Application of baricitinib in treatment of cerebral arterial thrombosis

Abstract

The invention discloses an application of baricitinib in treatment of cerebral arterial thrombosis, and the baricitinib is used as a neuroprotective agent and is applied to treatment of cerebral arterial thrombosis after large vascular occlusion. The application of the invention reduces neuroinflammatory response, reduces nerve injury, protects nerves, improves stroke prognosis, and improves treatment effect.

Description

Technical Field

[0001] The present invention relates to the fields of molecular biology and medical technology, and particularly to an application of baricitinib in the treatment of ischemic stroke. Background Art

[0002] Stroke has become the second leading cause of death globally, characterized by high incidence, high disability rate, and high fatality rate. Among them, ischemic stroke is the most common subtype, accounting for approximately 70%. Previous studies have mainly focused on how to improve the rate of vascular recanalization. Currently, the recanalization rate of acute large vessel occlusion in the anterior circulation stroke has been increased to 80% - 94.0% through endovascular treatment. Unfortunately, up to 90% of the vascular recanalization rate has not been fully translated into clinical benefits for patients, and the proportion of patients with good prognosis is less than 50%. Even when the blood vessels are successfully recanalized, 55% - 60% of the patients still have poor neurological prognosis, which is clinically referred to as "ineffective recanalization". Both early stroke and reperfusion after recanalization can trigger a cascade of inflammatory reactions, leading to severe secondary injury. Therefore, inhibiting the inflammatory response induced by stroke has attracted increasing attention. Summary of the Invention

[0003] In view of the above-mentioned defects or deficiencies in the prior art, it is desirable to provide an application of baricitinib in the treatment of ischemic stroke to reduce neuroinflammatory response, reduce nerve damage, protect nerves, improve stroke prognosis, and enhance the treatment effect.

[0004] An application of baricitinib in the treatment of ischemic stroke provided by the present invention uses baricitinib as a neuroprotective agent and applies it in combination with recanalization treatment after large vessel occlusion in ischemic stroke.

[0005] Further, as a neuroprotective agent, baricitinib inhibits the neuroinflammatory response after stroke, reduces the volume of cerebral infarction and cerebral edema, reduces nerve cell damage, and improves neurological prognosis.

[0006] Further, as an immunosuppressant, baricitinib reduces neuroinflammatory response, reduces nerve damage, protects nerves, and improves stroke prognosis by inhibiting the infiltration of immune cells into the brain after stroke.

[0007] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0008] The present invention uses baricitinib as a JAK1 / 2 inhibitor. By inhibiting the JAK2 / STAT3 pathway, it reduces the infarct volume, alleviates cerebral edema, and improves the neurological function score after ischemic stroke. It has a wide range of immunosuppressive and anti-inflammatory effects and neuroprotective effects on nerve cells, and can effectively improve the treatment effect.

[0009] It should be understood that the content described in the Summary of the Invention section is not intended to limit the key or important features of the embodiments of the present invention, nor to limit the scope of the present invention. Other features of the present invention will become readily understood through the following description. Brief Description of the Drawings

[0010] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments read in conjunction with the accompanying drawings:

[0011] Figure 1 Schematic diagram of the modified neurological deficit scores of MCAO mice at different time points for each group;

[0012] Figure 2 Schematic diagram of the neurological scores of MCAO mice 14 days after modeling for each group;

[0013] Figure 3 Schematic diagram of TTC staining of the cerebral infarction area;

[0014] Figure 4 Schematic diagram of statistical analysis of the cerebral infarction volume;

[0015] Figure 5 Schematic diagram of comparison of CD4+ T cells infiltrating the brain;

[0016] Figure 6 Schematic diagram of comparison of neutrophils infiltrating the brain;

[0017] Figure 7 Schematic diagram of comparison of microglial cell activation in the brain;

[0018] Figure 8 Schematic diagram of comparison of activation of M1 (pro-inflammatory) microglial cells in the brain;

[0019] Figure 9 Schematic diagram of comparison of activation of M2 (anti-inflammatory) microglial cells in the brain. Detailed Description of the Embodiments

[0020] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It can be understood that the specific embodiments described herein are only for explaining the related invention and not for limiting the invention. Additionally, it should be noted that for the sake of description, only parts related to the invention are shown in the drawings.

[0021] It should be noted that, without conflict, the embodiments in the present invention and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the drawings and in conjunction with the embodiments.

[0022] Please refer to Figures 1 to 9, embodiments of the present invention provide an application of baricitinib in the treatment of ischemic stroke. Baricitinib, as a neuroprotective agent, is applied in combination with recanalization treatment after large vessel occlusion in ischemic stroke;

[0023] Baricitinib, as a neuroprotective agent, inhibits neuroinflammatory responses after stroke, reduces the volume of cerebral infarction and cerebral edema, reduces nerve cell damage, and improves the prognosis of nerve function;

[0024] The baricitinib, as an immunosuppressant, reduces neuroinflammatory responses and nerve damage, protects nerves, and improves the prognosis of stroke by inhibiting the infiltration of immune cells into the brain after stroke.

[0025] In this embodiment, baricitinib (trade name Baricitinib Tablets, national drug approval number H20234188) was approved for marketing by the National Medical Products Administration (NMPA) in 2023 for the treatment of rheumatoid arthritis and alopecia areata. Based on some previous treatment data for autoimmune inflammatory diseases, 2 mg or 4 mg of baricitinib was recommended in most randomized controlled trials (RCTs), and it had good tolerance and safety. Its most common adverse reactions only included elevated low-density lipoprotein (LDL) cholesterol, upper respiratory tract infection, headache, herpes simplex, and urinary tract infection, and no hemorrhagic adverse events occurred. Two large clinical trials also showed that baricitinib had high safety in patients with alopecia areata.

[0026] The Janus kinase (JAK / STAT) signaling pathway is considered to be one of the central communication nodes of cell functions. Inhibiting JAK activity can induce immunosuppression and reduce abnormally elevated serum pro-inflammatory cytokines mediated by the JAK / STAT signaling pathway. At the same time, JAK inhibitors can also reduce various pro-inflammatory cytokines such as IL-6 and IFN-γ in patients, which are related to the innate cytokine storm, and have broad anti-inflammatory activities. Inhibiting the JAK / STAT signaling pathway can mediate the occurrence of immune inflammatory events to a great extent.

[0027] In this application, baricitinib is used as a JAK1 / 2 inhibitor. By inhibiting the JAK2 / STAT3 pathway, it reduces the infarct volume, alleviates cerebral edema, and improves the neurological function score after ischemic stroke, has broad immune inflammatory inhibition and nerve cell protection effects, and can effectively improve the treatment effect.

[0028] Example 1

[0029] A neurological function experiment was conducted using MCAO mice. The experimental groups and test substances are shown in Table 1.

[0030] Table 1 Experimental groups and test substances

[0031]

[0032] The neurological function recovery of mice after treatment was evaluated by neurological function scores, and the specific results are as Figure 1 and Figure 2 shown (** represents P < 0.01, *** represents P < 0.001). As can be seen from the figure, compared with the experimental control group, the neurological function scores of MCAO mice after baricitinib treatment were significantly reduced, and at the same time, the 30 mg / kg group was significantly lower than the 10 mg / kg group, showing a dose-dependence. This indicates that baricitinib has a significant effect on improving the neurological function of MCAO mice and shows a dose-dependence, and the improvement is more obvious with the increase of the dose.

[0033] Example 2

[0034] As Figure 3 shown, TTC staining was performed on the cerebral infarction area to quantitatively evaluate the brain protection effect of baricitinib; as Figure 4 shown (* represents P < 0.05, *** represents P < 0.001), statistical analysis was performed on the cerebral infarction volume; as can be seen from the figure, after treatment with baricitinib, the cerebral infarction volume of MCAO mice decreased and was significantly lower than that of the experimental control group.

[0035] Example 3

[0036] As Figure 5 shown, compared with the experimental control group, after baricitinib treatment of ischemic stroke, the infiltration of CD4+ T cells in the brain was significantly reduced, balancing the inflammatory response in the brain, and then improving the nerve damage at the stroke site.

[0037] Example 4

[0038] As Figure 6 shown, compared with the experimental control group, after baricitinib treatment of ischemic stroke, the infiltration of neutrophils in the brain was significantly reduced, balancing the inflammatory response in the brain, and then improving the nerve damage at the stroke site.

[0039] Example 5

[0040] Compared with the experimental control group, as Figure 7 shown, it was shown that after baricitinib treatment of ischemic stroke, there was no obvious effect on the total number of activated microglia in the brain; however, Figure 8 it was shown that after baricitinib treatment of stroke, the activation of pro-inflammatory M1 microglia was inhibited, reducing the inflammatory response in the brain; at the same time, Figure 9 it was shown that after baricitinib treatment of stroke, the activation of anti-inflammatory M2 microglia was promoted, inhibiting the inflammation in the brain after stroke and reducing nerve damage;

[0041] In summary, baricitinib can reduce the inflammatory response in the brain by inhibiting the activation of M1 microglia while promoting the activation of M2 microglia, thereby reducing neurological damage in the brain after stroke and improving the prognosis.

[0042] In the description of this specification, the descriptions of terms such as "one embodiment" and "some embodiments" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or instance. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0043] The above are only the preferred embodiments of the present application and are not used to limit the present application. For those skilled in the art, the present application can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included within the protection scope of the present application.

Claims

1. A use of baricitinib for treating ischemic stroke, characterized in that: Baricitinib is a neuroprotective agent used in the combined treatment of recanalization after large vessel occlusion in ischemic stroke.

2. The use of baricitinib for treating ischemic stroke according to claim 1, characterized in that: The baricitinib acts as a neuroprotectant to inhibit neuroinflammatory response after stroke, reduce the volume of cerebral infarction and brain edema, reduce nerve cell damage, and improve neurological function prognosis.

3. The use of baricitinib for treating ischemic stroke according to any one of claims 1 or 2, characterized in that: Baricitinib is an immunosuppressant that inhibits the infiltration of immune cells into the brain after stroke, reduces neuroinflammatory response, reduces nerve damage, protects nerves, and improves stroke prognosis.

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