Application of aromatic amino acid decarboxylase inhibitors in the preparation of drugs for treating hepatic encephalopathy

Abstract

This application discloses the use of an inhibitor of aromatic amino acid decarboxylase in the preparation of a drug for treating hepatic encephalopathy. This application targets aromatic amino acid decarboxylase and, through mouse experiments, demonstrates that inhibiting the activity of aromatic amino acid decarboxylase can reverse some symptoms of hepatic encephalopathy, suggesting that aromatic amino acid decarboxylase inhibitors have the potential to be used in the preparation of drugs for treating hepatic encephalopathy.

Description

Technical Field

[0001] The present application relates to the field of liver disease treatment, and specifically, to the use of an inhibitor of aromatic amino acid decarboxylase in the preparation of a drug for treating hepatic encephalopathy. Background Art

[0002] Gut flora imbalance plays a key role in the pathogenesis of hepatic encephalopathy. The main evidence includes: 1) patients with hepatic encephalopathy have obvious flora imbalance; 2) fecal microbiota transplantation can effectively treat and prevent hepatic encephalopathy. However, fecal microbiota transplantation is difficult to implement, and for severe patients, it may have serious risks such as inducing infection. Therefore, there is an urgent clinical need to explore the specific mechanism by which intestinal flora imbalance induces hepatic encephalopathy and develop targeted treatments based on this. Summary of the Invention

[0003] In response to the shortcomings of existing methods, this application proposes an application targeting bacterial aromatic amino acid decarboxylase, particularly the application of an inhibitor of aromatic amino acid decarboxylase in the preparation of drugs for treating hepatic encephalopathy, which is used to prepare drugs for treating hepatic encephalopathy using substances related to intestinal bacteria.

[0004] The present application provides an embodiment of the use of an inhibitor of aromatic amino acid decarboxylase in the preparation of a drug for treating hepatic encephalopathy.

[0005] Alternatively, the aromatic amino acid decarboxylase is produced by intestinal bacteria.

[0006] Specifically, the intestinal bacteria include Ruminococcus gnavus.

[0007] More specifically, the amino acid sequence of the aromatic amino acid decarboxylase is shown in SEQ No. 1.

[0008] Optionally, the hepatic encephalopathy is induced by non-alcoholic fatty liver disease.

[0009] Furthermore, the hepatic encephalopathy is induced by liver cirrhosis.

[0010] Optionally, the inhibitor of aromatic amino acid decarboxylase includes at least one of the following substances: an enzyme inhibitor of aromatic amino acid decarboxylase, a preparation that inhibits the expression of aromatic amino acid decarboxylase genes, a phenylethylamine-specific monoclonal antibody, a probiotic that inhibits the abundance of active Ruminococcus R.gnavus, and a preparation that inhibits the abundance of active Ruminococcus R.gnavus.

[0011] Further optionally, the enzyme inhibitor of aromatic amino acid decarboxylase is (S)-α-FMT; the preparation for inhibiting aromatic amino acid decarboxylase gene expression is a preparation combination capable of achieving gene editing; and the phenylethylamine-specific monoclonal antibody is PEA-mAB.

[0012] Optionally, the inhibitor of aromatic amino acid decarboxylase can achieve at least one of the following functions: maintaining the phenylethylamine content in brain tissue, maintaining motor ability, maintaining memory ability, reducing coma caused by cirrhosis, reducing flapping tremors, reducing the occurrence of astrocyte swelling in the cerebral cortex, reducing the occurrence of microglial activation, and reducing neuroinflammation.

[0013] The beneficial technical effects brought about by the technical solutions provided in the embodiments of the present application include:

[0014] (1) This application targets aromatic amino acid decarboxylase and demonstrates through mouse experiments that inhibiting the activity of aromatic amino acid decarboxylase can reverse some of the symptoms of hepatic encephalopathy, making inhibitors of aromatic amino acid decarboxylase promising for the preparation of drugs for the treatment of hepatic encephalopathy.

[0015] (2) The present application targets aromatic amino acid decarboxylase, and the inhibitors provided can be compounds targeting enzyme activity, gene expression inhibitors, bacterial inhibitors targeting intestinal bacteria that produce aromatic amino acid decarboxylase, or specific antibodies targeting enzyme metabolites, which are conducive to the further development of drugs suitable for clinical use.

[0016] (3) After the experimental mice were treated with the aromatic amino acid decarboxylase inhibitor of the present application, the typical symptoms of hepatic encephalopathy were significantly improved, providing rich evidence for further clarifying the pathogenesis of hepatic encephalopathy.

[0017] Additional aspects and advantages of the present application will be given in part in the following description, which will become apparent from the following description, or will be learned through practice of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The above and / or additional aspects and advantages of the present application will become apparent and easily understood from the following description of the embodiments in conjunction with the accompanying drawings, in which:

[0019] Figure 1 This is a metagenomic analysis showing the relationship between the abundance of AADC genes encoded by intestinal flora in patients with liver disease and the severity of related diseases. The graphical results show that the abundance of AADC genes encoded by intestinal flora increases and is positively correlated with the severity of the disease.

[0020] Figure 2 Schematic diagram of the grouping of experimental mice to verify the effect of the AADC inhibitor (S)-α-FMT on the mouse model of liver cirrhosis.

[0021] Figure 3 Based on Figure 2 The results of the brain tissue phenylethylamine levels were statistically analyzed in different groups.

[0022] Figure 4 Based on Figure 2 The results of the open field test were statistically analyzed for the groups.

[0023] Figure 5 Based on Figure 2 The results of the water maze experiment were statistically analyzed in groups.

[0024] Figure 6 Based on Figure 2 The results of the statistics of the proportion of non-comatose mice in the groups.

[0025] Figure 7 Based on Figure 2 The results of the statistical analysis of the physiological status of astrocytes in the cerebral cortex by group.

[0026] Figure 8 Based on Figure 2 The results of the physiological state of microglia in the cerebral cortex were statistically analyzed by group.

[0027] Figure 9 Schematic diagram of the grouping treatment of experimental mice to verify the effect of PEA-mAB, a PEA-specific monoclonal antibody, on the mouse model of liver cirrhosis.

[0028] Figure 10 Based on Figure 9 The results of the brain tissue phenylethylamine levels were statistically analyzed in different groups.

[0029] Figure 11 Based on Figure 9 The results of the open field test were statistically analyzed for the groups.

[0030] Figure 12 Based on Figure 9 The results of the water maze experiment were statistically analyzed in groups.

[0031] Figure 13 Based on Figure 9 The results of the statistics of the proportion of non-comatose mice in the groups.

[0032] Figure 14 Based on Figure 9 The results of the statistical analysis of the physiological status of astrocytes in the cerebral cortex by group.

[0033] Figure 15 Based on Figure 9 The results of the physiological state of microglia in the cerebral cortex were statistically analyzed by group. DETAILED DESCRIPTION

[0034] The following describes the embodiments of the present application in conjunction with the accompanying drawings. It should be understood that the embodiments described below in conjunction with the accompanying drawings are exemplary descriptions for explaining the technical solutions of the embodiments of the present application and do not constitute a limitation on the technical solutions of the embodiments of the present application.

[0035] Those skilled in the art will understand that, unless otherwise stated, the terms "said" and "the" used herein may also include plural forms. It should be further understood that the term "including" used in the specification of this application refers to the presence of the described features, steps, and operations, but does not exclude the implementation of other features, information, data, steps, operations, elements, components, and / or combinations thereof supported by the technical field. The term "and / or" used herein refers to at least one of the items defined by the term, for example, "A and / or B" can be implemented as "A", or as "B", or as "A and B".

[0036] In order to make the objectives, technical solutions and advantages of this application clearer, the implementation methods of this application will be further described in detail below with reference to the accompanying drawings.

[0037] 1. Discovering the Target

[0038] Metagenomic analysis has found that the abundance of aromatic amino acid decarboxylase (AADC) genes, encoded by gut microbiota, is increased in patients with liver disease and positively correlated with disease severity. Metagenomic analysis requires confirming the ratio of specific genes or gene types to all genes in gut bacteria.

[0039] This application first analyzed the metagenomic data of cirrhosis from a specific range of patients (114 controls and 120 cirrhosis patients). ShortBred (version 0.9.5) was used to quantify the abundance of the AADC gene: first, the AADC sequences were clustered at 95% similarity, and then the UniRef90 database was used to identify short tag sequences. Finally, these tag sequences were quantified in the metagenomic samples, and the quantitative data were normalized by RPKM (reads per kilobase of transcript per million mapped reads). At the same time, MetaPhlAn2 (version 2.7.7) was used to quantify species abundance. The results showed that in patients with cirrhosis, the abundance of AADC genes and R.gnavus species derived from the intestinal flora R.gnavus (active Ruminococcus) increased. As Figure 1 As shown in AB, the abundance of AADC genes (A) and R. gnavus species (B) derived from the intestinal flora of patients with HBV-related cirrhosis is increased.

[0040] Next, the metagenomic data of the non-alcoholic fatty liver disease cohort (73 cases in total) were analyzed using the same analysis method as above. The results showed that in patients with non-alcoholic fatty liver disease, the AADC gene derived from the intestinal flora R.gnavus and the abundance of R.gnavus species were positively correlated with the severity of the disease. Figure 1 As shown in CD, in patients with nonalcoholic fatty liver disease, the abundance of AADC genes derived from intestinal flora R. gnavus and R. gnavus species increased in patients with disease activity scores greater than 1; Figure 1 As shown in EF, in patients with non-alcoholic fatty liver disease, the abundance of AADC genes derived from intestinal flora R. gnavus and R. gnavus species increased with the increasing grade of fatty liver lesions (*p<0.05).

[0041] 2. Confirm the treatment effect on the target

[0042] Gut microbiota-derived AADC can induce a hepatic encephalopathy-like phenotype in a mouse model of liver cirrhosis. AADC inhibitors and phenylethylamine (PEA)-specific antibodies can reverse this phenotype. The specific experimental process is as follows:

[0043] 2.1 Intestinal bacteria R. gnavus expressing the AADC gene can cause hepatic encephalopathy in cirrhotic mice, and the symptoms of hepatic encephalopathy in mice can be reversed by the AADC inhibitor (S)-α-FMT.

[0044] Mice were grouped as Figure 2 , cirrhosis model, cirrhosis model colonization Rg; liver failure model colonization Rg and (S)-α-FMT treatment followed by behavioral experiments; liver decompensation model model, and finally neuropathological analysis.

[0045] Mice were treated with a cirrhosis model by intraperitoneal injection of 10% CCl4 at a dose of 10 ml / kg mouse body weight three times a week for 8 weeks. Mice were then treated with an antibiotic mixture containing 1 g / L ampicillin, 1 g / L neomycin, 0.5 g / L vancomycin, and 1 g / L metronidazole for 3 consecutive days to eliminate the intestinal flora, followed by a 3-day water washout period. Mice were then treated with sterile saline or 1×10 9 CFU / 0.2ml R. gnavus were administered orally three times a week for 8 weeks. Four weeks after oral administration of the bacteria, the corresponding groups began oral administration of the AADC inhibitor (S)-α-FMT (45mg / kg) twice a week for 4 weeks. After the treatment, the open field test and water maze test were performed. Finally, the mice were injected intraperitoneally with 40% CCl4 to induce severe liver damage, and the coma was continuously monitored for 72 hours. All mice were euthanized and their brain tissues were collected.

[0046] The relevant experimental methods and tests are as follows:

[0047] (1) Open field test

[0048] Mice were individually placed in a 40 cm high square area (50 cm x 50 cm). The square area was divided into a 4 x 4 grid, with a central area and a peripheral area ( Figure 4 Each mouse test lasted 10 minutes. Between each mouse, the arena was thoroughly cleaned with 70% ethanol to remove any residual odor. The position and movement of the mice were monitored using an EthoVision XT 15 (Noldus). Parameters were quantified, including total distance moved and distance moved in the central area.

[0049] (2) Water maze experiment

[0050] The water maze apparatus consists of a circular pool with a diameter of 1.5 meters, divided into four quadrants, filled with opaque water maintained at a temperature of 22 ± 1 ° C. In the pool, a platform with a diameter of 10 cm is placed in the center of a quadrant and is placed approximately 1 cm below the water surface ( Figure 5 ). Visual cues were placed around the apparatus to help the mice find their way. Each mouse underwent three trials per day for five days, starting in one of the three quadrants where the platform was not located. The time required to locate the underwater platform was recorded, with a maximum cutoff of 60 seconds. If the mouse could not find the platform within this time frame, it was gently guided to the platform and allowed to stay on the platform for 10 seconds to familiarize itself with the location. On the 6th day, the test was carried out, the platform was removed, and the position and movement of the mouse were recorded using EthoVision XT 15 (Noldus), and the time the mouse spent in the platform quadrant within 60 seconds was counted.

[0051] (3) Targeted metabolomics detection

[0052] Brain tissue was homogenized with methanol (250 μl methanol / 100 mg tissue), and the supernatant was centrifuged (14,000 rpm, 10 min, 4°C). The brain tissue supernatant was filtered through a 0.22 μm pore size filter and the filtrate was stored at -80°C for LC-MS / MS analysis.

[0053] A 100 μl sample was separated on a Prelude SPLC system at 40°C using a Waters Acquity UPLC HSS T3 column (2.1 × 100 mm, 1.8 μm). The mobile phases used were: (a) 1 mM ammonium formate and 0.1% formic acid in water, (b) 0.1% formic acid in acetonitrile, with a gradient of 5% B (0 min), 85% B (1 min), 95% B (5 min), 95% B (5.5 min), and 5% B (6 min), at a flow rate of 0.3 ml / min. Mass spectrometric analysis was performed using a TSQ Quantiva triple quadrupole mass spectrometer in multiple reaction monitoring mode. The H-ESI source operated in positive mode. The parameters were as follows: ion pair (122.152 m / z, 77.04 m / z), collision energy 28.55 V; ion pair (138.152 m / z, 77.04 m / z), collision energy 27.494 V; ion pair (161.152 m / z, 144.11 m / z), collision energy 10.253 V; ion pair (177.152 m / z, 160.054 m / z), collision energy 10 V. Peak detection was visualized and analyzed using Thermo Xcalibur software.

[0054] (4) Immunostaining and 3D reconstruction

[0055] Fresh mouse hemibrain was fixed with 4% (w / v) paraformaldehyde. 4 μm coronal sections were generated by vibrator. The sections were heated at 100°C for 40 min in citrate buffer to obtain antigens. Endogenous peroxidase activity was blocked with hydrogen peroxide / methanol (30%) (treated at 25°C for 30 min). Tissue sections were blocked with 1% BSA and incubated at 4°C with rabbit anti-NeuN antibody (1:400, ProteinTech Group, Inc.), or rabbit anti-iba-1 antibody (1:500, Abcam), or rabbit anti-MAP2 antibody (1:500, ProteinTech Group, Inc.) or Alexa Fluor TM The cells were incubated overnight with 488-labeled mouse anti-GFAP antibody (Thermo Fisher). TM 488 or Alexa Fluor TMSections were stained with a 633-conjugated anti-rabbit IgG secondary antibody. Sections were imaged on a Nikon AX laser scanning confocal system, and 3D image reconstruction was performed using Imaris 10.0.0 (Bitplane). For microglia, cell body volume, convex hull volume, total branch length, and number of intersections were calculated. For astrocytes, the relative intensity of GFAP (glial fibrillary acidic protein) fluorescence, cell volume, and number of branch points were calculated.

[0056] (5) Statistical analysis

[0057] Data are expressed as mean ± standard deviation (SD). Multiple groups were analyzed using one-way ANOVA followed by Bonferroni post hoc test. Survival data were analyzed using the Log-rank (Mantel-Cox) test. P < 0.05 was considered significant and is indicated by *P < 0.05, **P < 0.01, and ***P < 0.001.

[0058] like Figure 4 As shown, Figure 4 A schematic diagram of the open field test facility and central area is shown, along with a heat map comparing overall activity among the three groups. The total distance traveled and the distance traveled in the central area of ​​the open field test are also shown (n=12 mice / group). The activity range of mice in the Rg-treated group was concentrated around the periphery, while the activity range of mice in the Rg+PDCI-treated group was not significantly different from that of the control group.

[0059] Figure 5 Schematic diagram of the water maze apparatus, starting point, and platform locations, along with corresponding statistics on the time mice spent in the platform quadrant after the platform was removed during the water maze experiment (n = 12 mice / group). Mice in the Rg-treated group had difficulty swimming toward the target quadrant, while the activity paths of mice in the Rg+PDCI-treated group did not differ significantly from those in the control group.

[0060] The results showed that R.gnavus colonization could increase the phenylethylamine content in the brain tissue of mice ( Figure 3 ), which weakened the mice's motor skills and caused them to exhibit anxiety-like behaviors ( Figure 4 ) and impaired memory ( Figure 5 ).

[0061] The proportion of mice that were not in a coma was further counted, and a line graph of the proportion of mice that were not in a coma when severe liver damage was induced in mice was drawn. The results are as follows Figure 6 As shown, the number of non-comatose mice in the Rg-treated group was smaller, that is, the number of comatose mice was more, which was significantly different from that in the control group; the number of non-comatose mice in the Rg+PDCI-treated group was not significantly different from that in the control group.

[0062] Combining the results of immunostaining and metabolomics, e.g. Figure 7 As shown, left panel: Representative images of GFAP (astrocytes, red) immunofluorescence labeling in the cerebral cortex of each treatment group (scale bar: 20 μm). Representative astrocytes were 3D reconstructed (scale bar: 8 μm), and the color represents the cell volume (scale bar: 20 μm). Right panel: Relative intensity of GFAP fluorescence, astrocyte cell volume, and number of branch points (n = 6 or 8 per group). The results showed that astrocytes in the cerebral cortex of mice treated with Rg were swollen, while the morphology of astrocytes in the cerebral cortex of mice treated with Rg+PDCI was not significantly different from that in the control group.

[0063] like Figure 8 Shown are representative images of Iba-1 (microglia, green) immunofluorescence labeling in the cerebral cortex of each treatment group (scale bar: 20 μm); three-dimensional reconstruction of representative microglia and drawing of their convex hulls (grey shades) (scale bar: 8 μm); colors indicate somatic volume and branch length (scale bar: 20 μm); right panel: microglial cell soma volume, convex hull volume, total branch length, and number of intersections (n ​​= 6 or 8 per group). The results showed that mice in the Rg-treated group developed neuroinflammation, while mice in the Rg+PDCI-treated group showed no significant difference from the control group.

[0064] The above results show that when mice have severe liver damage, the proportion of cirrhotic mice colonized with R. gnavus increases and they develop flapping tremors similar to those in HE patients. Furthermore, detection of encephalopathy-related pathological indicators found that R. gnavus induced swelling of astrocytes in the mouse cerebral cortex and triggered neuroinflammation characterized by microglial activation, and the above phenomena could be effectively reversed by (S)-α-FMT.

[0065] 2.2 R. gnavus can cause hepatic encephalopathy in cirrhotic mice, and the symptoms of hepatic encephalopathy in mice can be reversed by the PEA-specific monoclonal antibody PEA-mAB

[0066] Mice were grouped as Figure 9 The mice were divided into three groups: cirrhosis model IgG control treatment, cirrhosis model colonization Rg and IgG control treatment, cirrhosis model colonization Rg and PEA-mAB treatment; behavioral experiments were subsequently performed, liver decompensation model was established, and finally neuropathological analysis was performed.

[0067] Mice were treated with a cirrhosis model by intraperitoneal injection of 10% CCl4 at a dose of 10 ml / kg mouse body weight three times a week for 8 weeks. Mice were then treated with an antibiotic mixture containing 1 g / L ampicillin, 1 g / L neomycin, 0.5 g / L vancomycin, and 1 g / L metronidazole for 3 consecutive days to eliminate the intestinal flora, followed by a 3-day water washout period. Mice were then treated with sterile saline or 1×10 9 CFU / 0.2ml R. gnavus were gavaged orally three times a week for 8 weeks. Four weeks after gavage, the corresponding groups began intraperitoneal injections of PEA-mAB (1 mg / kg, Creative Diagnostics, Catalog #CABT-L2510) or IgG control (1 mg / kg, Thermo Fisher Scientific) twice a week for 4 weeks. After treatment, open field and water maze tests were performed. Finally, mice were injected intraperitoneally with 40% CCl4 to induce severe liver damage, and coma was continuously monitored for 72 hours. All mice were euthanized, and their brain tissues were collected. The relevant experimental methods and tests were the same as above.

[0068] The phenylethylamine content in the brain tissue of mice in each treatment group was counted. The results are as follows Figure 10 As shown, the phenylethylamine content in the brain tissue of mice in the Rg+IgG treatment group increased extremely significantly, the increase in the Rg+PEA-mAB treatment group was significantly reduced compared with the Rg+IgG treatment group, and there was no significant difference between the Rg+PEA-mAB treatment group and the control group.

[0069] like Figure 11 As shown, in the open field test, the activity of mice in the Rg+IgG treatment group was not significantly different from that in the control group, but the Rg+PEA-mAB treatment group was more active than the Rg+IgG treatment group; the mice in the Rg+IgG treatment group tended to move around the arena compared with the control group, which was significantly different from the control group, but there was no significant difference between the Rg+IgG treatment group and the Rg+PEA-mAB treatment group.

[0070] like Figure 12 As shown in the data, in the water maze test, the mice in the Rg+IgG treatment group had difficulty swimming toward the target quadrant, which was significantly different from the control group. The Rg+PEA-mAB treatment group had slightly stronger orientation than the Rg+IgG treatment group, which was significant, but also significantly different from the control group.

[0071] The proportion of mice that were not unconscious was counted, and the results were as follows Figure 13As shown, the number of non-comatose mice in the Rg+IgG treatment group was smaller, that is, the number of comatose mice was larger, which was significantly different from that in the control group; the number of comatose mice in the Rg+PEA-mAB treatment group was not significantly different from that in the control group.

[0072] The results of immunostaining and metabolomics are shown in Figure 14 and Figure 15 .

[0073] like Figure 14 Left: Representative images of GFAP (astrocytes, red) immunofluorescence labeling in the cerebral cortex of each treatment group (scale bar: 20 μm). Three-dimensional reconstruction of representative astrocytes (scale bar: 8 μm), with color representing cell volume (scale bar: 20 μm). Right: Relative intensity of GFAP fluorescence, astrocyte cell volume, and number of branch points (n = 6 or 8 per group). The results showed that astrocytes in the cerebral cortex of mice treated with Rg + IgG were swollen, while the morphology of astrocytes in the cerebral cortex of mice treated with Rg + PEA-mAB was not significantly different from that in the control group.

[0074] like Figure 15 Figure 2: Representative images of Iba-1 (microglia, green) immunofluorescence labeling in the cerebral cortex of each treatment group (scale bar: 20 μm); 3D reconstruction of representative microglia and drawing of their convex hulls (grey shades) (scale bar: 8 μm); colors indicate somatic volume and branch length (scale bar: 20 μm); right panel: microglial soma volume, convex hull volume, total branch length, and number of intersections (n ​​= 6 or 8 per group). The results showed that mice in the Rg + IgG treatment group developed neuroinflammation, while mice in the Rg + PEA-mAB treatment group showed no significant difference from the control group.

[0075] In summary, IgG had no significant effect on mice, but R. gnavus colonization still increased the phenylethylamine content in the mouse brain tissue. Neurological function evaluation was similar to the results described above, and this phenomenon could be effectively reversed by the PEA-mAB, a PEA-specific monoclonal antibody.

[0076] 3. Confirm application prospects

[0077] Based on the above experimental results, inhibitors of bacterial aromatic amino acid decarboxylase can be used in the preparation of drugs for treating hepatic encephalopathy. Furthermore, aromatic amino acid decarboxylase is produced by intestinal bacteria, and the primary producer has been confirmed to be active Ruminococcus gnavus. Amino acid sequencing revealed the amino acid sequence of the aromatic amino acid decarboxylase as shown in SEQ No. 1. Targeting this aromatic amino acid decarboxylase, the aromatic amino acid decarboxylase inhibitor includes at least one of the following: an aromatic amino acid decarboxylase enzyme inhibitor, a formulation that inhibits aromatic amino acid decarboxylase gene expression, a phenylethylamine-specific monoclonal antibody, a probiotic that inhibits the abundance of active Ruminococcus gnavus, or a formulation that inhibits the abundance of active Ruminococcus gnavus. More specifically, the aromatic amino acid decarboxylase enzyme inhibitor is (S)-α-FMT; the formulation that inhibits aromatic amino acid decarboxylase gene expression is a formulation combination capable of achieving gene editing; and the phenylethylamine-specific monoclonal antibody is PEA-mAB.

[0078] The hepatic encephalopathy to which this application applies is induced by non-alcoholic fatty liver disease. It can further be induced by cirrhosis. The aromatic amino acid decarboxylase inhibitor can achieve at least one of the following functions: maintaining phenylethylamine levels in brain tissue, maintaining motor function, maintaining memory, reducing coma caused by cirrhosis, reducing asterixis, reducing the occurrence of astrocyte swelling in the cerebral cortex, reducing the occurrence of microglial activation, and reducing neuroinflammation.

[0079] Those skilled in the art will appreciate that the steps, measures, and schemes in the various operations, methods, and processes discussed in this application may be interchanged, modified, combined, or deleted. Furthermore, other steps, measures, and schemes in the various operations, methods, and processes discussed in this application may also be interchanged, modified, rearranged, decomposed, combined, or deleted. Furthermore, steps, measures, and schemes in the related art that are similar to those disclosed in this application may also be interchanged, modified, rearranged, decomposed, combined, or deleted.

[0080] The above is only part of the implementation methods of the present application. It should be pointed out that for ordinary technicians in this technical field, without departing from the technical concept of the solution of the present application, other similar implementation methods based on the technical ideas of the present application also fall within the protection scope of the embodiments of the present application.

Claims

1. Use of an inhibitor of aromatic amino acid decarboxylase in the preparation of a medicament for treating hepatic encephalopathy, characterized in that: The amino acid sequence of the aromatic amino acid decarboxylase is shown in SEQ No. 1; the aromatic amino acid decarboxylase is produced by Ruminococcus activatus R. gnavus Production; the inhibitor of aromatic amino acid decarboxylase comprises at least one of the following substances: an enzyme inhibitor of aromatic amino acid decarboxylase and a phenylethylamine-specific monoclonal antibody; The enzyme inhibitor of aromatic amino acid decarboxylase is (S)-α-FMT; the phenylethylamine-specific monoclonal antibody is PEA-mAB.

2. The use according to claim 1, characterized in that The hepatic encephalopathy is induced by non-alcoholic fatty liver disease.

3. The use according to claim 2, characterized in that The hepatic encephalopathy is induced by liver cirrhosis.

4. The use according to claim 1, wherein The inhibitor of aromatic amino acid decarboxylase can achieve at least one of the following functions: maintaining the phenylethylamine content in brain tissue, maintaining motor ability, maintaining memory ability, reducing coma caused by cirrhosis, reducing flapping tremors, reducing the occurrence of astrocyte swelling in the cerebral cortex, reducing the occurrence of microglial activation, and reducing neuroinflammation.

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