypoxia, with an effect showing a trend superior to acetazolamide. Anti-high-altitude hypoxia drugs prepared using berberine as the active ingredient can be used to prevent or treat pathological states of hypoxia in the heart, brain, and lung tissues caused by low pressure and hypoxia.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to the application of berberine in the preparation of anti-hypoxia drugs. Background Technology

[0002] High altitude is one of the most challenging conditions globally. my country has vast plateau areas, and hypoxia is the primary problem encountered by those living, working, and traveling in these regions. With social and economic development, hundreds of thousands of people travel to plateau areas for work, military activities, scientific research, and tourism. However, the low-pressure, low-oxygen environment of these areas restricts human life activities. There are many factors that cause hypoxia, which can be divided into physiological and pathological hypoxia. Normative hypoxia and high-altitude hypoxia are physiological hypoxia. Compared to normobaric hypoxia, hypoxia caused by the decrease in atmospheric oxygen partial pressure and the reduction in atmospheric pressure in high-altitude environments simultaneously threaten human physiological functions, making the prevention and treatment of high-altitude hypoxia damage more difficult. Currently, there are many drugs on the market that can treat and improve hypoxia, such as nimodipine, aminophylline tablets, and nifedipine. However, only Rhodiola rosea preparations and acetazolamide are actually effective for treating high-altitude hypoxia.

[0003] Berberine, also known as palmatine or palm-leaf balsamine, is an isoquinoline alkaloid mainly derived from plants in the Menispermaceae family. Its pharmacological activities are primarily focused on antibacterial and antiviral activity. It also exhibits effects on the nervous and cardiovascular systems, as well as anti-inflammatory and antioxidant properties. However, its application in high-altitude medicine or hypoxia-related diseases has not been observed. The structural formula of berberine is as follows:

[0004] . Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide a new use of berberine, namely, the application of berberine in the preparation of anti-altitude hypoxia drugs.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] This invention provides the application of berberine in the preparation of anti-hypoxia drugs; the anti-hypoxia drugs are anti-high altitude hypoxia drugs.

[0008] The anti-hypoxia drug is formulated with berberine as the active ingredient, combined with a pharmaceutically acceptable carrier and / or excipients, into a pharmaceutically acceptable dosage form. The pharmaceutically acceptable dosage form includes tablets, granules, capsules, pills, syrups, suspensions, emulsions, powders, oral liquids, or injections.

[0009] Berberine effectively scavenges excess free radicals produced in hypoxic heart, brain, and lung tissues, enhancing antioxidant capacity, alleviating lipid peroxidation, and reducing oxidative stress damage induced by high-altitude hypoxia. Berberine also reverses the decrease in ATP and Na+ levels in heart, brain, and lung tissues during hypoxia. + -K + -ATP and Ga 2+ -Mg 2+ - Changes in ATPase activity can alleviate energy metabolism disorders induced by high-altitude hypoxia; berberine can alleviate inflammatory responses induced by high-altitude hypoxia by reducing the levels of TNF-α and IL-6 and increasing the level of IL-10 in the heart, brain, and lung tissues; therefore, berberine can be used in the preparation of drugs for the prevention or treatment of hypobaric hypoxia-induced injuries, including acute mountain sickness, high-altitude hypoxic brain injury, high-altitude hypoxic myocardial injury, and high-altitude hypoxic lung injury caused by high-altitude hypobaric hypoxia.

[0010] This invention demonstrates through whole-animal simulation experiments of high-altitude hypoxia that berberine has significant anti-high-altitude hypoxia activity, can prolong the survival time of normobaric hypoxic mice, improve the survival rate of acute decompression hypoxic mice, and has a significant protective effect against tissue damage induced by high-altitude hypoxia. Its mechanism of action is related to alleviating oxidative stress damage, energy metabolism disorders, and inflammatory responses caused by high-altitude hypoxia.

[0011] In summary, berberine has a significant effect against high-altitude hypoxia, and its effect tends to be better than that of acetazolamide. Anti-high-altitude hypoxia drugs prepared with berberine as the active ingredient can be used to prevent or treat pathological conditions of hypoxia in the heart, brain and lung tissues caused by low pressure and low oxygen. Detailed Implementation

[0012] To better understand the essence of the present invention, the following examples use animal experiments and results of berberine to illustrate its excellent anti-altitude hypoxia activity.

[0013] Example 1: Mouse Occlusive Hypoxia Tolerance Experiment

[0014] 1. Experimental Methods: Fifty male SPF-grade BALB / c mice were randomly divided into five groups after acclimatization for 3 days: hypoxia model group, acetazolamide group (200 mg / kg), low-dose berberine group (25 mg / kg), medium-dose berberine group (50 mg / kg), and high-dose berberine group (100 mg / kg), with 10 mice in each group. A single intraperitoneal injection of 0.1 mL / 10 g was administered. The hypoxia model group received an equal volume of physiological saline. Thirty minutes after administration, each mouse was placed in a 250 mL wide-mouth bottle containing 5 g of soda lime (one mouse per bottle). The bottle opening was coated with Vaseline and sealed to prevent air leakage. Timing was immediately established until respiration ceased. The survival time of mice in the sealed wide-mouth bottle was used as the indicator to compare the hypoxia tolerance time of each drug group. The results are shown in Table 1.

[0015] 2. Experimental Results: As shown in Table 1, compared with the hypoxia model group, the low, medium, and high doses of berberine all prolonged the survival time of mice in a normobaric, closed hypoxic environment in a dose-dependent manner. Furthermore, the survival time of the low, medium, and high doses of berberine was significantly longer than that of the acetazolamide positive control group (P<0.05 or P<0.01), with the survival time extension rate of the medium and high doses exceeding 100%.

[0016]

[0017] Example 2: Mouse Acute Decompression Hypoxia Tolerance Experiment

[0018] 1. Sixty healthy male Balb / c mice were randomly divided into three groups after 3 days of acclimatization: a hypoxia model group, an acetazolamide group (200 mg / kg), and a berberine group (100 mg / kg), with 20 mice in each group. The mice were administered a single intraperitoneal injection of 0.2 mL / 20 g. -1 The hypoxia model group was given an equal volume of physiological saline. Thirty minutes after administration, the animals were placed in a hypobaric chamber with the door sealed. The chamber was then depressurized and ascended at a rate of 1000 m / min, stopping at 5000 m and 8000 m for 5 minutes each, finally reaching an altitude of 10000 m. This altitude was maintained for 1 hour, after which the inlet valve was adjusted, and the animals were slowly lowered to normal altitude. The door was then opened, and the animal mortality rate within 1 hour was observed and recorded. Analysis of variance was performed on the experimental results. The results are shown in Table 1.

[0019] 2. Experimental results: As shown in Table 1, after 1 h of exposure to a low-pressure, low-oxygen environment (10000 m), the mortality rate of the hypoxia model group reached 100%, while the mortality rates of the acetazolamide group and the berberine group were 85% and 60%, respectively. This indicates that berberine can effectively reduce the mortality rate of mice under acute hypoxia conditions.

[0020]

[0021] Example 3: Protective effect of mice against tissue damage in mice simulating high-altitude hypoxia

[0022] 1. Experimental Methods

[0023] Forty healthy male BABL / C mice were randomly divided into four groups (n=10 per group) after acclimatization for 3 days: normal control group, hypoxia model group, acetazolamide group (200 mg / kg), and berberine group (200 mg / kg). The drugs were administered intraperitoneally at a volume of 0.2 mL / 20 g. -1 The hypoxia model group was given an equal volume of physiological saline. Mice in the normal group did not experience hypoxia. Forty minutes after administration, mice in the remaining groups were placed in a hypobaric chamber with the chamber door sealed. The chamber was depressurized and the mice were ascended to an altitude of 8000 m at a speed of 10 m / s. This altitude was maintained for 9 hours. Then, the air inlet valve was adjusted, and the mice were descended to the local altitude at a speed of 20 m / s. The chamber door was opened, and the mice were quickly euthanized by dislocation. Brain, heart, and lung tissues were harvested, washed three times with physiological saline, blotted dry with filter paper, and stored at -80°C for later use. Biochemical indicators were measured, and all procedures were performed according to the kit instructions.

[0024] 2. Experimental Results

[0025] (1) Effects of berberine on oxidative stress-related indicators in the heart, brain and lung tissues of mice with simulated high-altitude hypoxia

[0026]

[0027]

[0028] As shown in Tables 3-5, compared with the normal control group, the MDA content in the heart, brain, and lung tissues of mice in the hypoxia model group was significantly increased, and the SOD activity was significantly decreased (P<0.01). Compared with the hypoxia model group, the MDA content in the heart, brain, and lung tissues of mice pretreated with berberine was significantly decreased (P<0.01), and the SOD activity was significantly increased (P<0.01). These results indicate that berberine can effectively scavenge excess free radicals generated in the heart, brain, and lung tissues of hypoxic mice, improve antioxidant capacity, alleviate lipid peroxidation, and reduce oxidative stress damage induced by high-altitude hypoxia.

[0029] (2) Effects of berberine on energy metabolism-related indicators in the heart, brain, and lung tissues of mice simulating high-altitude hypoxia

[0030]

[0031]

[0032]

[0033] As shown in Table 6-8, compared with the normal control group, the ATP content and Na+ content in the heart, brain, and lung tissues of mice in the hypoxia model group were significantly higher. + -K + -ATP and Ga 2+ -Mg 2+ -ATPase activity decreased, but the berberine group was able to reverse these changes and alleviate energy metabolism disorders induced by high-altitude hypoxia.

[0034] (3) Effects of berberine on inflammatory markers in the heart, brain and lung tissues of mice with simulated high-altitude hypoxia

[0035]

[0036]

[0037]

[0038] As shown in Tables 9-11, compared with the normal control group, the levels of TNF-α and IL-6 in the heart, brain, and lung tissues of mice in the hypoxia model group were significantly increased (P<0.01), and the level of IL-10 was significantly decreased (P<0.01). Conversely, the levels of TNF-α and IL-6 in the heart, brain, and lung tissues of mice in the berberine group were significantly decreased (P<0.01), and the level of IL-10 was significantly increased (P<0.01). These results indicate that berberine can alleviate the inflammatory response induced by high-altitude hypoxia.

[0039] In summary, berberine has a significant effect against high-altitude hypoxia, and its effect tends to be better than that of acetazolamide. Anti-high-altitude hypoxia drugs prepared with berberine as the active ingredient can be used to prevent or treat pathological conditions of hypoxia in the heart, brain and lung tissues caused by low pressure and low oxygen.

[0040] This invention demonstrates through whole-animal simulation experiments of high-altitude hypoxia that berberine has significant anti-high-altitude hypoxia activity, can prolong the survival time of normobaric hypoxic mice, improve the survival rate of acute decompression hypoxic mice, and has a significant protective effect against tissue damage induced by high-altitude hypoxia. Its mechanism of action is related to alleviating oxidative stress damage, energy metabolism disorders, and inflammatory responses caused by high-altitude hypoxia.

Claims

1. The application of berberine in the preparation of anti-hypoxia drugs, wherein the anti-hypoxia drugs are anti-high altitude hypoxia drugs.

2. The application according to claim 1, characterized in that: Berberine effectively removes excess free radicals generated in hypoxic heart, brain, and lung tissues, enhances antioxidant capacity, alleviates lipid peroxidation, and reduces oxidative stress damage induced by high-altitude hypoxia.

3. The application according to claim 1, characterized in that: Berberine works by reversing the decrease in ATP and Na+ levels in the heart, brain, and lung tissues during hypoxia. + -K + -ATP and Ga 2+ -Mg 2+ - Changes in ATPase activity can alleviate energy metabolism disorders induced by high-altitude hypoxia.

4. The application according to claim 1, characterized in that: Berberine alleviates inflammatory responses induced by high-altitude hypoxia by reducing the levels of TNF-α and IL-6 and increasing the level of IL-10 in the heart, brain, and lung tissues.

5. The application according to claim 1, characterized in that: The anti-hypoxia drug is formulated into a pharmaceutically acceptable dosage form by adding berberine as the active ingredient to a pharmaceutically acceptable carrier and / or excipients.

6. The application according to claim 5, characterized in that, The pharmaceutically acceptable dosage forms are tablets, granules, capsules, pills, syrups, suspensions, emulsions, powders, oral liquids, or injections.

Images