Application of indole-3-formaldehyde in preparation of medicine for treating pulmonary arterial hypertension

Abstract

The invention discloses application of indole-3-formaldehyde in preparation of a medicine for treating pulmonary arterial hypertension, and belongs to the technical field of medicines. The indole-3-formaldehyde disclosed by the invention can be used for effectively relieving related pathological changes of rats with pulmonary arterial hypertension. Therefore, the indole-3-formaldehyde has a huge application prospect in preventing and / or relieving pulmonary arterial hypertension related diseases. The invention provides a new drug choice for the treatment of pulmonary arterial hypertension, and has significant clinical transformation potential.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly relates to the use of indole-3-carboxaldehyde in the preparation of drugs for treating pulmonary arterial hypertension. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a cardio-pulmonary vascular disease that seriously endangers human physical and mental health. It is characterized by a progressive increase in pulmonary vascular resistance, resulting in abnormally elevated pulmonary artery pressure, increased cardiac burden, and ultimately leading to right heart failure and premature death. The pathological core is pulmonary vascular remodeling, manifested as endothelial dysfunction, abnormal smooth muscle proliferation, and vascular occlusive lesions. Current clinical treatments mainly rely on endothelin receptor antagonists (such as bosentan), phosphodiesterase 5 inhibitors (such as sildenafil), and prostacyclin analogs, etc. However, these drugs have problems such as insufficient targeting, obvious drug resistance after long-term use, low response rate in some patients, etc., and cannot reverse pulmonary vascular remodeling. Therefore, developing new multi-target treatment strategies is an urgent need in the field of PAH.

[0003] In recent years, the role of the gut microbiota and its metabolites in cardiovascular diseases has attracted much attention. Research shows that active molecules (such as indole compounds) generated by gut microbiota through the metabolism of precursor substances such as tryptophan can participate in disease regulation by modulating immune inflammatory responses, vascular endothelial function, and fibrosis processes. Indole-3-carboxaldehyde (ICA), as a key gut microbiota metabolite, is mainly produced by probiotics such as Lactobacillus and Bifidobacterium through the tryptophan metabolic pathway, and has anti-inflammatory, antioxidant, and immunomodulatory functions.

[0004] Studies have shown that PAH patients often suffer from gut microbiota dysbiosis, characterized by a decrease in the abundance of ICA-producing probiotics, resulting in a reduction in endogenous ICA synthesis, which in turn exacerbates the pulmonary vascular inflammation and fibrosis processes. This pathological association suggests that supplementing exogenous ICA may intervene in the core pathological processes of PAH. However, current research on the treatment of PAH with microbial metabolites is still blank. Existing studies on natural products mainly focus on plant extracts (such as echinacoside, curcumin), but such substances have limitations such as low bioavailability and dose-dependent toxicity. In contrast, ICA, as an endogenous metabolite in the human body, has the advantages of high natural safety, potential for multi-target regulation, and strong compatibility with the host physiological environment, but its application potential in PAH has not been explored.

[0005] Based on the above scientific issues, the present invention first proposes using indole-3-carboxaldehyde as a natural metabolite derived from the intestinal flora for the treatment of PAH, and animal experiments confirm that it can improve pulmonary vascular remodeling and restore right heart function. The present invention provides a brand-new microbial metabolite intervention strategy for the treatment of PAH. Summary of the Invention

[0006] The present invention provides the use of indole-3-carboxaldehyde in the preparation of a medicament for treating pulmonary arterial hypertension.

[0007] In one embodiment of the present invention, the improvement or alleviation of pulmonary arterial hypertension includes any one or more of the following:

[0008] (a) Improving right ventricular systolic pressure (RVSP);

[0009] (b) Reducing right ventricular hypertrophy index (RVHI);

[0010] (c) Reducing the wall thickness of small pulmonary arteries;

[0011] (d) Reducing the percentage of the wall thickness of small pulmonary arteries in the diameter;

[0012] (e) Reducing the percentage of the wall area of small pulmonary arteries in the total vascular area.

[0013] 3. In one embodiment of the present invention, the oral product includes but is not limited to drugs.

[0014] 4. In one embodiment of the present invention, the drug further includes a pharmaceutical carrier and / or a pharmaceutical excipient.

[0015] 5. In one embodiment of the present invention, the pharmaceutical carrier includes microcapsules, microspheres, nanoparticles, and / or liposomes.

[0016] 6. In one embodiment of the present invention, the pharmaceutical excipient includes a filler, a binder, a wetting agent, a disintegrant, a lubricant, a formulating agent, and / or a flavoring agent.

[0017] 7. In one embodiment of the present invention, the dosage form of the drug includes a suspension, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a dropping pill, an injection, a suppository, an enema, an aerosol, a patch, or a drop.

[0018] 8. The present invention also provides an oral product for alleviating pulmonary arterial hypertension, characterized in that the oral product includes indole-3-carboxaldehyde.

[0019] 9. In one embodiment of the present invention, the drug can be administered by oral administration, gavage, enema administration, subcutaneous injection, or skin coating.

[0020] Advantageous Effects:

[0021] (a) Improve pulmonary vascular remodeling;

[0022] (b) Reduce the wall thickness of pulmonary arterioles;

[0023] (c) Reduce the percentage of the wall thickness of pulmonary arterioles to the diameter;

[0024] (d) Reduce the percentage of the wall area of pulmonary arterioles to the total vascular area;

[0025] (e) Improve right ventricular systolic pressure;

[0026] (f) Reduce the right ventricular hypertrophy index.

[0027] Therefore, indole-3-carboxaldehyde has great application prospects in the prevention and / or alleviation of pulmonary hypertension. Brief Description of the Drawings

[0028] Figure 1 For the right ventricular systolic pressure (A) and right ventricular hypertrophy index (B) of four groups of rats.

[0029] Figure 2 For observing the pathological changes of pulmonary arterioles of four groups of rats by HE staining.

[0030] Figure 3 For the wall thickness of blood vessels (A), the percentage of the wall thickness of pulmonary arterioles to the diameter (B), and the percentage of the wall area of pulmonary arterioles to the total vascular area (C) of four groups of rats. Detailed Embodiments

[0031] The present invention will be further described in detail below with reference to specific embodiments, so that those skilled in the art can understand the present invention more clearly.

[0032] The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Based on the specific embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the protection scope of the present invention.

[0033] In the embodiments of the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art; in the embodiments of the present invention, unless specifically specified, the technical means used are all conventional means well known to those skilled in the art.

[0034] Example 1: Construction and Sampling of MCT Rat Model

[0035] (1) Test Samples

[0036] The required solvent is composed of 5% DMSO + 40% PEG300 + 5% Tween80 + 50% normal saline (by volume). According to the drug concentration of 1 g / kg, ICA was dissolved in the solvent.

[0037] (2) Experimental animals

[0038] Clean-grade male SD rats, 8 weeks old, with a body weight range of 240 ± 20 g, were provided by Hunan Slack Jingda Experimental Animal Co., Ltd. The production license number of experimental animals is: SCXK(Xiang)2019--0004. Breeding conditions: temperature 22 ± 2 °C, humidity 55 ± 5%, day-night light-dark alternation time 12 h / 12 h, and the rats had free access to food and water. After one week of adaptive feeding of the rats, the experiment was carried out.

[0039] (3) Modeling and grouping

[0040] The clean-grade SD rats were randomly divided into a normal control group (Control), a model group (MCT), an indole-3-carbaldehyde group (MCT + ICA), and a solvent gavage group (MCT + solvent). The MCT group was intraperitoneally injected with monocrotaline (60 mg / kg, dissolved in normal saline) once, the Control group was intraperitoneally injected with an equal volume of normal saline, the MCT + solvent group was gavaged with the solvent (5% DMSO + 40% PEG300 + 5% Tween80 + 50% normal saline), and the MCT + ICA group was gavaged with an ICA solution (1 g / kg) dissolved in the same solvent. The MCT + solvent group and the MCT + ICA group were gavaged once a day starting from the day after the MCT injection and continued for 3 weeks.

[0041] Example 2: Hemodynamics and right ventricular hypertrophy index of four groups of rats

[0042] (a) Hemodynamics

[0043] The rats were anesthetized by intraperitoneal injection of 3% sodium pentobarbital. A heparinized catheter was inserted into the right ventricle through the right external jugular vein. The pressure waveform was monitored in real time through a pressure sensor, and the peak systolic pressure (RVSP) in the stable state was recorded. The catheter position was confirmed by the characteristic pressure waveform (the right ventricular waveform showed a sharp rise in systolic pressure). The data were continuously recorded for 10 cardiac cycles by a biological signal acquisition system (Evolution software) and the mean value was taken. The depth of anesthesia was controlled throughout the experiment, and the data with catheter misplacement or thrombus interference were excluded. The inter-group differences were analyzed by one-way analysis of variance (ANOVA).

[0044] The experimental results showed that the right ventricular systolic pressure of rats in the MCT group was significantly higher than that in the Control group. There was no significant difference in RVSP between the MCT+solvent group and the MCT group, indicating that the solvent had no effect on RVSP. However, RVSP in the MCT+ICA group was significantly lower than that in the MCT group, suggesting that ICA treatment could effectively alleviate the increase in right ventricular systolic pressure caused by pulmonary hypertension( Figure 1 A).

[0045] (b) Right ventricular hypertrophy index

[0046] After the rats' hearts were removed, the left and right atria, large blood vessels and other tissues were cut off along the atrioventricular groove, leaving the left and right ventricles. Then, the right ventricle (RV), left ventricle and interventricular septum (LV+S) were separated along the posterior interventricular groove, washed and the moisture was blotted with filter paper. The RVHI (RV weight / LV+S weight) was accurately weighed with an electronic balance and calculated. The whole operation followed the principle of blinding (the experimental personnel did not contact the grouping information), and the ventricles were separated along the anatomical landmarks to ensure the integrity of the interventricular septum. One-way analysis of variance (ANOVA) was used to analyze the differences between groups.

[0047] The experimental results showed that RVHI in the MCT group was significantly higher than that in the Control group. There was no significant difference in RVHI between the MCT+solvent group and the MCT group (p = 0.905). However, RVHI in the MCT+ICA group was significantly lower than that in the MCT group, confirming that ICA treatment could reverse right ventricular hypertrophy caused by pulmonary hypertension( Figure 1 B).

[0048] Example 3: HE staining was used to observe the pathological changes of pulmonary arterioles in four groups of rats

[0049] The lung tissue sections of four groups of rats were sampled and their pathological changes were observed. First, the tissue sections were dewaxed and rehydrated: the paraffin-embedded tissue sections were dewaxed twice in xylene I and II for 10 minutes each time, rehydrated with gradient (100%, 95%, 80%, 70%) ethanol, and rinsed three times with PBS solution for 5 minutes each time. Then, hematoxylin and eosin staining was performed: the sections were immersed in hematoxylin staining solution for 5 min, then washed with distilled water for 5 min, briefly differentiated in hydrochloric acid ethanol for 10 s, and then blued with bluing solution and rinsed with running water. The well-blued slides were taken out of the water and immersed in eosin solution for 5 s for staining. Then, clearing and mounting were carried out: the sections were successively placed in absolute ethanol I (2 min), absolute ethanol II (2 min), absolute ethanol III (2 min), n-butanol I (2 min), n-butanol II (2 min), xylene I (2 min), xylene II (2 min). The cleared sections were sealed with neutral balsam, the excess balsam was removed, the slides were cleaned and dried. Finally, observation was carried out under a microscope and image acquisition was performed.

[0050] The results showed that the Control group exhibited normal lung tissue structure, with neatly arranged cells, thin and uniform alveolar walls, clear alveolar cavities, and normal pulmonary arterioles. In the MCT group, the vascular walls of the pulmonary arterioles were thickened (indicated by the arrow), suggesting pathological changes caused by pulmonary hypertension. The HE staining results of the MCT+solvent group showed that the structure of its pulmonary arterioles was similar to that of the MCT group, indicating that the solvent itself had no obvious protective effect on lung tissue. However, the structure of the pulmonary arterioles in the MCT+ICA group was improved, and the degree of thickening of the vascular walls of the pulmonary arterioles was reduced, indicating that ICA treatment had a certain alleviating effect on the pathological changes caused by pulmonary hypertension( Figure 2 ).

[0051] To further quantify these pathological changes, we calculated the wall thickness (WT) of the blood vessels in the four groups of rats respectively( Figure 3 A), the percentage of the wall thickness of the pulmonary arterioles to the diameter (WT%)( Figure 3 B), and the percentage of the wall area of the pulmonary arterioles to the total vascular area (WA%)( Figure 3 C). The results showed that compared with the Control group, the WT, WT%, and WA% of the rats in the MCT group increased significantly, indicating that pulmonary hypertension led to obvious vascular structural changes. These indexes of the MCT+solvent group were similar to those of the MCT group, further confirming that the solvent itself had no significant effect on lung tissue structure. However, the wall thickness, WT%, and WA% of the MCT+ICA group were significantly lower than those of the MCT group and close to the level of the Control group, indicating that ICA treatment could significantly alleviate the vascular structural abnormalities caused by pulmonary hypertension and had a significant therapeutic effect( Figure 3 ).

Claims

1. Use of indole-3-carboxaldehyde in the preparation of a medicament for treating pulmonary hypertension.

2. The application according to claim 1, characterized in that, The improvement or alleviation of pulmonary hypertension includes any one or more of the following: (a) Improvement of right ventricular systolic pressure (RVSP); (b) Reduction of right ventricular hypertrophy index (RVHI); (c) Reduction of the thickness of the pulmonary arteriole vascular wall; (d) Reduction of the percentage of the thickness of the pulmonary arteriole wall to the diameter; (e) Reduction of the percentage of the area of the pulmonary arteriole wall to the total area of the blood vessel.

3. The application according to claim 1, characterized in that, The oral product includes but is not limited to drugs.

4. The application according to claim 3, characterized in that, The drug also includes a pharmaceutical carrier and / or a pharmaceutical excipient.

5. The application according to claim 5, characterized in that The pharmaceutical carrier includes microcapsules, microspheres, nanoparticles and / or liposomes.

6. The application according to claim 5, characterized in that, The pharmaceutical excipient includes a filler, a binder, a wetting agent, a disintegrant, a lubricant, an excipient and / or a flavoring agent.

7. The application according to claim 4, wherein The dosage form of the drug includes a suspension, a granule, a capsule, a powder, a tablet, an emulsion, a solution, a dropping pill, an injection, a suppository, an enema, an aerosol, a patch or a drop.

8. An oral product for relieving pulmonary hypertension, characterized in that, The oral product includes indole-3-carboxaldehyde.

9. The application according to claim 1, characterized in that: The drug can be administered by oral administration, gavage, enema administration, subcutaneous injection, or skin coating.

Images