Use of a tyk2 inhibitor in the manufacture of a medicament for the prevention and / or treatment of sae

Abstract

The application relates to the technical field of biological medicine, and discloses application of a TYK2 inhibitor in preparation of a medicine for preventing and / or treating SAE. The application provides application of a TYK2 inhibitor in preparation of a medicine for preventing and / or treating sepsis-associated encephalopathy (SAE). The application first applies the TYK2 inhibitor to blood-brain barrier damage caused by LPS, proves the protective effect of the TYK2 inhibitor (including deuterium canexetil and Tl1041) on endothelial cells in the blood-brain barrier and microglial cells, astrocytes and neuron cells in brain tissues, indicates that the TYK2 inhibitor can relieve blood-brain barrier damage caused by LPS, and points out a possible direction for applying the TYK2 inhibitor to treat sepsis-associated encephalopathy and blood-brain barrier damage caused by the sepsis-associated encephalopathy in the clinic.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the use of TYK2 inhibitors in the preparation of drugs for the prevention and / or treatment of SAE. Background Technology

[0002] Sepsis is a life-threatening syndrome of organ dysfunction caused by a dysregulated response to infection, clinically affecting primarily the respiratory, circulatory, liver, kidneys, hematopoietic or coagulation systems, and central nervous system (CNS). The CNS, as one of the early sites of involvement, frequently develops sepsis-associated encephalopathy (SAE), with reported incidence rates reaching up to 70% in sepsis patients. SAE patients often present with altered consciousness, delirium, cognitive impairment, and even coma, significantly impacting short-term survival and long-term quality of life. Studies suggest that blood-brain barrier (BBB) ​​disruption is closely related to the neuropsychiatric symptoms of SAE, and the degree of BBB dysfunction is correlated with the severity of cognitive and long-term neurological outcomes.

[0003] However, current clinical management of sepsis still focuses on infection control and organ perfusion optimization, combined with ICUABCDEF (A–F) bundled management, sleep and sensory optimization management, a "pain-priority, mild sedation" strategy, and routine management of complications such as epilepsy. For neurological damage in sepsis (including sepsis-associated encephalopathy), prevention primarily involves maintaining cerebral perfusion with adequate crystalloid fluid and norepinephrine to raise blood pressure. Clinical studies have found that dexmedetomidine can reduce delirium and has also been found to have a protective effect on the blood-brain barrier (BBB). However, as an α2-receptor agonist, dexmedetomidine may inhibit the sympathetic nervous system, leading to bradycardia and hypotension, which contradicts the blood pressure-raising treatment. Furthermore, melatonin, minocycline, and statins have also been found to have some protective effect on the BBB in basic research, but the level and amount of evidence are limited, and all have certain limitations. For example, statins are considered potentially beneficial in the long-term prevention of sepsis and its associated brain dysfunction, but there is a lack of evidence regarding their use in the treatment of acute SAE. Minocycline's protective effect on the blood-brain barrier (BBB) ​​requires administration before the establishment of a sepsis model to be effective; post-model administration of minocycline does not significantly improve BBB permeability. Therefore, evidence-based treatment targeting BBB protection and repair, along with its supporting biomarkers, remains a key weakness in SAE management.

[0004] TYK2 (Tyrosine Kinase 2) inhibitors are a class of drugs that target tyrosine kinase 2 (TYK2). By selectively inhibiting TYK2 kinase activity, they block the activation of the downstream JAK-STAT signaling pathway, thereby inhibiting the production of inflammatory factors and abnormal activation of immune cells, ultimately exerting anti-inflammatory and immunomodulatory effects. TYK2 inhibitors include TYK2-JH1 inhibitors targeting the JH1 domain and TYK2-JH2 inhibitors targeting the JH2 domain. Currently, TYK2 inhibitors under development and on the market are mainly used to treat skin and connective tissue diseases, including psoriasis, plaque psoriasis, rheumatoid arthritis, uveitis, Sjögren's syndrome, and intermediate uveitis. Currently, there is a lack of applications for TYK2 inhibitors in the prevention and treatment of sepsis and sepsis-related encephalopathy. Summary of the Invention

[0005] This invention provides the use of TYK2 inhibitors in the preparation of medicaments for the prevention and / or treatment of sepsis-associated encephalopathy (SAE), in order to address the problem of the lack of specific drugs for the prevention and / or treatment of sepsis-associated encephalopathy.

[0006] In a first aspect, the present invention provides the use of a TYK2 inhibitor in the preparation of a medicament for the prevention and / or treatment of sepsis-associated encephalopathy.

[0007] In one alternative embodiment, the TYK2 inhibitor comprises deuterocelexitinib, Tll041, and / or a pharmaceutically acceptable salt formulation thereof.

[0008] In one alternative implementation, the prevention and / or treatment of sepsis-associated encephalopathy includes alleviating blood-brain barrier damage caused by sepsis-associated encephalopathy and / or restoring brain cell abnormalities caused by blood-brain barrier damage.

[0009] In one alternative implementation, the relief of blood-brain barrier damage caused by sepsis-associated encephalopathy includes relieving vascular endothelial cell apoptosis caused by sepsis-associated encephalopathy.

[0010] In one optional embodiment, the restoration of brain cell abnormalities caused by blood-brain barrier damage includes inhibiting microglia activation caused by blood-brain barrier damage, preventing astrocyte end-foot damage caused by blood-brain barrier damage, and / or alleviating neuronal apoptosis caused by blood-brain barrier damage.

[0011] In one alternative embodiment, the drug may further comprise pharmaceutically acceptable excipients.

[0012] In one alternative embodiment, the pharmaceutically acceptable excipients include at least one of the following: pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and film-forming materials.

[0013] In one alternative embodiment, the dosage form of the drug includes at least one of powder, tablet, granule, capsule, solution, emulsion, suspension, injection, aerosol, ointment and drops.

[0014] In a second aspect, the present invention also provides a medicament for the prevention and / or treatment of sepsis-associated encephalopathy, the medicament comprising a TYK2 inhibitor.

[0015] In one alternative embodiment, the TYK2 inhibitor comprises deuterocelexitinib, Tll041, and / or a pharmaceutically acceptable salt formulation thereof.

[0016] In one alternative implementation, the prevention and / or treatment of sepsis-associated encephalopathy includes alleviating blood-brain barrier damage caused by sepsis-associated encephalopathy and / or restoring brain cell abnormalities caused by blood-brain barrier damage.

[0017] In one alternative implementation, the relief of blood-brain barrier damage caused by sepsis-associated encephalopathy includes relieving vascular endothelial cell apoptosis caused by sepsis-associated encephalopathy.

[0018] In one optional embodiment, the restoration of brain cell abnormalities caused by blood-brain barrier damage includes inhibiting microglia activation caused by blood-brain barrier damage, preventing astrocyte end-foot damage caused by blood-brain barrier damage, and / or alleviating neuronal apoptosis caused by blood-brain barrier damage.

[0019] In one alternative embodiment, the drug may further comprise pharmaceutically acceptable excipients.

[0020] In one alternative embodiment, the pharmaceutically acceptable excipients include at least one of the following: pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and film-forming materials.

[0021] In one alternative embodiment, the dosage form of the drug includes at least one of powder, tablet, granule, capsule, solution, emulsion, suspension, injection, aerosol, ointment and drops.

[0022] The technical solution of this invention has the following advantages: This invention provides the application of TYK2 inhibitors in the preparation of drugs for the prevention and / or treatment of SAE. As a barrier structure at the interface between the central nervous system (CNS) and the peripheral environment, the blood-brain barrier (BBB) ​​successfully separates circulating blood in the brain tissue from the CNS, while strictly controlling the exchange of substances between the circulating blood and brain tissue, such as the transport of nutrients and the excretion of metabolic waste, thereby maintaining the homeostasis of the CNS. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can impair the barrier function of the blood-brain barrier by downregulating the expression of tight junction proteins, increasing blood-brain barrier permeability, generating reactive oxygen species (ROS), increasing the expression of proteins such as matrix metalloproteinase 9 (MMP-9), and degrading tight junctions and the extracellular matrix, thereby further promoting the occurrence and development of sepsis-associated encephalopathy (SAE). Based on this, this invention is the first to apply TYK2 inhibitors to LPS-induced blood-brain barrier damage, demonstrating the protective effects of TYK2 inhibitors (including deuterocelexitinib and Tll041) on microglia, astrocytes, neurons, and endothelial cells. This indicates that TYK2 inhibitors can alleviate LPS-induced blood-brain barrier damage and restore brain cell abnormalities caused by blood-brain barrier damage, pointing to a possible direction for the clinical application of TYK2 inhibitors in the treatment of sepsis-related encephalopathy and the resulting blood-brain barrier disruption. Attached Figure Description

[0023] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0024] Figure 1 This is a schematic diagram of LPS and subsequent drug injection and tissue sampling procedures; Figure 1 In the diagram, (A) is the flowchart for the Evans blue staining experiment; (B) is the flowchart for the biotin injection experiment. Figure 2 This refers to the extravasation of EB on the upper surface of brain tissue in each group; Figure 2 In the middle, from left to right, are the blank control group, LPS model group, deuterated cecoxitinib treatment group, and Tll041 treatment group; Figure 3 This is a quantitative result of the EB absorbance after homogenization of brain tissue; Figure 4 This is a fluorescence signal image of a brain slice after biotin injection; Figure 4 In the figure, (A) blank control group; (B) LPS model group; (C) deuterocelexitinib treatment group; (D) Tll041 treatment group; scale bar, 1 mm.

[0025] Figure 5 This is a statistical chart showing the number of leaking blood vessels after biotin injection; Figure 6 The ultrastructure of brain microvessels in the LPS injection group; Figure 6 In this context, TJ stands for tight junction; PVS for perivascular space; PE for perivascular edema; MT for mitochondria; L for lumen; E for endothelial cell; and B for basement membrane. Figure 7 This is an electron micrograph of the brain tissue of mice in the LPS-injected group who were given deuterium-colicitinib via gavage. Figure 7 In this text, L represents the lumen; MT represents the mitochondria; E represents the endothelial cell; and B represents the basement membrane. Figure 8Immunofluorescence staining images of microglia in the blank control group, LPS model group and deuterocelexitinib treatment group (A) and microglia cell body volume statistics (B). Figure 8 Medium (A), scale bar, 30 μm; Figure 9 Immunofluorescence staining images of astrocytes in the blank control group, LPS model group, and deuterocelexitinib treatment group; scale bar, 30 μm; Figure 10 Immunofluorescence staining images (A) and fluorescence statistics (B) of neuronal cells in the blank control group, LPS model group and deuterocelexitinib treatment group; Figure 10 Medium (A), scale bar, 30 μm. Detailed Implementation

[0026] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0027] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0028] (1) Information on reagents and materials is shown in Table 1: Table 1 Reagent and Material Information

[0029] (2) Laboratory animals: Strain: C57BL / 6J mice Source: Purchased by Beijing Institute of Brain Science and Brain-Inspired Intelligence Sex: Male Age: 8 weeks (3) Preparation of compounds: LPS: Dissolved in physiological saline, working concentration is 0.3 mg / mL; Deuterated clexicitinib: Purchased from MCE, catalog number HY-117287; taking the preparation of 1 mL as an example, take 10 mg of deuterated clexicitinib, add 50 μL DMSO, 400 μL PEG300, 50 μL Tween-80 and 500 μL normal saline in sequence, mix while adding, and sonicate to dissolve if necessary, to obtain the deuterated clexicitinib drug solution with a working concentration of 10 mg / mL; Tll041: Purchased from Hangzhou Gaoguang Pharmaceutical Co., Ltd., dissolved in physiological saline, working concentration is 10 mg / mL; 2% uranium acetate: Dissolve 2 g of uranium acetate in 100 mL of double-distilled water; 2% OsO4 stock solution: 2g of high-purity OsO4 crystals (Sigma, catalog number 201030) were diluted to 100 mL of ultrapure water to obtain a 2% (w / v) OsO4 stock solution, which was stored in a sealed container at 4°C away from light. 1% OsO4: Add 1% by volume of 2% OsO4 stock solution to a 4% PFA solution (4 g PFA dissolved in 100 mL PBS buffer); Biotin (sulfo-NHS-Biotin): Dissolve in PBS buffer to a working concentration of 20 mg / mL; 2% EB: Dissolve 2g EB in 100 mL PBS buffer and filter sterilize using a 0.22 μm filter membrane.

[0030] Example 1: TYK2 inhibitors can significantly slow down LPS-induced blood-brain barrier damage. To investigate the effects of TYK2 inhibitors on blood-brain barrier disruption, mice were treated with TYK2 inhibitors after injection of LPS. The degree of blood-brain barrier disruption was assessed by the extravasation of Evans blue onto the surface of brain tissue in each group. The specific experimental procedure is as follows (experimental flowchart shown). Figure 1 ): Experiment 1: Evans Blue Staining Experimental grouping and treatment: Sixteen C57BL / 6J mice were randomly divided into four groups, with n≥3 mice in each group. The four groups were: ① Blank control group (5 mice): intraperitoneal injection of 10 μL / g saline, followed by gavage administration of saline at a dose of 10 μL / g 30 min later; ② LPS model group (4 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of saline at a dose of 10 μL / g 30 min later; ③ Deuterocelexitinib treatment group (3 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of deuterocelexitinib at a dose of 30 mg / kg 30 min later; ④ Tll041 treatment group (4 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of Tll041 at a dose of 30 mg / kg 30 min later.

[0031] like Figure 1As shown in Figure A, mice were injected with LPS or saline for 6 hours, followed by an intravenous injection of Evansblue (EB) at a dose of 20 μg per mouse. Two hours after injection, brain slices were collected from each mouse, with 2-3 slices taken from each group for statistical analysis to assess the degree of blood-brain barrier disruption. The experimental results are shown below. Figure 2 and Figure 3 As shown.

[0032] Figure 2 This is an image of the upper surface of brain tissue taken after LPS injection, used to assess EB extravasation. Figure 2 It can be seen that the LPS model group had the deepest EB staining, followed by the deuterocelexitinib treatment group and the Tll041 treatment group, while the blank control group had the lightest staining, indicating that the TYK2 inhibitors deuterocelexitinib and Tll041 can both slow down the destruction of BBB by LPS. Figure 3 This is a quantitative statistical graph of the absorbance of brain tissue homogenate after LPS injection, composed of... Figure 3 It can be seen that the LPS model group was significantly higher than the other three groups, indicating that both the TYK2 inhibitor deuterocelecitinib and Tll041 can slow down the damage of LPS to the BBB.

[0033] Experiment 2: Biotin Injection Experimental grouping and treatment: Twenty-one C57BL / 6J mice were randomly divided into four groups, with n ≥ 3 mice in each group. The four groups were: ① Blank control group (3 mice): intraperitoneal injection of 10 μL / g saline, followed by gavage administration of saline at a dose of 10 μL / g 30 min later; ② LPS model group (6 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of saline at a dose of 10 μL / g 30 min later; ③ Deuterocelexitinib treatment group (5 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of deuterocelexitinib at a dose of 30 mg / kg 30 min later; ④ Tll041 treatment group (7 mice): intraperitoneal injection of LPS at a dose of 3 mg / kg, followed by gavage administration of Tll041 at a dose of 30 mg / kg 30 min later.

[0034] like Figure 1 As shown in Figure B, 8 hours after injection of LPS or saline, biotin (4 mg / mouse) was injected intravenously. Two hours after injection, the brain was perfused, frozen sections were prepared, and fluorescently stained. Two to three brain slices were taken from each group for statistical analysis. The degree of damage to the mouse's blood body bone bladder (BBB) ​​was assessed. The results are shown in Figure B. Figure 4 and Figure 5 As shown.

[0035] Figure 4 This is a fluorescence signal image of a brain slice after biotin injection, by Figure 4 It can be seen that the LPS model group ( Figure 4 Compared to the other three groups (Group B) Figure 4 China A Figure 4 C and Figure 4 The strongest fluorescence signal was observed in the middle D (T1041), indicating the most significant extravasation into blood vessels. This suggests that the TYK2 inhibitors deuterocelexitinib and T11041 can slow down the destruction of the BBB by LPS and reduce its extravasation into blood vessels. Figure 5 This is a statistical chart showing the number of leaking blood vessels after biotin injection. Figure 5 It can be seen that the number of leaking vessels in the LPS model group was significantly higher than that in the other three groups, indicating that the TYK2 inhibitors deuterocelecitinib and Tll041 can slow down the damage of LPS to the BBB.

[0036] In summary, both deuterocelexitinib and Tll041 significantly reduced LPS-induced BBB damage.

[0037] Example 2: TYK2 inhibitors can alleviate endothelial cell apoptosis. To investigate the effect of TYK2 inhibitors on endothelial cell (EC) apoptosis, mice were treated with TYK2 inhibitors after injection of LPS, and the apoptosis of mouse brain endothelial cells was assessed by observing the endothelial cells of blood vessels under electron microscopy. The specific experimental procedure is as follows: Six C57BL / 6J mice were randomly divided into two groups of three. The two groups were: ① LPS model group: LPS was administered intraperitoneally (ip) at a dose of 3 mg / kg, followed by gavage administration of physiological saline at a dose of 10 μL / g 30 min later; ② Deuterated clexicitinib treatment group: LPS was administered intraperitoneally (ip) at a dose of 3 mg / kg, followed by gavage administration of deuterated clexicitinib at a dose of 30 mg / kg 30 min later. Eight hours after LPS injection, biotin (4 mg / mouse) was injected via the retroorbital vein. Two hours after circulation, brain tissue was harvested via cardiac perfusion. The harvested brain tissue was fixed in 1% OsO4 solution, stained with 2% uranium acetate, routinely dehydrated and embedded, and then observed under transmission electron microscopy.

[0038] The results are as follows Figure 6 and Figure 7 As shown. Figure 6 This is an ultrastructural image of brain microvessels in the LPS model group. It can be seen that after LPS injection, the endothelial cells in the vascular lumen swelled, the nuclei condensed, and apoptotic endothelial cells appeared, suggesting that LPS can induce damage or apoptosis of brain endothelial cells. Figure 7 These are electron micrographs of the brain tissue of mice in the deuterocelexitinib treatment group after LPS injection. Figure 7It can be seen that the morphology of vascular endothelial cells in the deuterocelexitinib treatment group was more intact than that in the LPS model group, which means that the injection of deuterocelexitinib alleviated LPS-mediated endothelial cell apoptosis.

[0039] Example 3: Protective effects of TYK2 inhibitors on microglia, astrocytes, and neurons To investigate the effects of TYK2 inhibitors on microglia, astrocytes, and neurons, mice were treated with TYK2 inhibitors after injection of LPS. Immunofluorescence detection was performed on frozen sections of mouse brain tissue. The specific experimental procedure is as follows: (1) Sixteen C57BL6J mice were randomly divided into three groups, with n≥5 mice in each group. The three groups were: ① Blank control group (6 mice): 10 μL / g saline was injected intraperitoneally (ip), and 10 μL / g saline was administered by gavage 30 min later; ② LPS model group (5 mice): LPS was injected intraperitoneally (ip) at a dose of 3 mg / kg, and 10 μL / g saline was administered by gavage 30 min later; ③ Deuterocelexitinib treatment group (5 mice): LPS was injected intraperitoneally (ip) at a dose of 3 mg / kg, and 30 mg / kg deuterocelexitinib was administered by gavage 30 min later.

[0040] (2) Two hours after each group was given gavage, the mice were sacrificed and their brains were removed. Frozen sections were prepared and immunofluorescence was performed on microglia, astrocytes and neurons in the brain tissue. The activation, endplate integrity and apoptosis of the cells were quantitatively analyzed.

[0041] The results are as follows Figures 8-10 As shown. Figure 8 These are immunofluorescence staining images of microglia in the blank control group, LPS model group, and deuterocelexitinib treatment group. Figure 8 (A) and statistical diagram of microglia cell body volume ( Figure 8 (B) From Figure 8 As shown in Figure B, compared with the blank control group, the mean cell volume of microglia in the LPS model group was significantly increased, while the mean cell volume of microglia in the deuterated lecithinib treatment group was not significantly different from that in the blank control group. This indicates that deuterated lecithinib treatment significantly prevented LPS-mediated microglia activation.

[0042] Figure 9 These are immunofluorescence staining images of astrocytes in the blank control group, LPS model group, and deuterocelexitinib treatment group. Figure 9It was observed that the astrocyte terminal density in the LPS model group was relatively sparse, failing to completely encapsulate the blood vessels; while the astrocyte terminal density was relatively dense in the deuterocelexitinib treatment group and the blank control group. This indicates that deuterocelexitinib treatment significantly prevented LPS-mediated astrocyte terminal damage.

[0043] Figure 10 These are immunofluorescence staining images of neuronal cells in the blank control group, LPS model group, and deuterocelexitinib treatment group. Figure 10 (A) and fluorescence statistics ( Figure 10 (B) From Figure 10 It was found that, compared with the blank control group, the number of apoptotic cells in neurons in the LPS model group was significantly increased; while the number of apoptotic cells in neurons in the deuterated lexicitinib treatment group was significantly reduced compared with the LPS model group, and there was no significant difference compared with the blank control group. This indicates that deuterated lexicitinib treatment significantly prevented LPS-mediated neuronal apoptosis, restoring the degree of neuronal apoptosis to the normal physiological state level.

[0044] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. The use of TYK2 inhibitors in the preparation of drugs for the prevention and / or treatment of sepsis-associated encephalopathy.

2. The application according to claim 1, characterized in that, The TYK2 inhibitors include deuterocelexitinib, Tll041, and / or pharmaceutically acceptable salt formulations thereof.

3. The application according to claim 1 or 2, characterized in that, The prevention and / or treatment of sepsis-associated encephalopathy includes alleviating blood-brain barrier damage caused by sepsis-associated encephalopathy and / or restoring brain cell abnormalities caused by blood-brain barrier damage.

4. The application according to claim 3, characterized in that, The relief of blood-brain barrier damage caused by sepsis-associated encephalopathy includes the relief of vascular endothelial cell apoptosis caused by sepsis-associated encephalopathy.

5. The application according to claim 3, characterized in that, The restoration of brain cell abnormalities caused by blood-brain barrier damage includes inhibiting microglia activation caused by blood-brain barrier damage, preventing astrocyte end-foot damage caused by blood-brain barrier damage, and / or alleviating neuronal apoptosis caused by blood-brain barrier damage.

6. The application according to claim 1 or 2, characterized in that, The drug also contains pharmaceutically acceptable excipients.

7. The application according to claim 6, characterized in that, The pharmaceutically acceptable excipients include at least one of the following: pharmaceutically acceptable solvents, solubilizers, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and anti-flocculators, filter aids, release inhibitors, and film-forming materials.

8. The application according to claim 1 or 2, characterized in that, The dosage form of the drug includes at least one of the following: powder, tablet, granule, capsule, solution, emulsion, suspension, injection, aerosol, ointment, and drops.

9. A medicament for the prevention and / or treatment of sepsis-associated encephalopathy, characterized in that, The drug contains a TYK2 inhibitor.

10. The medicament according to claim 9, characterized in that, The TYK2 inhibitors include deuterocelexitinib, Tll041, and / or pharmaceutically acceptable salt formulations thereof.

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