Use of txnip inhibitors in the manufacture of a medicament for treating hypoxic brain injury

Abstract

The application discloses application of a TXNIP inhibitor in preparation of a drug for treating hypoxic brain injury and belongs to the technical field of biological medicines. The application discloses the following: the TXNIP inhibitor is used in preparation of a drug for treating hypoxic brain injury. The application discloses, for the first time, the key role of TXNIP in hypoxic brain injury, restores the intracellular oxidation-reduction balance by inhibiting the expression of TXNIP, promotes differentiation of oligodendrocytes and myelination, thereby realizing structural repair and improvement of nerve function on the hypoxic brain injury, and has clear molecular targeting and good clinical transformation application prospect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the application of TXNIP inhibitors in the preparation of drugs for treating hypoxic brain injury. Background Technology

[0002] Hypoxic-ischemic brain injury (HIBE) is a common neurological disorder in newborns, especially premature infants. Its main manifestations include white matter damage, abnormal myelin sheath development, and subsequent cognitive impairment, severely impacting the growth, development, and quality of life of affected children. Current clinical treatments for HIBE are relatively limited, primarily including supportive measures such as oxygen therapy, intracranial pressure control, hypothermia therapy, and rehabilitation training. While these methods can alleviate symptoms or slow disease progression to some extent, they cannot effectively block the hypoxia-induced neurological damage process at the molecular and cellular levels, and there is a lack of specific interventions targeting white matter damage and myelin sheath development disorders.

[0003] Recent studies have shown that oligodendrocyte differentiation disorder and impaired myelination are important pathological features of hypoxic-ischemic brain injury. However, the key molecular regulatory mechanisms of this process are not yet fully understood, and related targeted intervention strategies are still in the exploratory stage, lacking clearly defined and effective molecular targets and corresponding intervention methods. Therefore, identifying key regulatory factors involved in hypoxic injury at the molecular level and developing targeted intervention strategies are critical issues that urgently need to be addressed in this field.

[0004] Existing research on thioredoxin-interacting protein (TXNIP) mainly focuses on diabetes and metabolic-related diseases. Its role in hypoxic injury of the nervous system is still lacking in systematic research, and there are no relevant technical solutions for using it as an intervention target for hypoxic brain injury. Summary of the Invention

[0005] To address the lack of specific molecular intervention methods for hypoxic brain injury in existing technologies, this invention utilizes TXNIP inhibitors in the preparation of drugs for treating hypoxic brain injury, thereby blocking the hypoxia-induced neurological damage process at the molecular level, promoting myelin repair, and improving neurological function.

[0006] To achieve the above objectives, the present invention employs the following technical solution: This invention provides the application of TXNIP inhibitors in the preparation of drugs for treating hypoxic brain injury.

[0007] The above-mentioned approach restores intracellular redox balance by inhibiting TXNIP expression, promotes oligodendrocyte differentiation and myelin formation, thereby achieving structural repair and improvement of neurological function in hypoxic brain injury.

[0008] As one implementation, the TXNIP inhibitor is SRI-37330 or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, the TXNIP inhibitor is SRI-37330 hydrochloride.

[0010] The above-mentioned scheme provides specific inhibitory compounds with clear targeting and good efficacy.

[0011] In one implementation, the hypoxic brain injury is neonatal chronic hypoxic brain injury.

[0012] In one implementation, the neonatal chronic hypoxic-ischemic brain injury is accompanied by white matter damage and abnormal myelin sheath development.

[0013] The above-mentioned treatment plan is designed for specific patient groups and pathological characteristics, and has a more precise therapeutic effect.

[0014] In one implementation method, the drug is administered via nasal feeding.

[0015] As one implementation method, the nasal administration regimen is once daily, with each dose being 50-100 μg / g body weight.

[0016] In addition, the present invention provides a pharmaceutical composition for treating hypoxic-ischemic brain injury, comprising a TXNIP inhibitor and pharmaceutically acceptable excipients.

[0017] Compared with the prior art, the present invention has the following beneficial effects: This invention reveals for the first time the crucial role of TXNIP in neonatal chronic hypoxic-ischemic brain injury, elucidating its mechanism of involvement in oligodendrocyte differentiation arrest and myelination disorders, and revealing the intrinsic link between hypoxia-induced abnormal TXNIP expression and white matter damage. Compared to existing techniques that mainly rely on supportive care, this invention proposes an interventionable target at the molecular level, providing a new technical pathway for the study of the mechanisms of hypoxic-ischemic brain injury and targeted therapy.

[0018] Furthermore, this invention is the first to apply the TXNIP inhibitor SRI-37330 hydrochloride to the field of central nervous system hypoxia injury. Research results show that this drug can effectively inhibit hypoxia-induced TXNIP expression elevation, promote oligodendrocyte maturation and myelin basic protein expression, thereby improving white matter damage and related neurological dysfunction, representing a novel medical use with clear technical efficacy. This invention verified its technical efficacy at multiple levels—molecular, cellular, and overall function—through immunofluorescence, protein expression detection, and various behavioral experiments. The results indicate that the TXNIP inhibitor SRI-37330 hydrochloride not only promotes oligodendrocyte differentiation and myelin formation in brain tissue, achieving structural repair, but also significantly improves cognitive function, spatial memory, and social behavior.

[0019] Furthermore, this invention verifies the effect of nasogastric administration, which has advantages such as simple operation, good feasibility, minimal damage, and repeatable administration, and has good prospects for clinical translation and application. Attached Figure Description

[0020] Figure 1 This diagram illustrates stereotactic injection and nasogastric administration of drugs to the brain of model mice. In diagram A, two-day-old C57 mice and their mothers underwent hypoxia treatment for eight consecutive days (P2-P9). In diagram B, mice injected with the nuclear dye DAPI were used as controls, and the results indicate the drug injection area. In diagram C, newborn mice underwent hypoxia treatment according to the same procedure, and after modeling, the model mice were administered drugs via nasogastric administration starting at P10, continuing until the day before tissue sampling (P15 / P20). In diagram D, mice administered the nuclear dye DAPI via nasogastric administration were used as controls; tissue samples were taken at P16, and extensive distribution of the drug was observed in the forebrain and hindbrain under a fluorescence microscope.

[0021] Figure 2 The images show the results of SOX10, CC1, and MBP immunofluorescence staining in mice with a stereotactic injection of SRI into the brain. A shows a typical immunofluorescence staining image of SOX10 and CC1 in the corpus callosum (cc) region of P16 mice; B shows the CC1 staining in the cc region of the mice. + Mature oligodendrocytes account for 10% of SOX10 + Statistical results of cell proportions; C shows typical immunofluorescence staining patterns of MBP in the cortical region (CTX) and cc region of P16 mice; D shows statistical results of immunofluorescence staining intensity of MBP in the CTX and cc regions of P16 mice. ***P<0.001, ****P<0.0001.

[0022] Figure 3Immunofluorescence quantitative analysis was used to assess oligodendrocyte differentiation in P16 mice using three nasogastric feeding regimens. Image A shows typical immunofluorescence staining patterns of SOX10 and CC1 in the cc and CTX regions of P16 mice; image B shows CC1 in the cc and CTX regions of P16 mice. + Mature oligodendrocytes account for 10% of SOX10 + Cell proportion statistics. ***P<0.0001.

[0023] Figure 4 Results of immunofluorescence staining of MBP and detection of related protein expression in brain tissue of nasogastric-fed SRI model mice; where A is a typical immunofluorescence staining image of MBP in the CTX region of P21 mice; B is the statistical result of MBP immunofluorescence staining intensity; C is a typical image of Western blot results of HIF-1α, TXNIP, MBP, and Tublin in cortical tissue protein samples from three groups of P16 mice; D is the quantitative statistical result of the relative expression levels of HIF-1α, TXNIP, and MBP in P16 mice; E is a typical image of Western blot results of HIF-1α, TXNIP, MBP, and Tublin in cortical tissue protein samples from three groups of P21 mice; F is the quantitative statistical result of the relative expression levels of HIF-1α, TXNIP, and MBP in P21 mice. *P<0.05, ***P<0.001, ****P<0.0001.

[0024] Figure 5 To evaluate mouse behavior in open field, new location, and new object experiments; A shows typical movement trajectories of normoxic, hypoxic, and nasogastric-fed SRI mice during 10 minutes of spontaneous movement in an open field; B shows the total movement distance, distance moved in the central area of ​​the open field, and percentage of movement time for the three groups of mice; C shows the contact time and number of times the mice encountered objects in different locations; D shows the contact time and number of times the mice encountered new objects. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0025] Figure 6 This study evaluated the social motivation and social recognition abilities of mice in a three-box socialization experiment. Figure A shows typical activity heatmaps of normoxic mice, hypoxic mice, and hypoxic mice fed with nasogastric irrigated (SRI) in the first (top) and second (bottom) phases of the experiment. The bottom left corner shows the location of the social mouse at position S1, and the top right corner shows the location of the mouse at position S2 (in the empty cage, phase 1) or position S2 (in the social mouse, phase 2). Figure B shows the statistical analysis of the social preference index for the three groups of mice in phases 1 and 2. *P<0.05, ***P<0.001, ****P<0.0001.

[0026] Figure 7The purpose of this study was to assess the spatial learning and memory abilities of mice using the water maze test. Figure A shows typical trajectories of normoxic, hypoxic, and SRI-fed hypoxic mice during the water maze test phase. Figure B shows the statistical results of the time taken for the three groups of mice to find the platform during the training phase. Figure C shows the statistical graph of the number of times the three groups of mice traversed the quadrant containing the platform during the test phase. Figure D shows the statistical graph of the time taken for the three groups of mice to find the platform during the test phase. **P<0.01, ****P<0.001. Detailed Implementation

[0027] To enable those skilled in the art to better understand the present invention, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments. 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 skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0028] It should be noted that the terms "first," "second," etc., in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. Furthermore, the terms "comprising" and "having," and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0029] The present invention will now be described in further detail with reference to the accompanying drawings: The SRI-37330 hydrochloride used in the following embodiments of the present invention is an orally effective and selective small molecule inhibitor of TXNIP, with the molecular formula: C 16 H 20 ClF3N4O2S (hydrochloride), purchased from MedChemExpress. Example 1: Construction of a hypoxic mouse model and establishment of the administration method.

[0030] A chronic hypoxia model was established in newborn C57 mice by subjecting them to hypoxia for eight consecutive days (P2-P9) under normobaric hypoxia (10% O2) conditions. SRIs were administered to the model mice after the hypoxia treatment ended.

[0031] 1. Stereoscopic injection administration: Two-day-old C57 mice were subjected to hypoxia treatment for 8 consecutive days (P2-P9) along with their mothers, with an O2 concentration of 10%. After model establishment, stereotactic injection administration was performed on the tenth day of age (P10). The injection site was the cerebral cortex, and the dosage was 200 nmol per injection. The SRI dose was 20 μg. Samples were collected on P16 (see [link to relevant documentation]). Figure 1 (A). The nuclear dye DAPI is used to indicate the site of drug injection (see [reference]). Figure 1 (B)

[0032] 2. Multiple nasal feedings: Treat the offspring mice according to three protocols, as follows: Option 1: Administer SRI once daily via nasogastric tube, at a dose of 100 μg / g body weight each time; Option 2: One daily nasogastric feeding of 50 μg / g body weight SRI; Option 3: Administer via nasogastric tube once every other day, with a SRI dose of 100 μg / g body weight each time.

[0033] After the modeling process was completed, the model mice began nasal administration of drugs at P10. Figure 1 (C)

[0034] During nasal feeding, the animal was held still with one hand, and a 10 μL pipette was used to drip the medication into the animal's nasal cavity. After dripping, the mouse's head was held upwards for 30-60 seconds to prevent the medication from flowing out. Oligodendrocyte differentiation was compared at P16 for the three treatment regimens, and myelin protein expression was observed at P21 for the effective regimen. From administration to the day before sampling, the distribution of the drug after nasal feeding was indicated by the nuclear dye DAPI. Figure 1 The samples taken from P16 showed extensive distribution in the forebrain and hindbrain under a fluorescence microscope, indicating that the nasally administered drug could effectively reach the brain lesion area, providing a material basis for the subsequent drug efficacy.

[0035] Example 2: Analysis and evaluation of the morphological rescue effect of different SRI administration routes on myelin development in hypoxic mice. Immunofluorescence staining and Western blotting were used to observe the results in model mice at P16 or P21 after drug administration.

[0036] 1. Immunofluorescence staining was used to identify the expression of oligodendrocyte marker SOX10, mature oligodendrocyte marker CC1, and myelin protein MBP. 1) Results of stereotactic injection model mice Morphological studies were conducted on mice using a stereotactic injection model at P16. Compared to normoxic littermate control mice, the CC1 region of the corpus callosum (cc) in hypoxic mice injected with saline showed increased activity. +The proportion of cells was significantly reduced; while in hypoxic mice injected with SRI, CC1 + The proportion of cells was significantly higher than that in the saline group (see [link]). Figure 2 (A and B). Immunofluorescence staining results showed that, compared with the normooxygen control group, the CC1 concentration in the corpus callosum region of hypoxic model mice injected with physiological saline was significantly higher. + The proportion of mature oligodendrocytes among SOX10+ cells was significantly reduced, indicating that hypoxia inhibited oligodendrocyte differentiation and maturation. In contrast, hypoxic mice injected with SRI-37330 hydrochloride showed a significantly reduced CC1... + The proportion of cells was significantly higher than that in the saline group and approached normal levels. This result indicates that SRI-37330 hydrochloride can effectively rescue oligodendrocyte differentiation disorder caused by hypoxia.

[0037] Simultaneously, immunofluorescence staining using myelin basic protein MBP also revealed that the fluorescence intensity of MBP in hypoxic mice injected with saline in the cortex (CTX) and cc region was significantly lower than that in normal mice, while the fluorescence intensity of MBP in hypoxic mice injected with SRI was enhanced compared to the saline group, and there was no significant difference between them and normoxic control mice (see [link to study]). Figure 2 Staining results of myelin basic protein MBP in mice injected with SRI-37330 hydrochloride showed that the fluorescence intensity of MBP in the CTX and cc regions of hypoxic saline mice was significantly lower than that of the normal control group, indicating impaired myelin formation. However, the fluorescence intensity of MBP in hypoxic mice injected with SRI-37330 hydrochloride was significantly enhanced compared to the saline group, with no significant difference from the normal control group. This indicates that SRI-37330 hydrochloride can promote the expression of myelin proteins and repair myelin damage.

[0038] 2) Results of the nasogastric feeding model mice For mouse models administered the drug via nasogastric tube, the differentiation and maturation of oligodendrocytes at P16 were first compared among three nasogastric tube feeding regimens. Immunohistofluorescence staining showed that in the white matter region represented by CC and the gray matter region represented by CTX, the strategy of "once a day, 100 μg / g body weight" after hypoxia, i.e., continuous 100 μg regimen one, could stably and significantly promote the oligodendrocyte differentiation process that was inhibited after hypoxia injury, i.e., CC1. + Percentage of mature oligodendrocytes.

[0039] See results Figure 3 CC1 in mice in the hypoxic saline control group + The significantly reduced cell proportion indicates impaired oligodendrocyte differentiation. In the treatment groups, both regimen 1 (100 μg / g daily) and regimen 2 (50 μg / g daily) significantly increased CC1 levels. +The cell ratio was significantly improved, with regimen one showing better efficacy than regimen two. In contrast, while regimen three (100 μg / g every other day) also showed some improvement, its effect was not as significant as the daily dosing group. This result indicates that within the dosage range of 50-100 μg / g, SRI-37330 hydrochloride can effectively promote oligodendrocyte differentiation, and daily dosing is more effective than every other day dosing. Considering both efficacy and drug safety, once-daily dosing at 50-100 μg / g body weight is the preferred dosing regimen, with once-daily dosing at 100 μg / g body weight being the optimal regimen.

[0040] Subsequently, using the aforementioned protocol one (daily nasal feeding at a dose of 100 μg / g body weight), immunofluorescence staining of myelin basic protein (MBP) was performed on the brain tissue of P21 mice. The results showed that the MBP fluorescence intensity in P21 hypoxic mice fed with saline via nasal feeding was significantly lower than that in normal mice; while the fluorescence intensity in hypoxic mice fed with SRI via nasal feeding was increased compared to the saline group, and there was no difference between them and normoxic mice. Figure 4 (AB).

[0041] 2. Western blot analysis to identify the expression of relevant proteins in the brain tissue of nasally fed SRI model mice. After intranasal administration to mice at days P16 / 21, brain tissue was rapidly extracted after anesthesia and perfusion with PBS. Cortical tissue was dissected, minced into small pieces, and prepared with protein lysis buffer. Western blot analysis revealed that, using Tublin as the internal control protein, hypoxia significantly increased TXNIP levels in both age groups of mice, accompanied by a significant decrease in MBP levels. Conversely, intranasal administration of SRIs after hypoxia inhibited TXNIP levels, while simultaneously significantly increasing MBP levels. Figure 4 (CF), this result is consistent with the above histological staining.

[0042] The results suggest that both a single stereotactic injection (SRI) into the brain and multiple nasogastric feeding (SRI) regimens following hypoxia can promote oligodendrocyte development and myelination in the brains of hypoxic mice in the short term (P16). The stereotactic injection SRI regimen was not tested in older mice (P21) primarily due to considerations for future application expansion. Nasogastric feeding is less harmful to animals and more conducive to clinical translation; therefore, future behavioral studies will focus solely on the nasogastric feeding SRI regimen.

[0043] Example 3: Rescue effect of nasogastric feeding SRI on abnormal behavior in hypoxic mice Previous studies have shown that chronic hypoxia in newborn mice leads to anxiety and cognitive impairment. Therefore, this study further evaluated the rescue effect of nasogastric saline administration (SRI) on related behaviors after hypoxia. In the open field test, there was no significant difference in the total distance traveled by normoxic mice, hypoxic mice (nasogastric saline), and hypoxic mice receiving SRI. The percentage of distance traveled and time spent in the central area of ​​the open field was significantly reduced in hypoxic mice (nasogastric saline), while the distance traveled and time spent in the central area of ​​the open field were significantly greater in hypoxic mice than in normoxic mice, and there was no significant difference between them and normoxic mice. Figure 5 (AB). There was no significant difference in the total movement distance among the three groups of mice, ruling out the possibility that the drug affected the mice's spontaneous activity. This result indicates that TXNIP inhibitors can effectively alleviate anxiety caused by hypoxic-ischemic brain injury and restore the mice's exploratory desire.

[0044] The results of the novel location recognition experiment showed that, compared with normoxic mice, hypoxic mice (nasally fed saline) had significantly reduced contact time and contact frequency index for objects whose locations were changed, while hypoxic mice fed SRIs (short-injected saline) had significantly more contact time and contact frequency index for objects whose locations were changed than hypoxic mice, and there was no significant difference between them and normoxic mice. Figure 5 Similarly, hypoxic mice fed with nasal-administered SRIs also showed greater interest in novel stimuli, with significantly higher exposure time and frequency indices compared to hypoxic mice. Figure 5 (D). In the novel location recognition experiment, normoxic control group mice showed a clear preference for objects whose locations were changed, with higher contact time and contact frequency indices, indicating normal spatial recognition memory ability. Hypoxic model group mice showed significantly reduced contact time and contact frequency indices for objects whose locations were changed, indicating impaired spatial memory. Hypoxic mice treated with SRI-37330 hydrochloride showed a significant recovery in contact time and contact frequency indices for new locations, approaching the levels of the normoxic control group. Similarly, in the novel object recognition experiment, the contact time and contact frequency indices for new objects in the SRI-37330 hydrochloride treatment group were significantly higher than those in the hypoxic model group. This indicates that TXNIP inhibitors can significantly improve learning, memory, and object recognition dysfunction caused by hypoxic brain injury.

[0045] In the three-box social experiment, hypoxic mice did not show more interaction with social mouse S1 in the first stage; compared with normoxic mice, their social preference index was significantly lower, indicating that hypoxia caused abnormal social ability in mice. However, the social preference index of hypoxic mice fed with nasogastric SRI was significantly higher, and there was no significant difference compared with normal mice. Similarly, in the second stage of the social novelty test, hypoxic mice still did not show more interaction with social mouse S2, indicating abnormal social recognition ability; while the social preference index of hypoxic mice fed with nasogastric SRI to S2 mice was significantly higher, indicating normal social recognition ability (results are shown in Figure 1). Figure 6 (As shown). Mice in the hypoxia model group showed a decreased preference index for S2, indicating impaired social recognition ability. Mice in the SRI-37330 hydrochloride treatment group showed a significant recovery in their preference index for S2. This result demonstrates that TXNIP inhibitors can effectively rescue hypoxia-induced social behavioral impairments and restore social motivation and social recognition ability in mice.

[0046] The effects of hypoxia and intranasal feeding with SRI on spatial memory in mice were investigated using the water maze test. During the learning phase, all three groups of mice showed some learning ability, with a reduction in platform search time compared to the previous day. However, during the learning process, the platform search time was significantly longer for both hypoxic mice and mice receiving hypoxic intranasal feeding with SRI compared to normoxic mice each day, indicating that intranasal feeding with SRI cannot completely restore the learning impairment caused by hypoxia. On the sixth day of the test, hypoxic mice traversed the target quadrant significantly fewer times than normal mice, and their time to reach the platform for the first time was significantly longer than that of normal mice. Hypoxic mice receiving intranasal feeding with SRI showed significantly more traversals of the target quadrant than hypoxic mice, with no significant difference compared to normal mice; moreover, the time to reach the platform for the first time was significantly shorter for hypoxic mice than for hypoxic mice, with no significant difference compared to normal mice (see results). Figure 7 ).

[0047] Specifically, such as Figure 7 China A and Figure 7 As shown in Figure B, during the training phase, the latency of all three groups of mice in finding the hidden platform gradually shortened with increasing training days, indicating that the mice all possessed a certain learning ability. However, throughout the training process, the latency of the hypoxia model group was consistently longer than that of the normoxic control group, while the latency of the SRI-37330 hydrochloride treatment group, although slightly longer than that of the normoxic control group, was significantly shorter than that of the hypoxia model group. During the testing phase (after platform removal), as... Figure 7 C and Figure 7As shown in Figure D, mice in the normoxic control group crossed the target quadrant more times and reached the platform position more quickly. Mice in the hypoxic model group crossed the target quadrant more times and reached the platform position more quickly. Mice in the SRI-37330 hydrochloride treatment group crossed the target quadrant more times than the hypoxic model group, and reached the platform position more quickly, with no significant difference from the normoxic control group. This result confirms that TXNIP inhibitors can significantly improve the decline in spatial learning and memory abilities caused by hypoxic brain injury. These results indicate that nasogastric administration of SRIs can salvage cognitive and spatial memory abilities in hypoxic mice.

[0048] In summary, the technical solution of this invention mainly proposes the application of the TXNIP inhibitor SRI-37330 hydrochloride in the treatment of hypoxic-ischemic brain injury. In animal models, this drug, by inhibiting TXNIP expression and promoting oligodendrocyte differentiation and myelin formation, can effectively improve neurological dysfunction caused by hypoxia. These results provide a novel strategy for the treatment of neonatal hypoxic-ischemic brain injury. Specifically: This invention is the first to propose the application of the TXNIP inhibitor SRI-37330 hydrochloride in hypoxic-ischemic brain injury of the nervous system, especially for neonatal hypoxic-ischemic brain injury. This drug can: (1) inhibit TXNIP expression; (2) promote the differentiation of oligodendrocyte precursor cells; (3) promote myelin formation and repair; and (4) improve cognitive function and memory. Existing treatment methods mainly focus on supportive care in the acute phase, such as oxygen therapy, intracranial pressure control, and hypothermia therapy, which cannot directly regulate hypoxia-induced damage at the molecular level. Therefore, this invention provides an innovative molecular intervention strategy by targeting TXNIP, filling a gap in existing treatment methods.

[0049] This invention demonstrates for the first time that the TXNIP inhibitor SRI-37330 hydrochloride, administered via nasogastric tube, holds promise for the treatment of neonatal chronic hypoxic-ischemic brain injury, as well as other types of hypoxic-induced brain injury (such as stroke and ischemic brain injury). Furthermore, TXNIP, as a newly discovered target promoting myelin formation, may also provide new theoretical basis and technical pathways for research into the treatment of other myelin-related diseases, such as Alzheimer's disease and autism.

[0050] In summary, this invention provides a solid experimental foundation for further preclinical and clinical research and is expected to play an important role in the treatment of hypoxic-ischemic brain injury in newborns.

[0051] The above content is only for illustrating the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of the claims of this invention.

Claims

1. Application of TXNIP inhibitors in the preparation of drugs for treating hypoxic brain injury.

2. The application according to claim 1, characterized in that, The TXNIP inhibitor is SRI-37330 or a pharmaceutically acceptable salt thereof.

3. The application according to claim 2, characterized in that, The TXNIP inhibitor is SRI-37330 hydrochloride.

4. The application according to claim 1, characterized in that, The drug described is capable of improving white matter damage and related neurological dysfunction.

5. The application according to claim 4, characterized in that, The drug described above can inhibit hypoxia-induced increase in TXNIP expression.

6. The application according to claim 4, characterized in that, The drug is used to promote the maturation of oligodendrocytes and the expression of myelin basic protein.

7. The application according to claim 1, characterized in that, The drug is used to treat chronic hypoxic-ischemic brain injury in newborns.

8. The application according to claim 1, characterized in that, The drug is administered via nasogastric tube.

9. The application according to claim 8, characterized in that, Administer via nasal route once daily, with a dose of 50-100 μg / g body weight per dose.

10. A pharmaceutical composition for treating hypoxic-ischemic brain injury, characterized in that, It contains the TXNIP inhibitor SRI-37330 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

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