Use of malaviif and CCL5 neutralizing antibodies for treatment of sepsis-associated encephalopathy
By using maraviro and CCL5 neutralizing antibodies to inhibit the CCL5-CCR5 signaling pathway, the neurological function impairment problem in sepsis-associated encephalopathy was resolved, resulting in a significant improvement in survival rate and cognitive function.
Patent Information
- Application Number
- CN202511453543.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-13
- Publication Date
- 2026-01-20
AI Technical Summary
Current technologies lack effective treatments to reverse or improve neurological damage and long-term prognosis caused by sepsis-associated encephalopathy (SAE), especially the lack of specific drugs, which leads to high mortality and long-term cognitive impairment.
By using Maraviroc and CCL5 neutralizing antibodies or their pharmaceutically acceptable salts, we can alleviate hippocampal neuronal pathological damage, reduce the levels of key neuroinflammatory factors, and protect synaptic structure and function by inhibiting the CCL5-CCR5 signaling pathway.
It significantly improved the survival rate of septic mice to over 60%, improved anxiety-like behavior and learning and memory dysfunction, reduced pathological damage to hippocampal neurons, reduced the level of inflammatory factors, and protected synaptic structures.
Smart Images
Figure CN121360119A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the field of pharmaceutical chemistry and medicine, and specifically relates to a new use of Maraviroc and a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the preparation of a medicine for preventing and / or treating sepsis-associated encephalopathy (SAE). BACKGROUND
[0002] Sepsis is a disorder of host immune response caused by infection, which further leads to life-threatening organ dysfunction. Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis involving the central nervous system, and is clinically manifested as delirium, disturbance of consciousness, cognitive dysfunction and a series of neuropsychiatric symptoms. SAE is one of the common organ dysfunctions in severe patients.
[0003] Epidemiological investigations show that about 50%-70% of sepsis patients will have varying degrees of brain function impairment, and up to 30% of patients may develop long-term or even permanent cognitive dysfunction, which seriously affects the quality of life of patients and increases the social burden. What is particularly important is that the occurrence of SAE is significantly associated with the mortality of sepsis patients.
[0004] At present, there is a lack of specific therapeutic drugs for SAE in clinical practice, and the main treatment regimen is still limited to anti-infection and supportive treatment, which is difficult to effectively reverse or improve neurological impairment and long-term prognosis. Therefore, it has become a key scientific problem and clinical demand in this field to further elucidate the pathogenesis of SAE and to find new therapeutic targets and effective drugs on this basis. SUMMARY
[0005] In one aspect of the present application, the use of Maraviroc and a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the preparation of a medicine for sepsis-associated encephalopathy is provided.
[0006] The present application provides the use of Maraviroc or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating sepsis-associated encephalopathy, wherein the structure of Maraviroc is as follows:
[0007] The present application also provides the use of a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the preparation of a medicine composition for sepsis-associated encephalopathy.
[0008] Further, in the above technical solution, the drug is used for administration to prevent, alleviate or eliminate one or more symptoms and / or signs of the sepsis-associated encephalopathy; improve the survival rate of the individual; delay or arrest the progression of the sepsis-associated encephalopathy; reduce the severity of the sepsis-associated encephalopathy; and / or improve the prognosis of the sepsis-associated encephalopathy.
[0009] Further, in the above technical solution, the drug is used for administration to improve the survival rate and cognitive behavioral defects of the individual, in particular, the hippocampal pathological changes and the hippocampal neuroinflammatory factor changes of the brain tissue.
[0010] Further, in the above technical solution, the hippocampal pathological changes are selected from one or more of the following: dendritic spine reduction and synapse loss in the hippocampus, or phagocytic ability of microglia and changes in the level of neuronal pruning; and the hippocampal neuroinflammatory factor is selected from one or more of the following: IL-6, CD68, IL-1β, HMBG-1.
[0011] Further, in the above technical solution, the drug is used for administration to improve the survival rate of the individual; improve the behavioral function of the individual; inhibit the pathological changes of the hippocampus of the brain tissue in the individual; and / or inhibit the activation of CCL5-CCR5 signal in the individual.
[0012] Further, in the above technical solution, the pharmaceutical composition comprises the maraviroc or the pharmaceutically acceptable salt thereof as the only active ingredient. The pharmaceutical composition comprises the CCL5 neutralizing antibody or the pharmaceutically acceptable salt thereof as the only active ingredient.
[0013] Further, in the above technical solution, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
[0014] Further, in the above technical solution, the drug is used for oral administration, parenteral administration, topical administration, transdermal administration or rectal administration.
[0015] Further, in the above technical solution, the drug is in the form of a tablet, a capsule, a granule, a syrup, a patch, a suppository, an emulsion or a gel. Advantages of the Invention
[0016] The present application proves the new use of CCR5 antagonist Maraviroc and CCL5 neutralizing antibody in treating sepsis-associated encephalopathy (SAE) through in vivo experiments, which can significantly improve the survival rate of sepsis mice from about 30% to more than 60%, and effectively improve the anxiety-like behavior and learning and memory dysfunction of sepsis mice.
[0017] The core mechanism is to reduce the pathological damage of hippocampal neurons, reduce the levels of key neuroinflammatory factors (IL-6, IL-1β, CD68, HMBG-1) by inhibiting the CCL5-CCR5 signaling pathway, and protect the synaptic structure and function by protecting the dendritic spine density and synaptic-related protein expression, and inhibiting the abnormal synaptic phagocytosis of microglia, thereby providing a new target and effective strategy for the treatment of SAE. BRIEF DESCRIPTION OF DRAWINGS
[0018] Figure 1 Maraviroc improves the survival rate and behavioral disorders of sepsis mice; Figure 2 Maraviroc improves the hippocampal neuronal damage and neuroinflammation of CLP-induced sepsis mice; Figure 3 Maraviroc improves the hippocampal synaptic damage of CLP-induced sepsis mice; Figure 4 Anti-CCL5 improves the survival rate and behavioral disorders of sepsis mice; Figure 5 Anti-CCL5 improves the hippocampal neuronal damage and neuroinflammation of CLP-induced sepsis mice; Figure 6 Anti-CCL5 improves the hippocampal synaptic damage of CLP-induced sepsis mice. DETAILED DESCRIPTION
[0019] The present application will now be described in detail with specific reference to representative embodiments thereof. These embodiments are illustrative only and should not be taken in any way as limiting the scope of the application. Rather, the application is intended to encompass all alternatives, modifications and equivalents falling within the scope of the application as defined by the appended claims.
[0020] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
[0021] The term "Maraviroc" used herein has the following structural formula, and the molecular formula is C 29 H 41 F2N5O:
[0022] The term "CCL5 neutralizing antibody" as used herein refers to an antibody that is capable of specifically binding to human CCL5 (RANTES) protein and effectively blocking its binding to a receptor (e.g., CCR5), thereby neutralizing its biological activity. It includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, humanized antibodies, chimeric antibodies, single-chain antibodies, and antigen-binding fragments thereof (e.g., Fab, F(ab')2, scFv, etc.).
[0023] As used herein, a pharmaceutically acceptable salt of maraviroc includes a salt of maraviroc with an organic or inorganic acid. Exemplary pharmaceutically acceptable salts include, but are not limited to: hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. Preferably, the pharmaceutically acceptable salt is maraviroc hydrochloride.
[0024] The term "pharmaceutically acceptable" as used herein means that the compound, composition or carrier is appropriate for use in vivo without undue deleterious side effects in view of the
[0025] The term "individual" as used herein refers to a mammal or human, including, but not limited to, primates (monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, hamsters, gerbils, ferrets, and the like), lagomorphs, porcines (e.g., pigs, mini-pigs), equines, canines, felines, and the like. In a preferred embodiment, the individual is a mammal. In a further preferred embodiment, the individual is a human.
[0026] The term "treatment" as used herein refers to complete or partial cure or elimination of a disease, disorder, or pathological condition, including, but not limited to, one or a combination of two or more selected from the group consisting of: alleviating or eliminating the cause of the disease, disorder, or pathological condition; ameliorating or eliminating its pathologies; alleviating or eliminating one or more symptoms and / or signs thereof; retarding or arresting its progression; lessening its severity; reducing its incidence; reducing its recurrence; and improving its prognosis.
[0027] The inventors of the present application have found through experiments that Maraviroc or a pharmaceutically acceptable salt thereof, and a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, have significant therapeutic efficacy on animal subjects (e.g., mice) suffering from sepsis-associated encephalopathy, can improve the neurobehavioral performance of the animal subjects, reduce the pathological damage of brain tissues, reduce the level of inflammatory factors in the brain, and inhibit the overactivation of the neural inflammation-related signaling pathway.
[0028] Therefore, in one aspect, the present application provides the use of Maraviroc or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating sepsis-associated encephalopathy in a subject in need thereof.
[0029] In another aspect, the present application provides the use of a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating sepsis-associated encephalopathy in a subject in need thereof.
[0030] In some embodiments, the administration of the Maraviroc or a pharmaceutically acceptable salt thereof, or the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, can prevent, alleviate or eliminate one or more symptoms and / or signs of the sepsis-associated encephalopathy.
[0031] In some embodiments, the symptoms and signs include, but are not limited to: 1) acute cognitive dysfunction, such as inattention, disorientation, memory impairment; 2) changes in level of consciousness, including lethargy, somnolence, agitation, delirium or coma; 3) neuropsychiatric symptoms, such as anxiety, hallucinations, delusions; 4) movement disorders, such as tremor, myoclonus, flapping tremor; 5) seizures.
[0032] In some embodiments, the administration of the Maraviroc or a pharmaceutically acceptable salt thereof, or the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, can improve the survival rate of the subject.
[0033] In some embodiments, the administration of the Maraviroc or a pharmaceutically acceptable salt thereof, or the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, can delay or arrest the progression of the sepsis-associated encephalopathy; in other embodiments, alleviate the severity of the sepsis-associated encephalopathy; and / or in some embodiments, improve the prognosis of the sepsis-associated encephalopathy.
[0034] In some embodiments, the administration of the Maraviroc or a pharmaceutically acceptable salt thereof, or the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, can prevent, improve or eliminate the pathological changes and / or dysfunction of the brain tissues of the subject.
[0035] In some further embodiments, the pathological changes are selected from one or more of neural cell apoptosis, microglial cell activation, astrocyte proliferation, increased blood brain barrier permeability, brain edema, and inflammatory cell infiltration.
[0036] In some embodiments, the administration of the maraviroc or a pharmaceutically acceptable salt thereof, or the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof, can reduce the level of inflammatory factors in the individual, in particular in the brain tissue.
[0037] In some further embodiments, the inflammatory factors are one or more selected from the group consisting of tumor necrosis factor, interleukin, chemokine, and NO, preferably one or more selected from the group consisting of TNF-a, IL-1 b, IL-6, CCL5, CCL2, CXCL1, and INF-g, more preferably one or more selected from the group consisting of TNF-a, IL-1 b, and IL-6.
[0038] In some further embodiments, the inflammatory factors are one or more of TNF-a, IL-1 b, and IL-6 in the brain tissue.
[0039] In some embodiments, the administration of the maraviroc or a pharmaceutically acceptable salt thereof can function through antagonizing CCR5 receptor; and / or the administration of the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof can function through neutralizing CCL5.
[0040] In another aspect, the present application also provides the use of maraviroc or a pharmaceutically acceptable salt thereof and CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for preventing or treating complications of sepsis-associated encephalopathy.
[0041] In some embodiments, the complications are one or more of long-term cognitive dysfunction, permanent neurological deficit, or dementia.
[0042] In yet another aspect, the present application provides maraviroc or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising maraviroc or a pharmaceutically acceptable salt thereof, for use in: treating sepsis-associated encephalopathy in an individual in need thereof; preventing, alleviating, or eliminating one or more symptoms and / or signs of the sepsis-associated encephalopathy; improving survival rate of the individual; delaying or halting progression of the sepsis-associated encephalopathy; alleviating severity of the sepsis-associated encephalopathy; improving prognosis of the sepsis-associated encephalopathy; preventing, ameliorating, or eliminating pathological changes and / or dysfunction of brain tissue in an individual with sepsis-associated encephalopathy; reducing the level of inflammatory factors in brain tissue of the individual; and / or preventing or treating complications of sepsis-associated encephalopathy.
[0043] In yet another aspect, the present application provides a CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof, for use in: treating sepsis-associated encephalopathy in an individual in need thereof; preventing, alleviating, or eliminating one or more symptoms and / or signs of the sepsis-associated encephalopathy; increasing survival rate of the individual; delaying or arresting progression of the sepsis-associated encephalopathy; reducing severity of the sepsis-associated encephalopathy; improving prognosis of the sepsis-associated encephalopathy; preventing, ameliorating, or eliminating pathological changes and / or dysfunction of brain tissue in an individual with sepsis-associated encephalopathy; reducing levels of inflammatory factors in brain tissue of the individual; and / or preventing or treating complications of sepsis-associated encephalopathy.
[0044] In yet another aspect, the present application provides a method for treating sepsis-associated encephalopathy in an individual in need thereof; preventing, alleviating, or eliminating one or more symptoms and / or signs of the sepsis-associated encephalopathy; increasing survival rate of the individual; delaying or arresting progression of the sepsis-associated encephalopathy; reducing severity of the sepsis-associated encephalopathy; improving prognosis of the sepsis-associated encephalopathy; preventing, ameliorating, or eliminating pathological changes and / or dysfunction of brain tissue in an individual with sepsis-associated encephalopathy; reducing levels of inflammatory factors in brain tissue of the individual; and / or preventing or treating complications of sepsis-associated encephalopathy, the method comprising administering to the individual a therapeutically effective amount of maraviroc, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising maraviroc, or a pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof.
[0045] In some embodiments according to each of the aspects described above, the pharmaceutical composition comprises the maraviroc, or a pharmaceutically acceptable salt thereof, as the only active ingredient, or the CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof, as the only active ingredient.
[0046] In other embodiments, the pharmaceutical composition further comprises one or more other active ingredients. In such embodiments, the maraviroc, or a pharmaceutically acceptable salt thereof, and the one or more other active ingredients can be formulated separately and contained in separate pharmaceutical compositions, or formulated together in a single pharmaceutical composition comprising them; and / or the CCL5 neutralizing antibody, or a pharmaceutically acceptable salt thereof, and the one or more other active ingredients can be formulated separately and contained in separate pharmaceutical compositions, or formulated together in a single pharmaceutical composition comprising them.
[0047] The pharmaceutical composition optionally comprises one or more pharmaceutically acceptable carriers, such as excipients, disintegrants, diluents, binders, glidants, lubricants, pH adjusting agents, preservatives, dispersants, suspending agents, ointment bases, emulsifiers, emollients, penetration enhancers, surfactants, propellants, flavoring agents, sweetening agents, drug release modifiers, and the like. Suitable carriers can be selected by one skilled in the art depending on the desired formulation form, mode of administration, and release profile of the pharmaceutical composition, etc.
[0048] The terms "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", or "involve" and other variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps, although they are not necessarily present (i.e., these terms also cover the terms "consist essentially of" and "consist of").
[0049] The pharmaceutical composition can be formulated into dosage forms of solid, semi-solid, or liquid forms suitable for administration by any of the accepted modes of administration available in the art, including but not limited to: (1) for oral administration: for example, tablets, capsules, powders, granules, troches, aqueous or non-aqueous solutions or suspensions, syrups, elixirs, etc.; (2) for parenteral administration: for example, injectable dosages such as sterile solutions or suspensions; (3) for topical administration: for example, ointments, creams, gels, sprays, or the like for application onto the skin or mucosal membranes; (4) for transdermal administration: for example, patches, gels, etc.; (5) for vaginal or rectal administration: for example, suppositories, creams, gels, or effervescent tablets, etc.
[0050] As used herein, the term "therapeutically effective amount" refers to the amount of an active ingredient after administration which will achieve the intended therapeutic effect of the use or method.
[0051] The present application is illustrated in more detail by the following examples, which do not limit the present application in any manner, the scope of which is defined only by the claims.
[0052] Example 1: Maraviroc improves survival and behavioral impairment in sepsis mice To evaluate the therapeutic effect of CCR5 inhibitor maraviroc on sepsis-associated encephalopathy (SAE), we constructed a mouse model using CLP surgery. Survival analysis showed that the 120-hour survival rate of the maraviroc treatment group (61.11%) was significantly higher than that of the CLP model group (29.41%). Figure 1 A), the maraviroc treatment group had a significantly higher 120-hour survival rate (61.11%) than the CLP model group (29.41%). In the behavioral experiment, the open field test Figure 1B-D) showed that Maraviroc improved anxiety-like behaviors in model mice, increasing the percentage of central zone movement time from 5.77% to 11.15%. Morris water maze results showed that Figure 1 E-H), the escape latency of the treatment group was shortened from 35.84 seconds to 22.88 seconds, the number of platform crossings in spatial exploration increased from 0.875 times / minute to 1.75 times / minute, and the target quadrant residence time was prolonged from 9.40 seconds to 13.62 seconds, confirming that it can effectively improve the survival rate and cognitive function of SAE mice.
[0053] Example 2: Maraviroc improves CLP-induced hippocampal neuronal injury and neuroinflammation in sepsis mice The protective effect of Maraviroc on the hippocampus was evaluated by histological and molecular biological methods. HE and Nissl staining Figure 2 A-D) showed that Maraviroc treatment restored the number of neurons in the hippocampal CA1 and CA3 regions to 98.16% and 84.17%, respectively, significantly reducing the loss of neurons and morphological abnormalities caused by CLP. qPCR detection results Figure 2 E-H) further showed that the mRNA expression levels of key neuroinflammatory factors such as IL-6, CD68, IL-1β, and HMBG-1 in the hippocampal tissue of the treatment group were significantly inhibited, demonstrating that Maraviroc has a dual role in reducing neuronal injury and inhibiting neuroinflammation.
[0054] Example 3: Maraviroc improves CLP-induced synaptic injury in the hippocampus of sepsis mice This study explored the effects of Maraviroc on synaptic integrity and microglial function. Immunofluorescence and three-dimensional reconstruction Figure 3 A-C) showed that Maraviroc significantly inhibited the abnormal activation of microglia, reducing the number of CD68+ punctate plaques and phagocytosis of synaptophysin (SYP). Golgi staining Figure 3 D-E) confirmed that treatment improved the reduction of dendritic spine density caused by CLP. Western blot results showed Figure 3 F-K), on the 12th day after CLP, Maraviroc maintained the expression levels of synaptic proteins PSD95 and SYN-1, indicating that it effectively protected synaptic structure and regulated the synaptic pruning function of microglia by inhibiting CCR5 activation.
[0055] Example 4: Anti-CCL5 improves survival rate and behavioral disorders in sepsis mice The therapeutic effect was verified by stereotactic injection of CCL5 neutralizing antibody (source: Bio-Techne Company, Catalog Number: AF478) into the hippocampus. Survival rate statisticsFigure 4 A) shows that the survival rate of the Anti-CCL5 treatment group (71.43%) was significantly higher than that of the CLP model group (36.36%). In behavioral analysis, the open field test (OFT) ( Figure 4 B-D) shows that the proportion of central zone movement time in the treatment group increased from 4.55% to 8.25%. The Morris water maze (MWM) test ( Figure 4 E-H) shows that the escape latency of the treatment group was shortened from 37.40 seconds to 24.45 seconds, the number of platform crossings in spatial exploration increased from 0.80 times / minute to 3.90 times / minute, and the target quadrant residence time was extended from 18.05 seconds to 34.12 seconds, proving that blocking CCL5 can effectively improve the survival and cognitive behavior of SAE mice.
[0056] Example 5: Anti-CCL5 improves hippocampal neuronal injury and neuroinflammation in CLP-induced sepsis mice Histology and molecular biology tests confirmed the neuroprotective effect of CCL5 neutralizing antibodies. HE and Nissl staining (Nissl) ( Figure 5 A-D) shows that Anti-CCL5 treatment restored the number of neurons in the hippocampal CA1 and CA3 regions to 96.21% and 105.80%, respectively, effectively reducing neuronal pathological damage. qPCR results ( Figure 5 E-H) show that the expression levels of inflammatory factors such as IL-6, CD68, IL-1β, and HMBG-1 in the hippocampal tissue of the treatment group were significantly reduced, confirming that neutralizing CCL5 can effectively alleviate SAE-related hippocampal neuronal injury and neuroinflammatory response.
[0057] Example 6: Anti-CCL5 improves CLP-induced synaptic injury in sepsis mice This study further confirmed the protective effect of CCL5 neutralizing antibodies on synaptic structure. Immunofluorescence analysis (IFA) ( Figure 6 A-C) shows that Anti-CCL5 inhibits microglial activation, reducing the number of CD68+ plaques and phagocytosis of SYP. Golgi staining (Golgi) ( Figure 6 D-E) shows that treatment improves dendritic spine density. Western blot results ( Figure 6 F-H) show that the expression levels of PSD95 and SYN-1 proteins in the treatment group were significantly restored. The above results indicate that neutralizing CCL5 can protect synaptic integrity and inhibit abnormal synaptic pruning by microglia.
[0058] Those skilled in the art can, on the basis of the foregoing description, determine the essential characteristics of the present application and can make various changes and modifications to the present application to adapt it to various uses and conditions without departing from the spirit and scope of the present application. All such modifications and changes are also included within the scope of the present application. Therefore, the scope of the present application should be determined by the appended claims and their legal equivalents.
Claims
1. Use of Maraviroc or a pharmaceutically acceptable salt thereof having the following structure: in the manufacture of a medicament for the treatment of sepsis-associated encephalopathy. 。 2. Use of a CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment of sepsis-associated encephalopathy.
3. Use according to claim 1 or 2, wherein, The medicament is for administration to achieve one or more of the following: prevent, alleviate or eliminate symptoms and / or signs of the sepsis-associated encephalopathy; improve survival rate of the individual; delay or arrest progression of the disease; reduce severity of the disease; and / or improve prognosis of the disease.
4. The use according to claim 3, the medicament is for administration to improve survival rate and cognitive behavioral deficits of the individual, in particular hippocampal pathological changes and hippocampal neuroinflammatory factors changes in brain tissue.
5. The use according to claim 4, the hippocampal pathological changes are selected from one or more of dendritic spine reduction and synapse loss in hippocampus or microglial phagocytic capacity and changes in levels of neuronal pruning; the hippocampal neuroinflammatory factors are selected from one or more of IL-6, CD68, IL-1 β, HMBG-1.
6. The use according to claim 5, wherein the pharmaceutical composition is for administration to improve survival rate of the individual; improve behavioral function of the individual; inhibit hippocampal pathological changes in brain tissue of the individual; and / or inhibit activation of CCL5-CCR5 signaling in the individual.
7. Use according to claim 1 or 2, wherein, The pharmaceutical composition comprises the maraviroc or a pharmaceutically acceptable salt thereof as the sole active ingredient; or, the pharmaceutical composition comprises the CCL5 neutralizing antibody or a pharmaceutically acceptable salt thereof as the sole active ingredient.
8. The use according to claim 1, the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
9. The use according to claim 8, the medicament is for oral administration, parenteral administration, topical administration, transdermal administration or rectal administration.
10. The use according to claim 9, the medicament is in the form selected from tablet, capsule, granule, syrup, patch, suppository, emulsion or gel.