Application of TRPML1 specific small-molecule inhibitor ML-SI3

Abstract

The invention provides an application of a TRPML1 specific small-molecule inhibitor ML-SI3 in preparation of a drug for treating or preventing brain injury. The TRPML1 specific small-molecule inhibitor ML-SI3 has the beneficial effects that the TRPML1 specific small-molecule inhibitor ML-SI3 disclosed by the invention can be used for remarkably reducing the injury degree of neurons of rats with brain injury; the learning and memory ability of rats with brain injury is improved; the dyskinesia of rats suffering from brain injury is improved, and the brain function of the rats suffering from sudden cardiac arrest and cardiopulmonary resuscitation is comprehensively protected; the TRPML1 specific small-molecule inhibitor ML-SI3 provided by the invention provides a new medicine for protecting the brain function of a patient with sudden cardiac arrest, and has good market value and clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an application of a TRPML1 specific small molecule inhibitor ML-SI3. Background Art

[0002] Cardiac arrest (CA) refers to the sudden cessation of heart beating caused by various reasons in unexpected circumstances and time, which leads to the sudden cessation of normal cardiac pump function and effective circulation, causing severe ischemia, hypoxia and metabolic disorders of tissue cells throughout the body. Once cardiac arrest occurs, if it is not rescued and resuscitated immediately, it will cause irreversible damage to the patient's brain and other important organs and tissues of the human body after 4 to 6 minutes. Therefore, cardiopulmonary resuscitation (CPR) after cardiac arrest is a key step that should be taken to maximize the patient's survival probability, which is called the cardiac arrest survival chain. CPR is an effective method for rescuing cardiac arrest. However, during the process of cardiopulmonary resuscitation, severe brain hypoxia symptoms often occur, and the patient's brain cells will be greatly damaged, leaving behind varying degrees of central nervous system damage, which is called post-cardiac arrest brain injury (PCABI). Among patients with successful cardiac arrest resuscitation, 60% to 70% died of post-cardiac arrest brain injury, while among cardiac arrest survivors in my country, only about 10.2% of patients maintained good neurological function after resuscitation. Improving the acute neurological injury caused by cardiac arrest is the key to improving the patient's survival and discharge rate. Current strategies for preventing and treating brain injury after cardiac arrest can be divided into interventions aimed at reducing excitotoxicity, improving neuronal metabolism, limiting mitochondrial damage, and reducing neuroinflammation. Although there are currently a variety of strategies to try to protect brain function after cardiac arrest, neuroprotective drugs have not been found to effectively improve patient survival or neurological prognosis. A number of treatments such as NMDA, AMPA receptor antagonists, antioxidants, mitochondrial function protectors, anti-inflammatory drugs, and immunomodulation are still in preclinical research. A deep understanding of the complex pathophysiological changes after brain injury after cardiac arrest is the basis and the key to the development of targeted neuroprotective strategies to protect brain function in patients with cardiac arrest. Summary of the invention

[0003] The present application provides an application of ML-SI3, a TRPML1-specific small molecule inhibitor, in the preparation of a drug for treating or preventing brain damage caused by cardiac arrest.

[0004] In a first aspect, the present application provides a use of a TRPML1-specific small molecule inhibitor ML-SI3 in the preparation of a drug for treating or preventing brain injury.

[0005] According to some embodiments of the use described in the present application, the brain injury includes brain injury caused by cardiac arrest.

[0006] According to some embodiments of the application described in this application, the structural formula of the TRPML1-specific small molecule inhibitor ML-SI3 is as follows:

[0007]

[0008] According to some embodiments of the application described in the present application, when preparing a drug for treating or preventing brain injury, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 1-4 mg / kg.

[0009] In a second aspect of the present application, a drug for treating brain damage caused by cardiac arrest is provided, comprising a pharmaceutically active ingredient and a pharmaceutically acceptable excipient, wherein the pharmaceutically active ingredient comprises ML-SI3, a TRPML1-specific small molecule inhibitor.

[0010] According to some embodiments of the drug for treating brain damage caused by cardiac arrest described in the present application, the content of the active ingredient in the drug is 1-4 mg / kg.

[0011] According to some embodiments of the drug for treating brain damage caused by cardiac arrest described in the present application, the content of the active ingredient in the drug is 3 mg / kg.

[0012] According to some embodiments of the drug for treating brain damage caused by cardiac arrest described in the present application, the dosage form of the drug includes injection, tablet, capsule, granule, aerosol or oral liquid.

[0013] The beneficial effects of the present application include: the TRPML1-specific small molecule inhibitor ML-SI3 described in the present application can significantly reduce the degree of neuronal damage in brain-injured rats; improve the learning and memory abilities of brain-injured rats; improve the movement disorders in brain-injured rats, and has a comprehensive protective effect on the brain function of rats after cardiac arrest and cardiopulmonary resuscitation.

[0014] The TRPML1-specific small molecule inhibitor ML-SI3 described in the present application provides a new drug for protecting brain function in patients with cardiac arrest and has good market value and clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The preparation and drug administration time pattern diagram for brain-injured rats with return of spontaneous circulation (ROSC) after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR);

[0016] Figure 2a This is the Nissl staining image of the cerebral cortex section of the brain-injured rat after administration of ML-SI3;

[0017] Figure 2b This is a statistical chart of the degree of cerebral cortical damage (Nissl body percentage) in brain-damaged rats after administration of ML-SI3;

[0018] Figure 3a This is an analysis diagram of the water maze test results of brain-injured rats after administration of ML-SI3;

[0019] Figure 3b This is the time that rats stayed in the target quadrant on the sixth day after ML-SI3 administration, a statistical chart to evaluate their spatial memory ability (the longer the time, the better the memory ability);

[0020] Figure 4 This is an analysis chart of the balance beam test results of brain-injured rats after administration of ML-SI3;

[0021] Figure 5 This is an analysis diagram of the results of the Rotarod test in brain-injured rats after administration of ML-SI3;

[0022] Figure 6a This is an analysis diagram of the results of the open field experiment in brain-injured rats after administration of ML-SI3;

[0023] Figure 6b The middle left picture shows the total movement distance of brain-injured rats in an open field after administration of ML-SI3. Figure 6b The middle right picture shows the average movement rate statistics of brain-injured rats in an open field after administration of ML-SI3. DETAILED DESCRIPTION

[0024] Embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0025] In the present invention, the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0026] The present application provides the application of the TRPML1-specific small molecule inhibitor ML-SI3 for the preparation of a protective agent for brain function after cardiac arrest. Specifically, when the inhibitor is used to prepare a drug for treating brain damage in rats after cardiac arrest and cardiopulmonary resuscitation, the inhibitor can significantly reduce the degree of neuronal damage in brain-damaged rats; improve the learning and memory ability of brain-damaged rats; reduce movement disorders in brain-damaged rats, and has a comprehensive protective effect on the brain function of rats after cardiac arrest and cardiopulmonary resuscitation.

[0027] When treating rats with brain damage after cardiac arrest and cardiopulmonary resuscitation, the effective dose of the TRPML1 specific small molecule inhibitor ML-SI3 is 1-4 mg / kg, preferably 3 mg / kg.

[0028] Brain injury after cardiac arrest is the main cause of death in patients with cardiac arrest who undergo cardiopulmonary resuscitation. Excessive zinc and iron ions in neurons are involved in the pathological process of brain injury after cardiac arrest, but the source and mechanism of action of these metal ions are not yet clear. The inventors verified through experiments that the lysosomal ion channel TRPML1 mediates the release of zinc ions, causing blockage of autophagic flow and damage to mitochondria causing myocardial cell damage, but the role of TRPML1 in brain injury after cardiac arrest is still unclear. The inventors found that downregulating TRPML1 can improve the degree of brain injury in rats after cardiopulmonary resuscitation and reduce the levels of zinc and iron ions in neurons. For this reason, it is speculated that the TRPML1 channel is a key factor leading to excess zinc and iron ions in neurons after cardiac arrest. This study will provide a solid theoretical basis for a more accurate understanding of the pathological mechanism of brain injury after cardiac arrest, and provide a new target for protecting brain function after cardiac arrest in clinical practice-TRPML1. The following is an experiment conducted in this application to confirm the therapeutic effect of ML-SI3, a specific small molecule inhibitor of TRPML1, on rats with brain injury after cardiac arrest and cardiopulmonary resuscitation.

[0029] 1. Establishment of the CA / CPR recovery of spontaneous circulation (ROSC) model in SD rats and intervention of ML-SI3.

[0030] Figure 3. ML-SI3 intervention pattern of model ROSC rats / sham operation group. Figure 1 shown.

[0031] 1.1 Test instruments: ventilator, cold light source, monitor, oxygen cylinder, heating pad;

[0032] 1.2 Surgical instruments: venous puncture needle (24G), endotracheal tube (14G), surgical sutures (5-0, 2-0), razor, cotton swabs, cotton balls, gauze, medical tape, syringe, rubber band, air storage bag;

[0033] 1.3 Experimental materials: anesthetic 4% chloral hydrate (3-4ml / 500g), epinephrine (1:50 dilution, 1-2ml once, 1-2ml / time additional depending on the condition of the rat), furosemide (10mg / ml), 1ml of the original solution can be injected into the artery of each rat, and injected during rescue (the amount of infusion should be minimized when diuretics are not available), rocuronium bromide (1:10 dilution of the original solution, 1mg / ml; 0.5ml for the first administration, 0.2ml / time additional depending on the condition of the rat, a total of about 1ml can be injected for a 450g rat; oxygen inhalation for 3min after injection; a little diaphragm muscle strength can be retained.), anticoagulant heparin (0.5ml heparin + 500ml normal saline), normal saline.

[0034] 1.4 Experimental animals: Male SD rats weighing 450-500 g are optimal. Around 400 g is also acceptable. There are 24 rats, which are randomly divided into 4 groups, with 6 rats in each group.

[0035] 1.5 chloral hydrate 4%, onset time 2min, anesthesia maintenance time 95min; inject 0.5ml every 1h to maintain anesthesia, pay attention to heat preservation, heating pad, limb fixation, front teeth fixation. Glue the testicles to the lower abdomen, remove the hair at the proximal end of the tail, and ligate with a rubber band. The tail is cut layer by layer, the coccygeal artery is separated by a glass needle, the proximal end is clamped, 3 sutures are inserted into the 3cm-4cm coccygeal artery, the proximal end is clamped, and the lower end suture (1 ligated distal end, the tail end is placed under the coccygeal artery, the venous indwelling needle is punctured, the vascular clamp is opened, the venous indwelling needle is gently pushed in, and the upper end sutures are 2) ligated and fixed. The indwelling needle is connected to one end of the converter, and the other end of the converter is connected to the monitor to monitor blood pressure (normal value: 120-90 / 80mmHg) and heart rate (normal value: 250-600 times / min).

[0036] 1.6 Intubate the trachea, straighten the tongue, and use a cotton swab to clear oral secretions. Aim the cold light source at the rat's throat, observe the epiglottis, insert the tracheal tube (the tip of the tracheal tube faces up) at the moment the epiglottis opens, and pull out the tube core. After successful intubation, inhale pure oxygen for 5 minutes, and inject muscle relaxants when the blood pressure stabilizes. Connect one end of the ventilator (parameter setting: RR50-75 times / min, tidal volume 4-5ml) to a gas storage bag filled with oxygen, and the other end to the tracheal tube to monitor the airway pressure (the normal range before muscle relaxation is 8-12cmH2O, and the airway pressure after muscle relaxation is <20cmH2O. There may be pulmonary effusion or small airway obstruction. Appropriately increase the frequency and reduce the oxygen flow to ensure the minute ventilation. If the airway pressure is too low, the catheter may be dislocated).

[0037] 1.7 Induce cardiac arrest, give muscle relaxants, inject rocuronium 0.5 mg / time (administer slowly twice to avoid excessive blood pressure fluctuations), and clamp the endotracheal tube until spontaneous breathing disappears.

[0038] 1.8 Rescue: First, observe the heartbeat of the rat. Combined with the mean arterial pressure dropping to 40 mmHg, try to start timing when the heart is fibrillating without ejection and the MAP is close to 30 mmHg: 35s-60s, then start rescue. Airway management: open the airway and perform cardiopulmonary resuscitation: use the index and middle fingers to perform cardiac compression on the lower half of the sternum (200 times / min). Fluid management: epinephrine (1-2ml), if there is no spontaneous circulation after 1 minute (systolic blood pressure 65-90 mmHg), repeat the injection of epinephrine. Sodium bicarbonate (1ml), normal saline (0.5-1ml / time). If the spontaneous circulation is not restored after more than 5-10 minutes of cardiopulmonary resuscitation, give up rescue.

[0039] 1.9 Remove the tube and wean the ventilator. When the pharyngeal reflex is restored and the blood pressure can be maintained after inhaling air for 5 minutes, the endotracheal tube can be removed. Ligate the blood vessels and suture the incision.

[0040] The rats were divided into the following groups:

[0041] Sham group: sham-operated control rats were intraperitoneally administered with normal saline;

[0042] ML-SI3 group: sham-operated control rats were intraperitoneally administered ML-SI3 (3 mg / kg);

[0043] ROSC group: modeling group; SD rats were given normal saline intraperitoneally through CA / CPR spontaneous circulation recovery model;

[0044] ROSC+ML-SI3 group: the modeling group was combined with ML-SI3 administration; the SD rats were intraperitoneally administered ML-SI3 through the CA / CPR spontaneous circulation recovery model.

[0045] 2. Effect of administration of TRPML1-specific small molecule inhibitor ML-SI3 on ​​the degree of neuronal damage in injured rats

[0046] 2.1 Measurement method:

[0047] One day after modeling, the rats in the control group (Sham), modeling group (ROSC), modeling combined with ML-SI3 group (ROSC+ML-SI3), and control combined with ML-SI3 (Sham+ML-SI3) were anesthetized and perfused with PBS buffer by left ventricle puncture.

[0048] The whole brain was collected, fixed in 4% paraformaldehyde at room temperature for 24 hours, embedded in paraffin, cut into 3 μm thick slices with a microtome, placed in xylene for dewaxing, taken out after 30 minutes, and then transferred to 100%, 95%, 90%, 80%, and 70% ethanol solutions in sequence for 5 minutes each, and finally transferred to distilled water and left for 5 minutes. The dewaxed slices were immersed in 1% thionine for staining. Let stand in the dye solution for 10 minutes and rinse with distilled water. After staining, the slices were transferred to an ethanol solution for dehydration, then transferred to xylene for 5 minutes, and finally sealed with neutral glue for storage. Under a microscope, Nissl bodies appear dark, marking damaged neurons. The results are as follows: Figure 2a and Figure 2b shown.

[0049] from Figure 2a It can be seen that compared with the model group (ROSC; lower left figure), the ML-SI3 administration group (ROSC+ML-SI3; lower right figure) significantly reduced the number of dark blue Nissl bodies in the cerebral cortex tissue of the model group rats, indicating that ML-SI3 administration can significantly reduce the degree of neuronal damage in brain-injured rats. The sham operation group (Sham+Vehicle; upper left figure) and the sham operation + ML-SI3 group (Sham+ML-SI3; upper right figure) are negative controls for the model group rats, and the Nissl body staining of the rat cerebral cortex tissue is negative. The staining image scale is 50 microns. Figure 2b The percentage of damaged neurons (Nissl-positive staining) in the cortical neurons of rats in each group is indicated.

[0050] 3. Effects of ML-SI3 administration on learning and memory abilities of brain-injured rats

[0051] 3.1 Measurement method

[0052] Five days after ROSC, the rats in the control group (Sham), model group (ROSC), model combined with ML-SI3 group (ROSC+ML-SI3), and control combined with ML-SI3 (Sham+ML-SI3) were subjected to Morris water maze test on the sixth day. All data were statistically analyzed and graphed using Graphpad 7.0 software.

[0053] Acquisition training

[0054] (1) Place the rat in the water with its head facing the pool wall, and place it in one of the four starting positions: east, west, south, or north. Record the time (s) it takes for the animal to find the underwater platform. In the first few training sessions, if this time exceeds 60s, guide the animal to the platform. Allow the animal to stay on the platform for 10s.

[0055] (2) Remove the animal and dry it. If necessary, place the rat under a 150W incandescent lamp for 5 minutes and return it to the cage. Each animal is trained 4 times a day, with an interval of 15 to 20 minutes between two training sessions, and the training is continued for 5 consecutive days.

[0056] Probe Training

[0057] The day after the last acquisition training, the platform was removed and a 60-second exploration training was started. The animal was placed in the water from the opposite side of the original platform quadrant. The time the animal spent in the target quadrant and the number of times it entered the quadrant were recorded as the detection index of spatial memory.

[0058] Position training

[0059] The working memory of the animals was measured. The day after the exploratory training, the 4-day contraposition training was started. The platform was placed in the opposite quadrant of the original platform, and the method was the same as the acquisition training. The training was performed 4 times a day. The time to find the platform, the swimming distance, and the swimming speed were recorded each time.

[0060] Position detection training

[0061] The last position training was conducted on the second day. The method was similar to the above exploration training. The time the animal spent in the target quadrant and the number of times it entered the area were recorded within 60 seconds. The results were as follows: Figure 3a and Figure 3b shown.

[0062] from Figure 3a and Figure 3b It can be seen that the water maze trajectory diagram shows that compared with the model group rats (ROSC), the ML-SI3 administration group rats (ROSC+ML-SI3) can find the target quadrant faster and stay in the target quadrant longer within 60 seconds. Please see the statistical chart for the specific time that each group of rats stays in the target quadrant within 60 seconds. The water maze test shows that ML-SI3 administration can significantly improve the learning and memory ability of brain-injured rats.

[0063] 4. Effects of ML-SI3 administration on movement disorders in brain-injured rats

[0064] 4.1 Measurement method

[0065] Two days after ROSC, on the third day, the rats in the control group (Sham), model group (ROSC), model combined with ML-SI3 group (ROSC+ML-SI3), and control combined with ML-SI3 (Sham+ML-SI3) were subjected to balance beam test. All data were statistically analyzed and graphed using Graphpad 7.0 software.

[0066] Balance beam training

[0067] Before the formal test, the rats were trained on the balance beam. First, the rats were familiarized with the experimental environment. The rats could stay in the laboratory for a period of time. Then, they were gradually trained on the balance beam, starting with a thicker wooden stick, and the rats were asked to walk on it many times until they were proficient. Subsequently, the diameter of the wooden stick was gradually reduced to allow the rats to adapt to wooden sticks of different diameters. The training time could be determined according to the rats' degree of adaptation.

[0068] Formal operation

[0069] The rats were placed at the starting end of the balance beam. The timing was started and the time required for the animals to walk to the other end of the balance beam (passing time) was observed. The time taken for each group of rats to pass the balance beam was statistically analyzed. The results are shown in Table 1. Figure 4 shown.

[0070] from Figure 4 It can be seen that compared with the model group (ROSC), the administration of ML-SI3 (ROSC+ML-SI3) can significantly reduce the time for the model rats to pass the balance beam, indicating that the administration of ML-SI3 can significantly alleviate the movement disorders in brain-injured rats.

[0071] 5. The effect of ML-SI3 administration on movement disorders in brain-injured rats.

[0072] Two days after ROSC, on the third day, the rats in the control group (Sham), model group (ROSC), model combined with ML-SI3 group (ROSC+ML-SI3), and control combined with ML-SI3 (Sham+ML-SI3) were subjected to rotarod test. All data were statistically analyzed and graphed using Graphpad 7.0 software.

[0073] 5.1 Measurement method

[0074] The steps of the rat rotarod test are as follows:

[0075] a. Place the rat on the rotating rod and start rotating the rod, gradually increasing the speed;

[0076] b. Observe the behavior of the rats and record the duration of rotation and the speed of the rotating rod;

[0077] c. When the rat falls or loses balance, record the falling time and the speed of the rotating rod;

[0078] d. Conduct multiple tests to determine indicators such as the rats' endurance and exercise capacity;

[0079] e. Statistical analysis of the falling time of rats in each group;

[0080] The results are as follows Figure 5 shown.

[0081] from Figure 5 It can be seen that compared with the model group (ROSC), the administration of ML-SI3 (ROSC+ML-SI3) can significantly prolong the time for rats to fall off the rotating rod, indicating that the administration of ML-SI3 can significantly alleviate the movement disorders in rats with brain injury.

[0082] 6. Effect of ML-SI3 administration on movement disorders in brain-injured rats.

[0083] 6.1 Measurement method

[0084] Two days after ROSC, on the third day, the rats in the control group (Sham), model group (ROSC), model combined with ML-SI3 group (ROSC+ML-SI3), and control combined with ML-SI3 (Sham+ML-SI3) were subjected to open field test. All data were statistically analyzed and graphed using Graphpad 7.0 software.

[0085] Experimental preparation

[0086] Experimental apparatus: The open field apparatus used for rats is usually 100 cm × 100 cm × 40 cm in size.

[0087] Environmental conditions: The laboratory should be kept quiet and the lighting conditions should be controlled at a moderate level to reduce the influence of external factors on animal behavior.

[0088] Acclimation period: Before the experiment, rats should be adapted to the laboratory environment for at least 30 min to reduce stress response to the new environment.

[0089] Experimental procedures

[0090] Animal placement: At the start of the experiment, rats were gently placed in the center or in a corner of the open field apparatus.

[0091] Behavioral observation: Begin recording the rat's behavior in the open field. The observation period is usually 5 to 10 minutes, which is the standard length of time in most studies.

[0092] Behavioral indicators: record the behavior of rats, including the time spent in the center and edge of the open field, moving distance, cleaning behavior, standing behavior, etc.

[0093] Data Recording: The rats’ behaviors were recorded and analyzed using cameras and motion tracking software to improve the accuracy and objectivity of the data.

[0094] Data analysis

[0095] Behavioral analysis: Based on the data from the video recording and motion tracking software, the behavioral patterns of the rats were analyzed, including movement trajectories, staying areas, etc.

[0096] Statistical analysis: One-way ANOVA was used to analyze the data to draw scientific conclusions. Figure 6a and Figure 6b shown.

[0097] from Figure 6a and Figure 6b It can be seen that compared with the model group (ROSC), the administration of ML-SI3 (ROSC+ML-SI3) can significantly increase the total distance and speed of rats' movement in the open field. These behavioral changes indicate that the administration of ML-SI3 can significantly alleviate the movement disorders in rats with brain injury.

[0098] The inventors believe that the TRPML1-specific small molecule inhibitor ML-SI3 can significantly improve the brain injury function of rats after cardiac arrest and cardiopulmonary resuscitation, reduce the degree of neuronal damage in brain-injured rats, improve the learning and memory ability of brain-injured rats, and reduce movement disorders in brain-injured rats.

[0099] The above experimental results prove that the TRPML1 small molecule inhibitor ML-SI3 has a comprehensive protective effect on the brain function of rats after cardiac arrest and cardiopulmonary resuscitation. The application of the TRPML1 specific small molecule inhibitor ML-SI3 described in this application in the preparation of drugs for treating or preventing brain damage provides a new drug for protecting the brain function of patients with cardiac arrest, and has good market value and clinical application prospects.

[0100] Although the above embodiments have been shown and described, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. Changes, modifications, substitutions and variations of the above embodiments by those of ordinary skill in the art are all within the scope of protection of the present invention.

Claims

1. Use of a TRPML1-specific small molecule inhibitor ML-SI3 in the preparation of drugs for treating or preventing brain injury.

2. The use according to claim 1, characterized in that: The brain damage includes brain damage caused by cardiac arrest.

3. The use according to claim 1, characterized in that: The structural formula of the TRPML1 specific small molecule inhibitor ML-SI3 is as follows:

4. The use according to claim 1, characterized in that: When preparing a drug for treating or preventing brain injury, the effective dose of the TRPML1-specific small molecule inhibitor ML-SI3 is 1-4 mg / kg.

5. A drug for treating brain damage caused by cardiac arrest, characterized in that: The invention comprises active pharmaceutical ingredients and pharmaceutically acceptable excipients, wherein the active pharmaceutical ingredients comprise TRPML1-specific small molecule inhibitor ML-SI3.

6. The drug for treating brain damage caused by cardiac arrest according to claim 5, characterized in that: The content of the active pharmaceutical ingredient in the medicine is 1-4 mg / kg.

7. The drug for treating brain damage caused by cardiac arrest according to claim 5, characterized in that: The content of the active pharmaceutical ingredient in the medicine is 3 mg / kg.

8. The drug for treating brain damage caused by cardiac arrest according to claim 5, characterized in that: The dosage form of the drug includes injection, tablet, capsule, granule, aerosol or oral liquid.

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