Application of sulodexide in preparation of medicine for treating sepsis-related encephalopathy

Abstract

The invention discloses application of sulodexide in preparation of a medicine for treating sepsis-related encephalopathy, and belongs to the technical field of biological medicine. According to the application disclosed by the invention, the effect of preventing and / or treating sepsis-related encephalopathy of sulodexide is found for the first time; animal experiments prove that sulodexide improves cognitive impairment of a patient with sepsis-related encephalopathy by improving the survival rate of the patient with sepsis-related encephalopathy, inhibits brain neuroinflammation of the patient with sepsis-related encephalopathy, reduces brain tissue damage of the patient with sepsis-related encephalopathy, and improves the curative effect of the patient with sepsis-related encephalopathy. According to the present invention, with the application of the compound in the prevention and / or treatment of the sepsis-related encephalopathy, the microglial cell excitation of the sepsis-related encephalopathy patient can be inhibited, and the HMGB1 and / or RAGE pathway of the sepsis-related encephalopathy patient can be inhibited so as to prevent and / or treat the sepsis-related encephalopathy, such that the new idea is provided for the preparation of the sepsis-related encephalopathy product, and the wide application prospect is provided.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of sulodexide in the preparation of drugs for treating sepsis-associated encephalopathy. Background Technology

[0002] Sepsis is defined as a life-threatening organ dysfunction resulting from a dysregulated host response to infection, and is one of the leading causes of death in critically ill patients. Sepsis is often accompanied by short-term diffuse brain dysfunction and long-term irreversible cognitive impairment, known as sepsis-associated encephalopathy (SAE). Clinically, SAE manifests as confusion, delirium, cognitive impairment, and even coma, with a significant proportion of patients experiencing long-term cognitive impairment, severely impacting daily life and increasing the risk of death. Its pathogenesis is complex, involving the interaction of multiple factors, including neuroinflammation, blood-brain barrier disruption, metabolic disorders and mitochondrial dysfunction, and excessive activation of glial cells. The diagnostic criteria for SAE lack specificity and are an exclusionary diagnosis, requiring the exclusion of drug use and other causes of encephalopathy. Currently, there are also no specific treatments for SAE; existing protocols are mostly based on sepsis management (such as fluid resuscitation and antibiotics), but they cannot effectively reverse neuroinflammation and cognitive impairment. Timely and effective intervention or aggressive treatment is of great significance for the prognosis of this disease.

[0003] Sulodexide (SDX) is a highly purified mixture of glycosaminoglycans extracted from porcine intestinal mucosa, consisting of 80% heparin sulfate and 20% dermatan sulfate, similar in composition to glycocalyx. Sulodexide possesses antithrombotic, antiproliferative, and anti-inflammatory properties and is widely used as adjunctive therapy for diabetic nephropathy, chronic venous disease, and arterial disease.

[0004] However, there are currently no research reports on sulodide treatment for sepsis-associated encephalopathy. Summary of the Invention

[0005] The purpose of this invention is to provide the use of sulodexide in the preparation of medicaments for the treatment of sepsis-associated encephalopathy. This addresses the problem of the lack of highly effective drugs for the prevention and / or treatment of sepsis-associated encephalopathy in the prior art.

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

[0007] In this invention, the inventors have discovered for the first time that sulodexide has the effect of preventing and / or treating sepsis-associated encephalopathy (SAD). Specifically, sulodexide prevents and / or treats SAD by improving the survival rate of SAD patients, improving cognitive impairment in SAD patients, inhibiting neuroinflammation in the brain of SAD patients, reducing brain tissue damage in SAD patients, inhibiting microglial cell activation in SAD patients, and inhibiting the HMGB1 and / or RAGE pathways in SAD patients. This provides a new approach for the preparation of products for SAD and has broad application prospects.

[0008] In some implementations, the drug can improve the survival rate of patients with sepsis-associated encephalopathy.

[0009] In some implementation schemes, the drug can improve cognitive impairment in patients with sepsis-associated encephalopathy; wherein cognitive impairment includes at least one of memory decline and anxiety behavior.

[0010] It is understood that cognitive impairment can include conventional cognitive impairments in the prior art. For example, in this invention, cognitive impairment preferably includes at least one of memory decline and anxiety behavior.

[0011] In some implementations, the drug can suppress neuroinflammation in the brains of patients with sepsis-associated encephalopathy, where the neuroinflammation is caused by elevated levels of inflammatory factors.

[0012] In some preferred embodiments, the inflammatory factors include at least one of IL-1β and TNF-α.

[0013] It is understood that inflammatory factors may include those conventionally used in the prior art. For example, in this invention, inflammatory factors preferably include at least one of IL-1β and TNF-α.

[0014] In some implementations, the drug can reduce brain tissue damage in patients with sepsis-associated encephalopathy.

[0015] In some implementations, the drug can inhibit microglial cell activation in patients with sepsis-associated encephalopathy.

[0016] In some implementations, the drug alleviates neuroinflammation caused by sepsis-associated encephalopathy by inhibiting the HMGB1 and / or RAGE pathways in patients with sepsis-associated encephalopathy.

[0017] In some implementations, sulodex is used at a dose of 4-40 mg / kg, for example, 4 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg or other values ​​within this range.

[0018] In some implementations, sepsis-associated encephalopathy includes sepsis-associated encephalopathy modeled by an endotoxemia model.

[0019] It is understood that sepsis-associated encephalopathy can include conventional sepsis-associated encephalopathy in the prior art. For example, in this invention, sepsis-associated encephalopathy preferably includes sepsis-associated encephalopathy simulated by an endotoxemia model.

[0020] In a second aspect, the present invention provides a pharmaceutical composition for the prevention and / or treatment of sepsis-associated encephalopathy, the pharmaceutical composition comprising sulodexide.

[0021] In some embodiments, the pharmaceutical composition also includes a pharmaceutically acceptable carrier.

[0022] In this invention, the term "pharmaceutically acceptable carrier" refers to excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration to a subject. Pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. Pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0023] The pharmaceutical compositions provided by this invention can be prepared using any method known to those skilled in the art, based on the disclosure. Examples include, but are not limited to, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0024] In some embodiments, the dosage form of the pharmaceutical composition includes at least one of solid dosage forms, semi-solid dosage forms, and liquid dosage forms.

[0025] The pharmaceutical compositions provided by this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0026] The beneficial effects of this invention are as follows: Unlike existing technologies, this invention is the first to discover that sulodexide has the effect of preventing and / or treating sepsis-associated encephalopathy (SAE). Furthermore, animal experiments have demonstrated that sulodexide prevents and / or treats SAE by improving the survival rate of SAE patients, improving cognitive impairment in SAE patients, inhibiting neuroinflammation in the brain of SAE patients, reducing brain tissue damage in SAE patients, inhibiting microglial cell activation in SAE patients, and inhibiting the HMGB1 and / or RAGE pathways in SAE patients. This provides a new approach for the preparation of products for SAE and has broad application prospects. Attached Figure Description

[0027] Figure 1 The results of sulodexide improving the survival rate of rats in a sepsis-associated encephalopathy model in Example 1 of this invention; Figure 2 This is the result of an open field experiment in Example 2 of the present invention showing that sulodexide improves cognitive dysfunction in a rat model of sepsis-associated encephalopathy. Figure 3 The results of the elevated cruciate maze experiment in Example 2 of this invention show that sulodexide improves cognitive dysfunction in rats with sepsis-associated encephalopathy. Figure 4 This is the result of a novel object recognition experiment in Example 2 of the present invention, which showed that sulodexide improved cognitive impairment in a rat model of sepsis-associated encephalopathy. Figure 5 The results of Western blot analysis of sulodexate inhibiting neuroinflammation in the brain of rats with sepsis-associated encephalopathy model in Example 3 of this invention. Figure 6 HE staining results of sulodexate reducing brain tissue damage in a rat model of sepsis-associated encephalopathy in Example 4 of this invention; Figure 7 The results of sulodexate inhibiting microglial cell activation in a rat model of sepsis-associated encephalopathy in Example 5 of the present invention are shown, where (A) is the immunofluorescence result and (B) is the WB detection result. Figure 8 The image shows the Western blot (WB) results of sulodexide inhibiting the HMGB1 and RAGE pathways in a rat model of sepsis-associated encephalopathy to alleviate neuroinflammation, as described in Example 6 of this invention. Detailed Implementation

[0028] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0029] Experimental methods not specified in the examples are generally performed under conventional conditions and as described in the manual, or as recommended by the manufacturer. Unless otherwise specified, the general equipment, materials, reagents, etc. used are commercially available.

[0030] Example 1: Sulodide improves the survival rate of rats with sepsis-associated encephalopathy. 1.1 Establishment of a rat model of sepsis-associated encephalopathy Establishment of the endotoxemia model: Lipopolysaccharide (LPS) was dissolved in physiological saline beforehand to prepare a stock solution with a concentration of 1 mg / mL. Before injection, the LPS solution was diluted to 0.1 mg / mL. Three-day-old Sprague-Danwley newborn rats (hereinafter referred to as rats) were intraperitoneally injected with LPS (0.5 mg / kg) according to their body weight. Aspiration was performed before administration to avoid damage to intraperitoneal blood vessels. The entire process was completed within 30 seconds. After administration, the rats were returned to their mothers.

[0031] 1.2 Sulodide improves the survival rate of rats with sepsis-associated encephalopathy. Sulodide was administered to rats with the sepsis-associated encephalopathy model obtained in step 1.1. Specifically, sulodide injection (30 mg / mL) was diluted with physiological saline to the appropriate concentration and administered 2 hours after LPS injection.

[0032] The animal experiments were grouped as follows: saline control group (CT), LPS group, 4 mg / kg sulodexide group (SDX-L), 10 mg / kg sulodexide group (SDX-M), and 40 mg / kg sulodexide group (SDX-H).

[0033] The survival rates of rats in the different treatment groups mentioned above are as follows: Figure 1 As shown.

[0034] from Figure 1 The results showed that the 48-hour survival rate of newborn mice in the LPS group was significantly lower than that in the saline control group (CT). This indicates that the sepsis rat model was successfully established after LPS induction, and the survival rate of the sepsis rats was significantly reduced. Two hours after modeling, intraperitoneal injection of 4 mg / kg, 10 mg / kg, and 40 mg / kg sulodexide significantly improved the 48-hour survival rate of newborn mice in the LPS group, with the 40 mg / kg dose of sulodexide showing the best therapeutic effect.

[0035] Example 2: Sullodide improves cognitive impairment in a rat model of sepsis-associated encephalopathy. Cognitive impairment caused by sepsis-induced brain damage is becoming increasingly prominent in clinical practice, manifesting as memory decline and anxiety. This leads to a decrease in patients' quality of life, increases the costs of social healthcare and patient care, and places a significant burden on society and families. Therefore, it is of great significance to emphasize the prevention and treatment of sepsis-induced encephalopathy and its cognitive impairment.

[0036] Based on this, behavioral assessment experiments were conducted on rats 35 days after LPS modeling in Example 1. The animal experimental groups were as follows: saline control group (CT), LPS group, and LPS + 40 mg / kg sulopylidene group. Specifically, the open field test and the elevated cruciate test were used to detect anxiety-like behaviors in cognitive impairment in LPS-model septic rats, and the novel object recognition test was used to detect memory-impaired behaviors in cognitive impairment in LPS-model septic rats. The results are as follows: Figure 2-4 As shown.

[0037] All behavioral experiments were conducted between 9:00 a.m. and 5:00 p.m. Researchers were exposed to the rats seven days prior to the experiments to allow them to become familiar with the personnel. Three hours before the experiments, the rats were placed in the behavioral laboratory to allow them to acclimatize to the environment. Researchers were required to avoid making excessive noise or having strong odors during the testing process, as both could induce anxiety in the rats and affect the behavioral results.

[0038] The open field test (OFT) is as follows: Experimental Principle: Rats prefer darkness, so they tend to move around the perimeter of the experimental chamber. However, healthy rats, driven by curiosity, will explore the central area. Anxious rats, on the other hand, exhibit reduced exploration, thus spending less time in the open central area of ​​the chamber and exhibiting more stereotyped behaviors. The shorter the time a rat spends in the central area of ​​the chamber, the higher its anxiety level.

[0039] Experimental Procedure: The test rats were removed from their cages and carefully placed from the same position and angle into a corner of an open-top experimental chamber measuring 80cm (length) × 80cm (width) × 80cm (height). The operator left the behavioral laboratory, allowing the rats to explore freely for 5 minutes. The rats' movements were recorded using a video tracking system, and the time spent in the central area and the number of times the rats crossed the central area were counted. After the 5-minute test, the rats were returned to their cages. The OFT instrument was thoroughly wiped with 75% ethanol after each rat's experiment.

[0040] The Elevated Plus Maze (EPM) experiment is as follows: The elevated cross maze is composed of open arms and closed arms intersecting in a cross shape. The middle area of ​​the intersection is called the central area. The two arms are 20cm wide and 80cm long, and the closed arm is 40cm high. The maze is about 50cm above the ground.

[0041] Experimental Principle: Rats' curiosity prompts them to explore open and bright new areas (open arms), but their natural preference for darkness makes them willing to remain in closed arms. The height of the elevated maze is equivalent to a human being on the edge of a cliff, easily inducing fear and anxiety in the animals. The total number of times the rats entered the open and closed arms, the percentage of each, and the time spent in each arm reflect the rats' anxiety levels.

[0042] Experimental Procedure: a) Remove the test rats from their cages and gently place them facing the open arm in the central area of ​​the cross maze from the same position and angle. After placing the rats, the experimenters should quickly and quietly leave the behavior room; b) Record the rats' movements using a video tracking system, and count the number of times the rats entered the open arm (OE), the number of times they entered the closed arm (CE), the time spent in the open arm (OT), and the time spent in the closed arm (CT). The percentage of rats reaching the open arm (OE%) is calculated as OE / (OE+CE), and the percentage of rats spent in the open arm (OT%) is calculated as OT / (OT+CT). Each experiment lasts 5 minutes per rat; c) After each experiment, wipe the maze clean with a paper towel containing 75% alcohol to remove any odors, urine, and feces left by the rats.

[0043] The New Object Recognition (NOR) experiment is as follows: The experimental equipment includes: a set of equipment for the open field experiment: a square box (80cm long, 80cm wide, and 80cm high), a video tracking system and behavioral analysis software; three objects, A, B, and C. Objects A and B are exactly the same, while object C is very different from objects A and B, but similar in size.

[0044] Experimental principle: The natural tendency of experimental rats to explore new things means that they are more curious about new objects than familiar ones. By evaluating the behavioral method of how long experimental rats spend exploring familiar objects versus new, unfamiliar objects, we can assess the cognitive memory ability of experimental rats.

[0045] Experimental Procedure: The new object recognition experiment is mainly divided into the following two stages: the familiarization period and the testing period: a) First stage - Familiarization period: Two identical objects (A, B) are placed in the experimental box (ensuring the objects are odorless and fixed in place). A rat is placed in the box at an equal distance from both objects, facing away from the objects. The experimenter quietly leaves, allowing the rat to explore freely. The video tracking system records the rat's exploration time for each object within 5 minutes (valid exploration is defined as bringing the rat's mouth or nose within approximately 2-3 cm of the object). b) Second stage - Testing period: Conducted 1 hour after the first stage. Object B in the experimental box is replaced with another object C (A, C) of a different shape and color. Object C is ensured to be fixed in place. The rat is gently placed in from the same position, and the exploration time for objects A and C within 5 minutes is observed and recorded (only the first 30 seconds of each exploration is counted). After each rat completes one exploration, the experimental box and object surfaces are wiped with paper towels containing 75% alcohol to remove the rat's odor. S1 represents the total time the rat spent exploring object C, and S2 represents the total time the rat spent exploring object A.

[0046] from Figure 2 The results showed that the LPS group rats spent significantly less time in the central area of ​​the open field, suggesting anxiety-like behavior. Sulodide treatment significantly reversed this cognitive impairment in the LPS group rats. The results indicate that sulodide can improve anxiety behavior in rats with sepsis-associated encephalopathy.

[0047] from Figure 3 The results showed that the LPS group rats spent significantly less time in the open arm, suggesting anxiety-like behavior. Sulodide treatment significantly reversed this cognitive impairment in the LPS group rats. The results further indicated that sulodide can improve anxiety behavior in rats with sepsis-associated encephalopathy.

[0048] from Figure 4 The results showed that the LPS group rats had a significantly reduced ability to recognize new objects, suggesting that they had impaired memory. Sulodide treatment could significantly reverse this cognitive impairment in the LPS group rats. The results indicate that sulodide can improve the memory decline in rats with sepsis-associated encephalopathy.

[0049] Example 3: Sullodide inhibits neuroinflammation in the brain of a rat model of sepsis-associated encephalopathy. The hippocampus is considered a crucial brain region for performing working memory and cognitive functions. Clinical studies have shown that sepsis patients exhibit deficits in memory and language learning compared to non-sepsis patients, indicating a close link between hippocampal lesions and cognitive impairment in sepsis.

[0050] Based on this, Western blot (WB) experiments were performed on rats 24 hours after LPS modeling in Example 1 to detect the expression levels of inflammatory factors in hippocampal tissue. The animal experimental grouping was the same as in Example 2, and the results were as follows. Figure 5 As shown.

[0051] The WB experiment is detailed below: Rats treated as described above were sacrificed, and their hippocampal tissue was harvested. The tissue and lysis buffer were added at a ratio of 1 mg:10 μL, and the mixture was sonicated. Subsequently, it was centrifuged at 12000 rpm and 4°C for 15 min, and the supernatant (tissue protein extract) was collected. Quantitatively, 50-60 μg of the sample was loaded and subjected to SDS-PAGE gel electrophoresis. The protein bands were transferred to a PVDF membrane, blocked with 5% skim milk powder for 2 h, and incubated overnight at 4°C with primary antibody. The next day, the membrane was washed with 1×TBST, followed by incubation with HRP-labeled secondary antibody at room temperature on a shaker for 2 h. Finally, the membrane was washed and placed on a multi-functional imaging system for image recording. The gray values ​​of each band were measured using ImageJ software, and normalized using an internal control as a baseline to analyze the relative expression level of the target protein.

[0052] from Figure 5 The results show that sulodexide treatment can significantly reduce the expression levels of inflammatory factors IL-1β and TNF-α in the hippocampus of newborn rats in the LPS group, indicating that sulodexide can inhibit neuroinflammation in the brain of rats with sepsis-associated encephalopathy.

[0053] Example 4: Sulodide reduces brain tissue damage in a rat model of sepsis-associated encephalopathy. HE staining was performed on rats 24 hours after LPS modeling in Example 1 to detect morphological changes in hippocampal tissue. The animal experimental grouping was the same as in Example 2, and the results are as follows. Figure 6 As shown.

[0054] The HE staining experiment is detailed below: The rats treated as described above were sacrificed and their fresh brain tissue was fixed with 4% paraformaldehyde. The tissue was removed from the fixative within 48 hours and subjected to gradient dehydration, clearing, paraffin embedding, and tissue sectioning (4-6 μm). The tissue was then stained using conventional HE staining methods, and the morphological changes of the brain tissue were observed under an optical microscope.

[0055] from Figure 6 The results show that sulodexide treatment reduced neuronal damage in the hippocampus of newborn rats in the LPS group; the results indicate that sulodexide can reduce brain tissue damage in rats with sepsis-associated encephalopathy.

[0056] Example 5: Sullodide inhibits microglial cell activation in a rat model of sepsis-associated encephalopathy. Microglia are the primary immune cells inherent in the central nervous system. During sepsis, circulating pathogen-associated molecules and host-produced damage-associated molecules can activate microglia through various pathways, including a breached blood-brain barrier, vagal afferent pathways, or direct cytokine action. IBA1 is a marker of microglia. Its expression level is closely related to the number and activation state of microglia.

[0057] Immunofluorescence and Western blot experiments were performed on rats 24 hours after LPS modeling in Example 1 to detect the fluorescence intensity and expression level of IBA1. The animal experimental grouping was the same as in Example 2, and the results are as follows. Figure 7 As shown.

[0058] The immunofluorescence experiment is detailed below: Sacrificed rats treated as described above and cryopreserved their brains (40-45 μm). The sections were washed three times with PBS at room temperature for 10 min each time; blocked at room temperature for 1 hour; the blocking solution was then removed, and IBA1 antibody was added and incubated overnight at 4°C; the antibody was removed overnight, and the sections were washed three times with washing buffer for 10 min each time; then immunofluorescence secondary antibody was added (protected from light), and incubated at room temperature for 1 hour; the secondary antibody was removed, and the sections were washed three times with washing buffer for 10 min each time; the sections were mounted and allowed to air dry; an anti-fluorescence quencher (containing DAPI) was added, and the sections were covered with coverslips, pressed firmly, and observed under a fluorescence microscope. IBA1 staining showed green fluorescence, and DAPI staining of the cell nuclei showed blue fluorescence.

[0059] The WB experiment was the same as in Example 3.

[0060] from Figure 7 As can be seen, sulodexide treatment can inhibit the fluorescence intensity of the microglial marker IBA1 (…). Figure 7 A), while significantly reducing the expression level of IBA1 in the hippocampus of newborn rats in the LPS group ( Figure 7 B); the results showed that sulodexide could inhibit microglial cell activation in rats with sepsis-associated encephalopathy.

[0061] Example 6: Sulfodide inhibits the HMGB1 and / or RAGE pathways in a rat model of sepsis-associated encephalopathy to alleviate neuroinflammation. High-mobility protein 1 (HMGB1) is released from activated macrophages in a delayed manner upon stimulation by exogenous bacterial endotoxins. Previous studies have shown elevated HMGB1 levels in the cerebrospinal fluid and brain tissue of sepsis patients. HMGB1 has a high affinity for advanced glycosylation products (RAGE) on the cell surface.

[0062] Western blot (WB) experiments were performed on rats 24 hours after LPS modeling in Example 1 to detect the expression levels of HMGB1 and RAGE. The animal experimental grouping was the same as in Example 2, and the results are as follows. Figure 8 As shown.

[0063] The WB experiment was the same as in Example 3.

[0064] from Figure 8 The study showed that sulodexide treatment significantly reduced the expression levels of HMGB1 and RAGE in the hippocampus of newborn rats in the LPS group. The results indicate that sulodexide may alleviate neuroinflammation caused by sepsis-associated encephalopathy in rats by inhibiting the HMGB1 and RAGE pathways.

[0065] In summary, this invention is the first to discover that sulodexide has the effect of preventing and / or treating sepsis-associated encephalopathy. Furthermore, animal experiments have demonstrated that sulodexide prevents and / or treats sepsis-associated encephalopathy by improving the survival rate of patients with sepsis-associated encephalopathy, improving cognitive dysfunction in patients with sepsis-associated encephalopathy, inhibiting neuroinflammation in the brain of patients with sepsis-associated encephalopathy, reducing brain tissue damage in patients with sepsis-associated encephalopathy, inhibiting microglial cell activation in patients with sepsis-associated encephalopathy, and inhibiting the HMGB1 and / or RAGE pathways in patients with sepsis-associated encephalopathy.

[0066] It should be noted that all the above embodiments belong to the same inventive concept, and the descriptions of each embodiment have different focuses. Where the description in a particular embodiment is not detailed, please refer to the description in other embodiments.

[0067] The embodiments described above are merely illustrative of implementation methods of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. Use of sulodexide 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 drug can improve the survival rate of patients with sepsis-associated encephalopathy.

3. The application according to claim 1, characterized in that, The drug can improve cognitive impairment in patients with sepsis-associated encephalopathy; The cognitive impairment includes at least one of memory decline and anxiety behavior.

4. The application according to claim 1, characterized in that, The drug can inhibit neuroinflammation in the brain of patients with sepsis-associated encephalopathy; The brain neuroinflammation is caused by an increase in the levels of inflammatory factors.

5. The application according to claim 1, characterized in that, The drug can reduce brain tissue damage in patients with sepsis-associated encephalopathy.

6. The application according to claim 1, characterized in that, The drug can inhibit microglial cell activation in patients with sepsis-associated encephalopathy.

7. The application according to claim 1, characterized in that, The drug alleviates neuroinflammation caused by sepsis-associated encephalopathy by inhibiting the HMGB1 and / or RAGE pathways in patients with sepsis-associated encephalopathy.

8. The application according to any one of claims 1-7, characterized in that, The dosage of sulodex is 4-40 mg / kg.

9. A pharmaceutical composition for the prevention and / or treatment of sepsis-associated encephalopathy, characterized in that, The pharmaceutical composition includes sulodexide.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

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