CN118680941A - Application of sodium phenylbutyrate and tauroursodeoxycholic acid in the prevention, improvement or treatment of cognitive impairment - Google Patents

Abstract

The present invention belongs to the field of biomedicine technology, and discloses the use of sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA) in combination in the preparation of a drug for preventing, improving or treating cognitive impairment, and a pharmaceutical composition for preventing, improving or treating cognitive impairment: the pharmaceutical composition comprises a therapeutically effective amount of sodium phenylbutyrate and tauroursodeoxycholic acid. The present invention studies have confirmed that AMX0035 can improve anxiety-like behavior and cognitive impairment in mice, and increase the expression of MBP and PSD95; AMX0035 can alleviate cognitive impairment by promoting myelin regeneration and synaptic integrity, providing a promising treatment method for chemotherapy-induced cognitive impairment, and is expected to become a new strategy for the clinical treatment of CICI.

Description

Application of sodium phenylbutyrate and tauroursodeoxycholic acid in the prevention, improvement or treatment of cognitive impairment

Technical Field

The present invention relates to the field of biomedical technology, and in particular to application of sodium phenylbutyrate and tauroursodeoxycholic acid in combination in preventing, improving or treating cognitive impairment.

Background Art

While chemotherapy has been shown to save the lives of many patients, it has side effects. A concerning phenomenon, chemotherapy-induced cognitive impairment (CICI), also known as "chemo-brain" or "chemo-fog," is a side effect of this life-saving therapy. CICI refers to a range of cognitive impairments that cancer patients experience after receiving chemotherapy, including memory deficits, attention problems, and decreased processing speed. CICI is a major source of morbidity during and after cancer treatment, and it is a significant problem that we must address.

Although more than three-quarters of cancer patients experience CICI, the mechanisms mediating CICI have not been elucidated. Neuroimaging studies have shown that white matter integrity (WMI) is disrupted and hippocampal volume is reduced in chemotherapy patients with cognitive impairment. White matter (WM) plays a key role in supporting cognitive development and regulating communication between different brain regions. Synapses are the key connections between neurons, and synaptic function is key to healthy cognition. Studies have shown that enhancing hippocampal myelin regeneration and synaptic integrity can effectively reverse cognitive impairment.

A recent clinical study showed that after combined chemotherapy with doxorubicin (DOX) and cyclophosphamide (CYP), diffusion tensor imaging studies showed reduced white matter integrity. Preclinical studies have shown that DOX- and CYP-induced cognitive impairment leads to decreased synaptic proteins and disrupted synaptic integrity in the hippocampus.

In a recent clinical study, the compound AMX0035 (AMX), composed of sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA), reduced neuronal death in patients with amyotrophic lateral sclerosis (ALS). PBA and TUDCA have been shown to promote myelin regeneration and synaptic integrity in animal models of neurodegenerative diseases. However, whether AMX can improve chemotherapy-induced cognitive impairment and promote myelin and synaptic integrity is unknown.

Summary of the invention

The purpose of the present invention is to provide a method for preventing, improving or treating cognitive impairment by combining sodium phenylbutyrate and tauroursodeoxycholic acid.

In order to achieve its purpose, the present invention adopts the following technical solution:

The first aspect of the present invention provides the use of sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA) in combination for preparing a drug for preventing, improving or treating cognitive impairment.

In the above application technology solution, the medicine contains a therapeutically effective amount of sodium phenylbutyrate and tauroursodeoxycholic acid.

Preferably, in the above application technology solution, the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 2-4:1.

Preferably, in the above application technology solution, the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 3:1.

The second aspect of the present invention provides the use of AMX0035 in the preparation of a medicament for preventing, improving or treating cognitive impairment.

In the above application technology solution, the drug also contains a pharmaceutically acceptable carrier.

In any of the above-mentioned application technology solutions, the cognitive impairment is chemotherapy-induced cognitive impairment.

The third aspect of the present invention provides a pharmaceutical composition for preventing, improving or treating cognitive impairment, the pharmaceutical composition comprising a therapeutically effective amount of sodium phenylbutyrate and tauroursodeoxycholic acid.

In the above-mentioned pharmaceutical composition, the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 2-4:1; preferably, the drug is AMX0035.

The above-mentioned pharmaceutical composition, the drug is in the form of powder, capsule, tablet, emulsion, aqueous suspension, dispersion or solution.

The beneficial effects of the present invention are:

The present study showed that mice receiving AC chemotherapy showed anxiety-like behavior and cognitive impairment, accompanied by demyelination in the corpus callosum, cortex and hippocampus, as well as changes in MBP expression and synaptic morphology in the hippocampus and cortex and decreased PSD95 expression. AMX0035 can improve anxiety-like behavior and cognitive impairment in mice and increase the expression of MBP and PSD95;

AMX0035 can alleviate cognitive impairment by promoting myelin regeneration and synaptic integrity, providing a promising treatment for chemotherapy-induced cognitive impairment and is expected to become a new strategy for the clinical treatment of CICI.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the effects of AMX on chemotherapy-treated mice observed in the open field test: (A) total distance traveled in the open field; (B) average speed within the zone; (C) number of entries into the central zone; (D) representative route map of each group; data are expressed as mean ± SEM; **P < 0.01, ***P < 0.001 compared with the NC+NC group; #P < 0.05 compared with the AC+A group.

Figure 2 shows the effects of AMX on chemotherapy-treated mice observed in the Morris water maze test: (A) movement speed on the first day of training; (B) escape latency in the training trial; (C) number of entries into the platform during the probe test; (D) time spent in the target quadrant during the probe test; (E) representative route map of each group; data are expressed as mean ± SEM; compared with the NC+NC group, **P<0.01, ***P<0.001, ****P<0.0001; compared with the AC+A group, #P<0.05, ##P<0.01, ##P<0.001.

Figure 3 shows the effects of AMX on TEM and LFB in chemotherapy mice: (A) TEM observation of CC axons in each group, scale bar = 1 μm; (B) TEM observation of hippocampal axons in each group; scale bar = 1 μm; (C) Representative LFB staining images of CC myelin sheath in each group; scale bar = 100 μm; (D) Histogram of g-ratio values in CC in each group; (E) Histogram of g-ratio values in hippocampus of rats in each group; Data are expressed as mean ± SEM; **P < 0.01, ***P < 0.001 compared with NC + NC group. #P < 0.05, ##P < 0.01 compared with AC + A group.

Figure 4 shows (A) the expression of MBP protein in CC, cortex, and hippocampus of rats in each group; (B) representative immunofluorescence images of MBP expression in CC, cortex, and hippocampus of each group (green); Scale bar = 100 μm; (C, D, E) relative expression of MBP protein in CC, cortex, and hippocampus; (F, G, H) quantification of MBP density in CC, cortex, and hippocampus; data are expressed as mean ± SEM; compared with the NC+NC group, **P<0.01, ***P<0.001, ****P<0.0001; compared with the AC+A group, #P<0.05, ##P<0.01.

Figure 5 shows (A) transmission electron microscopy observation of synapses in the CA1 region of the hippocampus of rats in each group; scale bar = 500 nm; (B) expression of PSD95 protein in the cortex and hippocampus of rats in each group; (C, D) relative expression levels of PSD95 protein in the cortex and hippocampus; data are expressed as mean ± SEM; compared with the NC+NC group, ***P<0.001; compared with the AC+AMX group, #P<0.05, ##P<0.01.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with embodiments, but the present invention is not limited thereto.

The experimental methods in the following examples are conventional methods unless otherwise specified.

The Chinese corresponding to the abbreviations in the present invention are:

Example 1

1. Materials and Methods

1. Animals

Female C57BL/6J (12 weeks old; n = 60) were purchased from the Experimental Animal Center of Chongqing Medical University. Mice (5 per cage) were housed in a temperature- and humidity-controlled environment with a 12-h light/dark cycle. Mice had adequate food and water at all times. To minimize stress levels, the researchers handled the mice daily. Drug intervention began one week after mice were obtained from the breeders. All procedures strictly followed the guidelines approved by the Ethics Committee of Chongqing Medical University.

2. Animal Drug Administration

Sixty mice were randomly divided into four groups: NC+NC, NC+AMX0035 (NC+A), AC+NC, and AC+AMX0035 (AC+A). Normal saline or AC (2 mg/kg DOX doxorubicin + 50 mg/kg CYP cyclophosphamide) was intraperitoneally injected once a week for 4 weeks. All chemotherapy drugs were purchased from Sigma-Aldrich and dissolved in normal saline. The day after chemotherapy, mice in each group were orally administered with normal saline or 200 mg/kg AMX0035 (Aladdin, China; PBA and TUDCA were mixed at a mass ratio of 3:1) every day for 3 weeks. We selected the doses of all drugs based on previous studies.

3. Behavioral Testing

Open field test. Previous studies have shown that the open field test can be used to assess exploratory behavior, anxiety-like behavior, and general motor activity. The test chamber consisted of a square area surrounded by white acrylic walls (40x40x60 cm) and illuminated at 100lx. The central area refers to the 20x20 cm area in the middle of the field. On the day after the oral treatment was completed, each mouse was placed in the center of the apparatus for a single 5-min treatment. Before each test, the test chamber was cleaned with 75% ethanol to eliminate odors. The parameters recorded included total distance moved (m), number of entries into the central area, and movement speed.

Morris water maze test. The Morris water maze consists of a circular water tank with a diameter of 120 cm and a depth of 50 cm. The water tank is filled with opaque constant temperature circulating water. This maze is used to assess the spatial learning and memory ability of rodents. After the open field test, each mouse was trained 4 times in a row, each for 20 minutes, for 5 consecutive days. In each trial, the mouse was placed facing the wall of the water tank and was gently placed in the water at the designated starting point in the maze. To promote the development of spatial memory, the starting point in the maze changed every day. Video tracking software was used to record the movement path of each mouse in the maze and the time required to reach the platform in each training trial. Training ended if the mouse reached the hidden platform and stayed there for at least 2 seconds or could not find the platform within 60 seconds. Mice that did not find the platform within 60 seconds were guided to the platform and stayed there for 15 seconds. 24 hours after the last training trial, the platform was removed for a probe test. The mice were released into the water from a new location to ensure the use of spatial memory rather than through a specific swimming route. Each group of mice swam for 60 seconds. The time the mice stayed in the target quadrant was recorded as an indicator of their learning and memory abilities.

4. Tissue Preparation

After the Morris water maze test, pentobarbital (60 mg/kg) was injected intraperitoneally. After apical perfusion of normal saline, brain tissue was obtained and cut into two halves sagittally; one half was used for Luxol Fast Blue (LFB) and immunofluorescence staining, and the other half was used for protein blotting (western blot). Electron microscopic observation: After normal saline perfusion, brain tissue was perfused with 2.5% [volume/volume (v/v)] glutaraldehyde (prepared by diluting 25% glutaraldehyde solution with 0.2 M phosphate buffer) until hardening.

5. Luxol Fast Blue (LFB) staining

Luxol Fast Blue staining was used to stain phospholipids, the main component of myelin sheath, in blue. Brain tissue was embedded in OCT embedding medium and cut into 10 μm slices. The slices were air-dried at room temperature and stored at -20°C. After the slices were incubated in 60°C LFB staining solution overnight and in 95% ethanol for 10 minutes, they were incubated in 0.05% lithium carbonate aqueous solution for 10 seconds, then incubated in 70% ethanol solution for 20 seconds, and finally incubated in eosin dye for 30 seconds to stain the cytoplasm. Images were acquired using a Leica DMi8 microscope.

6. Transmission Electron Microscopy

Whole brains were extracted immediately after perfusion and stored in 4% (v/v) glutaraldehyde at 4°C overnight. After fixation, 1-mm-thick sections containing the anterior third of the corpus callosum (CC) and the hippocampus were isolated from each brain. These 1-mm-thick sections were then stained with a 70% saturated uranyl acetate solution and gradually dehydrated in ethanol/acetone. The sections were embedded in an aralite/Epon resin mixture, cut into 1-μm semi-thin sections, and stained with toluidine blue. Semi-thin sections were examined microscopically and cut into pyramids containing the CC genu and CA1 region, cut into 60-nm ultra-thin sections, and mounted on copper grids. The sections were stained with uranyl acetate and lead citrate and observed using a JEOL JEM-1400Plus transmission electron microscope. The g ratio was calculated as the axon diameter divided by the diameter of the entire myelinated fiber. ImageJ was used to measure the axon diameter and myelinated fiber diameter of the myelinated axons of each mouse.

7. Immunofluorescence

The sections were sliced and stored as described previously. First, they were rewarmed for 1 h at 37°C with 0.4% (v/v) Triton X-100 and 5% (v/v) normal goat serum (prepared in 0.01 M PBS). Afterwards, antigen retrieval was performed by placing the sections in sodium citrate solution at 95°C for 10 min and then incubated with primary antibodies against myelin basic protein (MBP) and postsynaptic density protein 95 (PSD95) at 4°C overnight. The sections were washed with 0.01 M PBS and incubated with secondary antibodies at 37°C for 1 h. DAPI was used to label cell nuclei. The stained sections were observed using Leica DMi8 and area quantification was performed using ImageJ.

8. Western Blotting

Proteins were extracted from the corpus callosum, hippocampus, and cortex by radioimmunoprecipitation. Tissues were disrupted by ultrasound and centrifuged at 4°C for 30 min. The resulting supernatant was combined with SDS-PAGE sample buffer and heated to 95°C for 10 min. Protein concentration was determined using an enhanced bicinchoninic acid protein assay kit. Fifty micrograms of protein were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis on 12.5% or 10% gels in a Mini-Protein 3 apparatus. Subsequently, the proteins were electroblotted onto a hydrophobic polyvinylidene fluoride transfer membrane with a pore size of 0.2 μm. Electrotransfer was performed at 250 mA in transfer buffer supplemented with 20% (v/v) methanol. After electrotransfer, the membrane was blocked with 5% (v/v) condensed milk at 37°C for 2 h, and then incubated with primary antibodies against MBP (1:1000, Wuhan Tri-Taiwan, China) and PSD95 (1:1000, Wuhan Tri-Taiwan, China) at 4°C overnight. The membrane was washed with TBST and then incubated with horseradish peroxidase (HRP)-labeled secondary antibodies (1:10000, Bio-Rad, China) at 37°C for 1 h. The membrane was stripped with ultrasensitive ECL reagent and observed using the Bio-Rad Laboratories ChemiDoc MP imaging system. The intensity of the protein was determined by Quantity One Software version 4.6.2.

9. Statistical Analysis

We used GraphPadPrism version 9.0.0 for analysis. Data are presented as mean ± standard error of the mean (SEM). One-way ANOVA was used for comparison among groups, and Tukey's post hoc test was used for comparison between two groups. P < 0.05 was considered statistically significant.

2. Results

1. AMX can improve chemotherapy-induced anxiety-like behavior and motor function defects in adult mice

The open field test showed significant differences in the total movement distance (P<0.01) (Figure 1A). The movement speed (P<0.001) (Figure 1B) and the number of entries into the central area (P<0.001) (Figure 1C) between the NC+NC group and the AC+NC group were significantly different. After oral administration of AMX for 3 weeks, the movement speed (P<0.05) (Figure 1B) and the number of entries into the central area (P<0.05) (Figure 1C) were significantly increased compared with the AC+NC group.

2. AMX can improve chemotherapy-induced spatial learning and memory deficits in adult mice

In the Morris water maze adaptation test, there was no difference in the basal swimming speed of mice (Figure 2A). As shown in Figure 2B, a time-dependent decrease was observed in all groups. Compared with the baseline value, the escape latency time was significantly shortened on the 4th and 5th days in the NC+NC group (P<0.01 and P<0.001), and the escape latency time was significantly shortened on the 5th day in the AC+NC group (P<0.01), indicating that the spatial learning and memory ability of rats in the AC+NC group was impaired. After AMX treatment, the escape latency on the 4th and 5th days was significantly shortened compared with the baseline (P<0.01 and P<0.001) (Figure 2B). In the probe test, mice in the AC+NC group stayed in the target quadrant less time (P<0.001) (Figure 2D), and the number of times they crossed the platform was significantly less than that in the NC+NC group (P<0.01) (Figure 2C). However, after AMX treatment, the target quadrant residence time (P<0.05) (Figure 2D) and the number of platform crossings (P<0.05) (Figure 2C) were significantly higher than those in the AC+NC group, suggesting that AMX can improve chemotherapy-induced spatial learning and memory in mice.

3. AMX promotes myelin regeneration in adult mice after chemotherapy

LFB staining showed that demyelination in the CC in the AC+A group was reduced compared with that in the AC+NC group (Fig. 3C). To investigate the changes in myelin structure, we observed the structure of myelinated nerve fibers in the CC and hippocampus by TEM (Fig. 3A,B). Electron microscopy of myelinated axons showed that the g ratio of myelinated nerve fibers in the CC and hippocampus in the AC+NC group was increased compared with that in the NC+NC group (P<0.01 in the cortex and P<0.001 in the hippocampus) (Fig. 3D,E), indicating that AMX improved myelination (P<0.01 in the cortex and P<0.05 in the hippocampus) (Fig. 3D,E).

To further investigate the loss of myelin, we examined the density of MBP by immunofluorescence (Fig. 4B) and measured the level of MBP by Western blotting (Fig. 4A). Compared with the NC+NC group, the MBP content (CC P<0.0001, cortex P<0.01, hippocampus P<0.001) (Fig. 4C, D, E) and MBP expression (CC P<0.001, cortex P<0.0001, hippocampus P<0.001) (Fig. 4F, G, H) in the AC+NC group were significantly decreased. Compared with the AC+NC group, the MBP content (CC P<0.01, cortex P<0.05, hippocampus P<0.05) (Fig. 4C, D, E) and MBP expression (all P<0.05) (Fig. 4F, G, H) in the CC, cortex and hippocampus of the AC+AMX group were increased.

4. AMX promotes synaptic integrity in adult mice after chemotherapy

Synaptic dysfunction and loss of synaptic integrity are among the early signs of cognitive impairment. To investigate whether our chemotherapy regimen affected the synaptic integrity of mice, we used TEM to observe synapses in the CA1 region of the hippocampus. TEM results showed that the synaptic clefts in the AC+NC group were blurred (Figure 5A). To further verify the changes in synaptic integrity, we used western blot to detect the key synaptic structural protein PSD95 (a marker of synaptic integrity) in the cortex and hippocampus (Figure 5B). As shown in Figure 5, the content of PSD95 in the cortex and hippocampus (both P<0.001) (Figure 5C, D) of the AC+NC group was reduced; however, the decrease in PSD95 content (cortex P<0.05, hippocampus P<0.01) (Figure 5C, D) was rescued after AMX treatment.

Analysis

Cognitive impairment is a common side effect of chemotherapy; however, current treatments have limited efficacy. Various clinical and basic studies have shown that there are significant white matter abnormalities in the brains of CICI patients or CICI model mice. It is well known that myelin can insulate axons and protect them from degeneration in demyelinating diseases.

Cognition is closely related to normal neuronal conduction, which depends on healthy myelin structure. Demyelination can disrupt neuronal conduction. In behavioral tests, cognitive dysfunction was observed in mice receiving chemotherapy. In addition, our results showed that myelin was lost in the CC, cortex, and hippocampus of the mouse brain after AC regimen treatment. Extensive myelin degeneration can lead to CICI. After administration of AMX, different regions of the mouse brain showed different degrees of myelin regeneration, and behavioral tests showed significant improvement in cognitive deficits. AMX can partially alleviate CICI by promoting myelin regeneration.

The hippocampus plays a crucial role in memory and learning, and synaptic plasticity is widely considered to be the underlying mechanism. Synapses facilitate communication between nerve cells by enabling the release of neurotransmitters from presynaptic neurons to postsynaptic neurons. Both presynaptic proteins, such as synaptophysin, and postsynaptic proteins, such as PSD95, play important roles in synaptic plasticity and cognitive function. Defects in synaptophysin and PSD95 have been associated with cognitive decline in neurodegenerative diseases, such as Alzheimer's disease and aging. For example, PSD95 expression is reduced in the brains of patients with Alzheimer's disease. Long-term CICI is associated with decreased expression of PSD95 in the hippocampus. Treatment with a blood-brain barrier-permeable histone deacetylase 6 (HDAC6) inhibitor can reverse long-term doxorubicin-induced cognitive impairment by restoring synaptic integrity. In our study, mice developed cognitive impairment after AC chemotherapy, and decreased expression of synaptic structural proteins was observed in the cortex and hippocampus. After administration of AMX, cognitive impairment was alleviated and the expression levels of synaptic structural proteins were increased.

The endoplasmic reticulum (ER) is an important organelle in eukaryotic cells that is involved in protein modification and folding, lipid biosynthesis, and regulation of cellular calcium levels. The imbalance between protein translation and protein modification and folding leads to the accumulation of unfolded or misfolded proteins in the ER lumen. This accumulation triggers ER stress and activates the unfolded protein response (UPR). However, long-term and unresolved UPR activation can induce apoptotic pathways to eliminate damaged cells. Multiple sclerosis (MS) is a disease mainly characterized by demyelination of the central nervous system (CNS), and several studies have shown that ER stress and UPR are involved in MS and experimental autoimmune encephalomyelitis (EAE). UPR activators, such as CHOP (ER stress-related transcription factor) and ATF4 (ER stress-related gene), have been found to have increased expression in demyelinating lesions in MS. In addition, in the EAE model, oligodendrocyte loss and severe myelin abnormalities were found in mice with Bip (an ER chaperone protein) gene knockout. Samma et al. demonstrated that atorvastatin can alleviate CICI by reducing the expression of ER stress markers CHOP and GRP78. Both PBA and TUDCA are known as ER stress inhibitors and have been shown to improve demyelination in various demyelinating diseases. In this study, we demonstrated that the combination of PBA and TUDCA (also known as AMX) can improve CICI by improving brain demyelination; however, whether AMX promotes myelin regeneration by inhibiting ER stress is unclear. Changes related to ER stress after chemotherapy and whether AMX promotes myelin regeneration by regulating ER stress need further study.

In summary, we demonstrated that chemotherapy causes anxiety and cognitive impairment through white matter damage and synaptic defects. AMX0035 can improve cognitive function in chemotherapy-treated mice by promoting myelin regeneration and synaptic integrity, suggesting that AMX0035 may be a new therapeutic strategy for cognitive impairment in chemotherapy-treated mice.

Our study showed that mice treated with AC chemotherapy exhibited anxiety-like behaviors and cognitive impairment, accompanied by demyelination in the corpus callosum, cortex, and hippocampus, as well as altered MBP expression and synaptic morphology and decreased PSD95 expression in the hippocampus and cortex. AMX0035 improved anxiety-like behaviors and cognitive impairment in mice and increased the expression of MBP and PSD95. Our results suggest that AMX0035 can alleviate cognitive impairment by promoting myelin regeneration and synaptic integrity, providing a promising treatment for chemotherapy-induced cognitive impairment.

Claims (10)

1. The application of sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA) in combination in the preparation of drugs for preventing, improving or treating cognitive impairment. 2. The use according to claim 1, characterized in that the medicine contains a therapeutically effective amount of sodium phenylbutyrate and tauroursodeoxycholic acid. 3. The use according to claim 2, characterized in that: the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 2-4:1. 4. The use according to claim 3, characterized in that: the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 3:1. 5. Use of AMX0035 in the preparation of drugs for preventing, improving or treating cognitive impairment. 6. The use according to claim 1 or 5, characterized in that the drug further contains a pharmaceutically acceptable carrier. 7. The use according to any one of claims 1 to 6, characterized in that the cognitive impairment is chemotherapy-induced cognitive impairment. 8. A pharmaceutical composition for preventing, improving or treating cognitive impairment, characterized in that the pharmaceutical composition comprises a therapeutically effective amount of sodium phenylbutyrate and tauroursodeoxycholic acid. 9. The pharmaceutical composition according to claim 8, characterized in that: the mass ratio of sodium phenylbutyrate to tauroursodeoxycholic acid is 2-4:1; preferably, the drug is AMX0035. 10. The pharmaceutical composition according to claim 9, characterized in that the drug is in the form of powder, capsule, tablet, emulsion, aqueous suspension, dispersion or solution.