WO2023184986A1 - Use of cd36 inhibitor in preparing medicament for inhibiting scarring after spinal cord injury - Google Patents

Use of cd36 inhibitor in preparing medicament for inhibiting scarring after spinal cord injury Download PDF

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WO2023184986A1
WO2023184986A1 PCT/CN2022/131056 CN2022131056W WO2023184986A1 WO 2023184986 A1 WO2023184986 A1 WO 2023184986A1 CN 2022131056 W CN2022131056 W CN 2022131056W WO 2023184986 A1 WO2023184986 A1 WO 2023184986A1
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spinal cord
inhibitor
injury
salvianolic acid
cord injury
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周松林
龚蕾蕾
顾芸
栾成成
陈子馨
孙华林
于彬
曹倩倩
王东
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南通大学
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  • the present invention relates to the field of biomedicine technology, and in particular to the application of CD36 inhibitors in the preparation of drugs for inhibiting scar formation after spinal cord injury.
  • the purpose of the present invention is to solve the technical problem in the prior art that there is no clinically effective drug for inhibiting the formation of glial scars.
  • CD36 inhibitors as drugs to repair nerve damage.
  • the CD36 inhibitor includes salvianolic acid B.
  • the salvianolic acid B is used to inhibit the formation of fibrous scars by fibroblasts in the spinal cord injury area.
  • the salvianolic acid B is used to promote astrocytes in the spinal cord injury area to pass through the fibrous scar area.
  • the salvianolic acid B is used to promote vascular regeneration in the spinal cord injury area.
  • This application also provides a nerve damage repair drug, including a CD36 inhibitor.
  • the CD36 inhibitor includes salvianolic acid B.
  • the present invention uses the spinal cord T10 hemisection model to intraperitoneally inject 100 microliters of three doses of the CD36 inhibitor salvianolic acid B (50, 100 and 200 ⁇ g/ml). After 8 weeks, it is found that the fibrous scar formed by the accumulation of fibroblasts in the injured area can be significantly inhibited. , at the same time, it also promotes the regeneration of local blood vessels after injury. This helps to better understand the important role of plant extracts in the repair process of nerve injury and provides new targets for treatment after nerve injury.
  • Figure 1 is used to demonstrate the high expression of CD36 in fibroblasts in the scar area after spinal cord injury in this example.
  • Figure 2 shows that the CD36 inhibitor salvianolic acid B in Example 1 inhibits the formation of fibrous scars by fibroblasts in the spinal cord injury area.
  • Figure 3 shows that the CD36 inhibitor salvianolic acid B described in Example 2 promotes astrocytes in the spinal cord injury area to pass through the fibrous scar area.
  • Figure 4 shows that the CD36 inhibitor salvianolic acid B described in Example 3 promotes vascular regeneration in the spinal cord injury area. .
  • CD36 inhibitors in drugs for repairing nerve damage, wherein the CD36 inhibitors include salvianolic acid B, specifically:
  • the salvianolic acid B is used to inhibit the formation of fibrous scars by fibroblasts in the spinal cord injury area;
  • the salvianolic acid B is used to promote astrocytes in the spinal cord injury area to pass through the fibrous scar area;
  • the salvianolic acid B is used to promote vascular regeneration in spinal cord injury areas.
  • the present application also provides a nerve damage repair drug, including a CD36 inhibitor, and the CD36 inhibitor includes salvianolic acid B.
  • CD36 is highly expressed in fibroblasts in the scar area after spinal cord injury.
  • Example 1 CD36 inhibitor salvianolic acid B inhibits the formation of fibrous scars by fibroblasts in the spinal cord injury area.
  • iridotome BVI Beaver, Oakville, Canada
  • CD36 inhibitor salvianolic acid B 50, 100 and 200 ⁇ g/ml 100 ⁇ l and control PBS 100 ⁇ l were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
  • Dilute the primary antibody anti-P4HB antibody (abcam, Mouse 1:100) with immunohistochemistry primary antibody diluent, add the primary antibody, and incubate at 4°C overnight. Discard the primary antibody and wash 3 times with PBS, 5 minutes each time.
  • Example 2 The CD36 inhibitor salvianolic acid B promotes astrocytes in the spinal cord injury area to pass through the fibrous scar area.
  • iridotome BVI Beaver, Oakville, Canada
  • CD36 inhibitor salvianolic acid B 50, 100 and 200 ⁇ g/ml 100 ⁇ l and control PBS 100 ⁇ l were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
  • Dilute the primary antibody anti-GFAP antibody (abcam, Chicken 1:100) with immunohistochemistry primary antibody diluent, add the primary antibody, and incubate at 4°C overnight. Discard the primary antibody and wash 3 times with PBS, 5 minutes each time.
  • Example 3 CD36 inhibitor salvianolic acid B promotes vascular regeneration in spinal cord injury areas.
  • iridotome BVI Beaver, Oakville, Canada
  • CD36 inhibitor salvianolic acid B 50, 100 and 200 ⁇ g/ml 100 ⁇ l and control PBS 100 ⁇ l were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
  • This study uses salvianolic acid B, a CD36 inhibitor that can pass through the blood-brain barrier, as a drug to inhibit the formation of local glial scars after central spinal cord injury and at the same time promote vascular regeneration.
  • the present invention uses the spinal cord T10 hemisection model to intraperitoneally inject 100 microliters of three doses of the CD36 inhibitor salvianolic acid B (50, 100 and 200 ⁇ g/ml). After 8 weeks, it is found that the fibrous scar formed by the accumulation of fibroblasts in the injured area can be significantly inhibited. , at the same time, it also promotes the regeneration of local blood vessels after injury. This helps to better understand the important role of plant extracts in the repair process of nerve injury and provides new targets for treatment after nerve injury.

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Abstract

The present invention provides use of a CD36 inhibitor in preparing a medicament for inhibiting scarring after spinal cord injury. The present invention relates to the field of biotechnology, and particularly to use of a CD36 inhibitor in a medicament for repairing nerve injury. According to the present invention, in a spinal cord T10 semi-transection model, CD36 inhibitor salvianolic acid B was intraperitoneally administered at 100 mL at three doses (50, 100, and 200 μg/mL). After 8 weeks, significantly inhibited fibrotic scarring induced by the local aggregation of fibroblasts around the injury was observed, as well as promoted local vascular regeneration at the injury. The present invention helps understand the importance of the plant extract in the nerve injury repair process, and provides a new target for treatment after nerve injury.

Description

CD36抑制剂在制备抑制脊髓损伤后疤痕形成药物中的应用Application of CD36 inhibitors in the preparation of drugs to inhibit scar formation after spinal cord injury 技术领域Technical field
本发明涉及生物医药技术领域，尤其涉及CD36抑制剂在制备抑制脊髓损伤后疤痕形成药物中的应用。The present invention relates to the field of biomedicine technology, and in particular to the application of CD36 inhibitors in the preparation of drugs for inhibiting scar formation after spinal cord injury.
背景技术Background technique
中枢神经损伤修复是临床上常见难题，给社会及家庭造成极大的负担。中枢神经受损后难以再生，主要原因是因为损伤局部由成纤维细胞、星型胶质细胞和小胶质细胞等细胞形成疤痕，阻碍了再生的神经轴突穿过损伤区域。因此，充分探讨中枢神经损伤疤痕形成的分子机制，有助于找到抑制疤痕形成的靶点，为临床治疗提供理论基础。另外，由于血脑屏障的存在，药物很难到达疤痕区域，目前临床上尚无有效抑制脊髓损伤后胶质疤痕形成的药物。Repair of central nervous system damage is a common clinical problem, which places a huge burden on society and families. It is difficult to regenerate the central nervous system after damage. The main reason is that scars are formed in the damaged area by cells such as fibroblasts, astrocytes, and microglia, which prevent regenerated nerve axons from passing through the damaged area. Therefore, fully exploring the molecular mechanism of scar formation in central nervous system injury will help find targets to inhibit scar formation and provide a theoretical basis for clinical treatment. In addition, due to the existence of the blood-brain barrier, it is difficult for drugs to reach the scar area. Currently, there is no clinically effective drug to inhibit glial scar formation after spinal cord injury.
发明内容Contents of the invention
本发明的目的是为了解决现有技术中临床上尚无有效抑制胶质疤痕形成的药物的技术问题。The purpose of the present invention is to solve the technical problem in the prior art that there is no clinically effective drug for inhibiting the formation of glial scars.
为了实现上述目的，本发明采用了如下技术方案：In order to achieve the above objects, the present invention adopts the following technical solutions:
CD36抑制剂在修复神经损伤药物中的应用。The application of CD36 inhibitors as drugs to repair nerve damage.
优选的，所述CD36抑制剂包括丹酚酸B。Preferably, the CD36 inhibitor includes salvianolic acid B.
优选的，所述丹酚酸B用于抑制脊髓损伤区成纤维细胞形成纤维疤痕。Preferably, the salvianolic acid B is used to inhibit the formation of fibrous scars by fibroblasts in the spinal cord injury area.
优选的，所述丹酚酸B用于促进脊髓损伤区星型胶质细胞穿过纤维疤痕区。Preferably, the salvianolic acid B is used to promote astrocytes in the spinal cord injury area to pass through the fibrous scar area.
优选的，所述丹酚酸B用于促进脊髓损伤区的血管再生。Preferably, the salvianolic acid B is used to promote vascular regeneration in the spinal cord injury area.
本申请还提供了一种神经损伤修复药物，包含CD36抑制剂。This application also provides a nerve damage repair drug, including a CD36 inhibitor.
优选的，所述CD36抑制剂包括丹酚酸B。Preferably, the CD36 inhibitor includes salvianolic acid B.
本发明利用脊髓T10半切模型，经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升，8周后，发现可以显著抑制损伤局部成纤维细胞聚集形成的纤维疤痕，同时，也促进损伤局部血管再生。这有助于更好地理解植物提取物在神经损伤修复过程中的重要作用，并为神经损伤后的治疗提供新的靶点。The present invention uses the spinal cord T10 hemisection model to intraperitoneally inject 100 microliters of three doses of the CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml). After 8 weeks, it is found that the fibrous scar formed by the accumulation of fibroblasts in the injured area can be significantly inhibited. , at the same time, it also promotes the regeneration of local blood vessels after injury. This helps to better understand the important role of plant extracts in the repair process of nerve injury and provides new targets for treatment after nerve injury.
附图说明Description of drawings
图1为用于展示本实施例中脊髓损伤后CD36在疤痕区成纤维细胞中高表达。Figure 1 is used to demonstrate the high expression of CD36 in fibroblasts in the scar area after spinal cord injury in this example.
图2为本实施例一所述CD36抑制剂丹酚酸B抑制脊髓损伤区成纤维细胞形成纤维疤痕。Figure 2 shows that the CD36 inhibitor salvianolic acid B in Example 1 inhibits the formation of fibrous scars by fibroblasts in the spinal cord injury area.
图3为本实施例二所述CD36抑制剂丹酚酸B促进脊髓损伤区星型胶质细胞穿过纤维疤痕区。Figure 3 shows that the CD36 inhibitor salvianolic acid B described in Example 2 promotes astrocytes in the spinal cord injury area to pass through the fibrous scar area.
图4为本实施例三所述CD36抑制剂丹酚酸B促进脊髓损伤区血管再生。。Figure 4 shows that the CD36 inhibitor salvianolic acid B described in Example 3 promotes vascular regeneration in the spinal cord injury area. .
具体实施方式Detailed ways
为使本发明的目的、技术方案和优点更加清楚，以下结合具体实施例，对本发明作进一步地详细说明。In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to specific embodiments.
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是，本发明还可以采用不同于在此描述的其他方式来实施，因此，本发明并不限于下面 公开说明书的具体实施例的限制。Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described here. Therefore, the present invention is not limited to the specific embodiments disclosed below. limit.
本申请提供了CD36抑制剂在修复神经损伤药物中的应用，其中所述CD36抑制剂包括丹酚酸B，具体的：This application provides the application of CD36 inhibitors in drugs for repairing nerve damage, wherein the CD36 inhibitors include salvianolic acid B, specifically:
所述丹酚酸B用于抑制脊髓损伤区成纤维细胞形成纤维疤痕；The salvianolic acid B is used to inhibit the formation of fibrous scars by fibroblasts in the spinal cord injury area;
所述丹酚酸B用于促进脊髓损伤区星型胶质细胞穿过纤维疤痕区；The salvianolic acid B is used to promote astrocytes in the spinal cord injury area to pass through the fibrous scar area;
所述丹酚酸B用于促进脊髓损伤区的血管再生。The salvianolic acid B is used to promote vascular regeneration in spinal cord injury areas.
本申请还提供了一种神经损伤修复药物，包含CD36抑制剂，所述CD36抑制剂包括丹酚酸B。The present application also provides a nerve damage repair drug, including a CD36 inhibitor, and the CD36 inhibitor includes salvianolic acid B.
实施例：脊髓损伤后CD36在疤痕区成纤维细胞中高表达。Example: CD36 is highly expressed in fibroblasts in the scar area after spinal cord injury.
一、成年小鼠脊髓T10右侧半切模型1. Adult mouse spinal cord T10 right hemisection model
24只8周龄雌性C57BL/6J小鼠随机分成四组(n＝10)，麻醉后，沿胸椎正中线切开皮肤，行T10椎板切除术，使用虹膜刀(BVI Beaver,Oakville,Canada)刀尖小心插入脊髓后正中沟，完全切断右侧脊髓。缝合肌肉层，然后用伤口夹固定皮肤。放置在37℃下复苏，直至完全清醒，并用止疼针缓解疼痛。所有动物实验均按照动物护理指南进行，并经江苏省实验动物管理委员会伦理认可，动物实验许可证为20150304-004。Twenty-four 8-week-old female C57BL/6J mice were randomly divided into four groups (n=10). After anesthesia, the skin was incised along the midline of the thoracic spine, and T10 laminectomy was performed using an iridotome (BVI Beaver, Oakville, Canada). The tip of the knife was carefully inserted into the posterior median sulcus of the spinal cord, and the right spinal cord was completely severed. The muscle layer is sutured, and the skin is secured with wound clips. Place at 37°C for resuscitation until fully awake, and use analgesic needles to relieve pain. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
二、脊髓疤痕组织的空间转录组测序2. Spatial transcriptome sequencing of spinal cord scar tissue
分别于脊髓损伤后3天(n＝8)，7天(n＝7)，14天(n＝6)和28天(n＝6)以及正常对照组(n＝5)，取包含T10损伤位点的一段3mm长脊髓组织(距离T10损伤位点上下各1.5mm)，进行接近单细胞水平的10×Visium空间转录组测序。经生物信息学分析，鉴定出参与形成胶质疤痕的成纤维细胞三个亚群，请参阅图1，进一步分析发现CD36特异性在2型成纤维细胞中高表达(图A)。 空间映射图也证实正常脊髓中CD36低表达。损伤后，CD36特异性在疤痕区高表达(图B)。3 days (n=8), 7 days (n=7), 14 days (n=6) and 28 days (n=6) after spinal cord injury and normal control group (n=5), including T10 injury A 3 mm long section of spinal cord tissue at the site (1.5 mm above and below the T10 injury site) was subjected to 10×Visium spatial transcriptome sequencing close to the single cell level. After bioinformatics analysis, three subpopulations of fibroblasts involved in the formation of glial scars were identified, see Figure 1. Further analysis found that CD36 was specifically highly expressed in type 2 fibroblasts (Figure A). Spatial mapping also confirmed the low expression of CD36 in normal spinal cord. After injury, CD36 is highly expressed specifically in the scar area (Figure B).
以下根据具体实施例对本申请进行阐述。The present application is described below based on specific embodiments.
实施例1：CD36抑制剂丹酚酸B抑制脊髓损伤区成纤维细胞形成纤维疤痕。Example 1: CD36 inhibitor salvianolic acid B inhibits the formation of fibrous scars by fibroblasts in the spinal cord injury area.
一、成年小鼠脊髓T10右侧半切模型1. Adult mouse spinal cord T10 right hemisection model
24只8周龄雌性C57BL/6J小鼠随机分成四组(n＝6)，麻醉后，沿胸椎正中线切开皮肤，行T10椎板切除术，使用虹膜刀(BVI Beaver,Oakville,Canada)刀尖小心插入脊髓后正中沟，完全切断右侧脊髓。缝合肌肉层，然后用伤口夹固定皮肤。放置在37℃下复苏，直至完全清醒，并用止疼针缓解疼痛。每天经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升。所有动物实验均按照动物护理指南进行，并经江苏省实验动物管理委员会伦理认可，动物实验许可证为20150304-004。Twenty-four 8-week-old female C57BL/6J mice were randomly divided into four groups (n=6). After anesthesia, the skin was incised along the midline of the thoracic spine, and T10 laminectomy was performed using an iridotome (BVI Beaver, Oakville, Canada). The tip of the knife was carefully inserted into the posterior median sulcus of the spinal cord, and the right spinal cord was completely severed. The muscle layer is sutured, and the skin is secured with wound clips. Place at 37°C for resuscitation until fully awake, and use analgesic needles to relieve pain. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
二、脊髓组织免疫荧光染色及纤维疤痕面积测量2. Immunofluorescence staining of spinal cord tissue and measurement of fibrous scar area
8周后，4％多聚甲醛灌注。再经4％多聚甲醛后固定12小时。弃掉多聚甲醛后，PBS洗三遍，每遍10min。剥离椎板，暴露脊髓，尽量保持脊髓完整性。取出的脊髓组织，收集损伤位点前后1.5mm距离的脊髓，经30％蔗糖脱水后，OCT包埋，冰冻切片厚度为10μm。加入免疫组化封闭液，室温封闭1h。用免疫组化一抗稀释液稀释一抗anti-P4HB antibody(abcam,Mouse 1:100)，加好一抗后，4℃过夜。弃掉一抗，PBS洗3遍，每遍5min。用免疫组化二抗稀释液稀释荧光二抗Alexa
Figure PCTCN2022131056-appb-000001
555 AffiniPure Sheep Anti--mouse IgG(1：400，Sigma)，加好二抗后，避光室温2h。 After 8 weeks, 4% paraformaldehyde was perfused. Then fixed with 4% paraformaldehyde for 12 hours. After discarding the paraformaldehyde, wash three times with PBS for 10 minutes each time. The lamina is peeled off, the spinal cord is exposed, and the integrity of the spinal cord is preserved as much as possible. The spinal cord tissue was taken out, and the spinal cord at a distance of 1.5 mm before and after the injury site was collected. After dehydration with 30% sucrose, it was embedded in OCT and the frozen section thickness was 10 μm. Add immunohistochemistry blocking solution and block at room temperature for 1 hour. Dilute the primary antibody anti-P4HB antibody (abcam, Mouse 1:100) with immunohistochemistry primary antibody diluent, add the primary antibody, and incubate at 4°C overnight. Discard the primary antibody and wash 3 times with PBS, 5 minutes each time. Dilute fluorescent secondary antibody Alexa with immunohistochemistry secondary antibody diluent
Figure PCTCN2022131056-appb-000001
555 AffiniPure Sheep Anti-mouse IgG (1:400, Sigma), after adding the secondary antibody, keep in the dark at room temperature for 2 hours.
弃掉二抗，PBS洗3遍，每遍5min。加入适量荧光封片剂，ZEISS正置荧光显微镜下观察，拍照。Discard the secondary antibody and wash 3 times with PBS, 5 minutes each time. Add an appropriate amount of fluorescent mounting medium, observe and take photos under a ZEISS upright fluorescence microscope.
观察损伤位点成纤维分布情况，拍照并统计各组纤维疤痕区的大小。Observe the distribution of fibroblasts at the injury site, take photos and count the size of the fibrous scar area in each group.
请参照图2，图2中，A:小鼠脊髓T10半切模型实验设计流程，经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升，维持8周。B:8周后，取各组包含疤痕的约3mm长一段脊髓，纵切后，使用P4HB标记疤痕区成纤维细胞，检测各组纤维疤痕大小。Bar＝200μm。C:通过比较各组P4HB荧光强度，发现CD36抑制剂丹酚酸B(100μg/ml和200μg/ml)显著抑制脊髓损伤区成纤维细胞形成纤维疤痕。*P<0.05，**P<0.01，***P<0.001。Please refer to Figure 2. In Figure 2, A: Experimental design process of mouse spinal cord T10 hemisection model. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally. , maintained for 8 weeks. B: After 8 weeks, an approximately 3 mm long section of spinal cord containing scars from each group was taken. After longitudinal sectioning, P4HB was used to mark fibroblasts in the scar area, and the size of the fibrous scars in each group was detected. Bar=200μm. C: By comparing the fluorescence intensity of P4HB in each group, it was found that the CD36 inhibitor salvianolic acid B (100 μg/ml and 200 μg/ml) significantly inhibited the formation of fibrous scars by fibroblasts in the spinal cord injury area. *P<0.05, **P<0.01, ***P<0.001.
结果显示，每天腹腔注射100μl CD36抑制剂丹酚酸B(100μg/ml和200μg/ml)显著抑制损伤位点成纤维细胞数量，显著减少纤维疤痕面积。The results showed that daily intraperitoneal injection of 100 μl of CD36 inhibitor salvianolic acid B (100 μg/ml and 200 μg/ml) significantly inhibited the number of fibroblasts at the injury site and significantly reduced the area of fibrous scars.
实施例2：CD36抑制剂丹酚酸B促进脊髓损伤区星型胶质细胞穿过纤维疤痕区。Example 2: The CD36 inhibitor salvianolic acid B promotes astrocytes in the spinal cord injury area to pass through the fibrous scar area.
一、成年小鼠脊髓T10右侧半切模型1. Adult mouse spinal cord T10 right hemisection model
24只8周龄雌性C57BL/6J小鼠随机分成四组(n＝6)，麻醉后，沿胸椎正中线切开皮肤，行T10椎板切除术，使用虹膜刀(BVI Beaver,Oakville,Canada)刀尖小心插入脊髓后正中沟，完全切断右侧脊髓。缝合肌肉层，然后用伤口夹固定皮肤。放置在37℃下复苏，直至完全清醒，并用止疼针缓解疼痛。每天经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升。所有动物实验均按照动物护理指南进行，并经江苏省实验动 物管理委员会伦理认可，动物实验许可证为20150304-004。Twenty-four 8-week-old female C57BL/6J mice were randomly divided into four groups (n=6). After anesthesia, the skin was incised along the midline of the thoracic spine, and T10 laminectomy was performed using an iridotome (BVI Beaver, Oakville, Canada). The tip of the knife was carefully inserted into the posterior median sulcus of the spinal cord, and the right spinal cord was completely severed. The muscle layer is sutured, and the skin is secured with wound clips. Place at 37°C for resuscitation until fully awake, and use analgesic needles to relieve pain. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
二、脊髓组织免疫荧光染色及纤维疤痕面积测量2. Immunofluorescence staining of spinal cord tissue and measurement of fibrous scar area
8周后，4％多聚甲醛灌注。再经4％多聚甲醛后固定12小时。弃掉多聚甲醛后，PBS洗三遍，每遍10min。剥离椎板，暴露脊髓，尽量保持脊髓完整性。取出的脊髓组织，收集损伤位点前后1.5mm距离的脊髓，经30％蔗糖脱水后，OCT包埋，冰冻切片厚度为10μm。加入免疫组化封闭液，室温封闭1h。用免疫组化一抗稀释液稀释一抗anti-GFAP antibody(abcam,Chicken 1:100)，加好一抗后，4℃过夜。弃掉一抗，PBS洗3遍，每遍5min。用免疫组化二抗稀释液稀释荧光二抗Alexa
Figure PCTCN2022131056-appb-000002
488 AffiniPure Sheep Anti--mouse IgG(1：400，Sigma)，加好二抗后，避光室温2h。 After 8 weeks, 4% paraformaldehyde was perfused. Then fixed with 4% paraformaldehyde for 12 hours. After discarding the paraformaldehyde, wash three times with PBS for 10 minutes each time. The lamina is peeled off, the spinal cord is exposed, and the integrity of the spinal cord is preserved as much as possible. The spinal cord tissue was taken out, and the spinal cord at a distance of 1.5 mm before and after the injury site was collected. After dehydration with 30% sucrose, it was embedded in OCT and the frozen section thickness was 10 μm. Add immunohistochemistry blocking solution and block at room temperature for 1 hour. Dilute the primary antibody anti-GFAP antibody (abcam, Chicken 1:100) with immunohistochemistry primary antibody diluent, add the primary antibody, and incubate at 4°C overnight. Discard the primary antibody and wash 3 times with PBS, 5 minutes each time. Dilute fluorescent secondary antibody Alexa with immunohistochemistry secondary antibody diluent
Figure PCTCN2022131056-appb-000002
488 AffiniPure Sheep Anti-mouse IgG (1:400, Sigma), after adding the secondary antibody, keep in the dark at room temperature for 2 hours.
弃掉二抗，PBS洗3遍，每遍5min。加入适量荧光封片剂，ZEISS正置荧光显微镜下观察，拍照。观察损伤位点星型胶质细胞分布情况，拍照并统计各组纤维疤痕区的大小。Discard the secondary antibody and wash 3 times with PBS, 5 minutes each time. Add an appropriate amount of fluorescent mounting medium, observe and take photos under a ZEISS upright fluorescence microscope. Observe the distribution of astrocytes at the injury site, take pictures and count the size of the fibrous scar area in each group.
请参阅图3，图3中A:小鼠脊髓T10半切模型实验设计流程，经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升，维持8周。B:8周后，取各组包含疤痕的约3mm长一段脊髓，纵切后，使用GFAP标记疤痕区星型胶质细胞，检测其分布情况和疤痕区面积大小。Bar＝200μm。C:通过比较各组GFAP荧光强度以及疤痕区面积大小，发现CD36抑制剂丹酚酸B(50μg/ml、100μg/ml和200μg/ml)显著促进脊髓损伤区星型胶质细胞穿过纤维疤痕区。*P<0.05，**P<0.01，***P<0.001。Please refer to Figure 3. A in Figure 3: Experimental design process of mouse spinal cord T10 hemisection model. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally. Lasts for 8 weeks. B: After 8 weeks, an approximately 3 mm long section of the spinal cord containing scars from each group was taken. After longitudinal sectioning, GFAP was used to mark astrocytes in the scar area, and their distribution and scar area size were detected. Bar=200μm. C: By comparing the fluorescence intensity of GFAP and the size of the scar area in each group, it was found that the CD36 inhibitor salvianolic acid B (50 μg/ml, 100 μg/ml and 200 μg/ml) significantly promoted astrocytes in the spinal cord injury area to penetrate the fibrous scar. district. *P<0.05, **P<0.01, ***P<0.001.
结果显示，每天腹腔注射100μl CD36抑制剂丹酚酸B(50μg/ml、100μg/ml和200μg/ml)显著促进脊髓损伤区星型胶质细胞穿过纤维疤痕区，显著减少纤 维疤痕面积。The results showed that daily intraperitoneal injection of 100 μl of CD36 inhibitor salvianolic acid B (50 μg/ml, 100 μg/ml and 200 μg/ml) significantly promoted astrocytes in the spinal cord injury area to penetrate the fibrous scar area and significantly reduced the fibrous scar area.
实施例3：CD36抑制剂丹酚酸B促进脊髓损伤区血管再生。Example 3: CD36 inhibitor salvianolic acid B promotes vascular regeneration in spinal cord injury areas.
一、成年小鼠脊髓T10右侧半切模型1. Adult mouse spinal cord T10 right hemisection model
24只8周龄雌性C57BL/6J小鼠随机分成四组(n＝6)，麻醉后，沿胸椎正中线切开皮肤，行T10椎板切除术，使用虹膜刀(BVI Beaver,Oakville,Canada)刀尖小心插入脊髓后正中沟，完全切断右侧脊髓。缝合肌肉层，然后用伤口夹固定皮肤。放置在37℃下复苏，直至完全清醒，并用止疼针缓解疼痛。每天经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升。所有动物实验均按照动物护理指南进行，并经江苏省实验动物管理委员会伦理认可，动物实验许可证为20150304-004。Twenty-four 8-week-old female C57BL/6J mice were randomly divided into four groups (n=6). After anesthesia, the skin was incised along the midline of the thoracic spine, and T10 laminectomy was performed using an iridotome (BVI Beaver, Oakville, Canada). The tip of the knife was carefully inserted into the posterior median sulcus of the spinal cord, and the right spinal cord was completely severed. The muscle layer is sutured, and the skin is secured with wound clips. Place at 37°C for resuscitation until fully awake, and use analgesic needles to relieve pain. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally every day. All animal experiments were conducted in accordance with the Animal Care Guidelines and were ethically approved by the Jiangsu Provincial Laboratory Animal Management Committee. The animal experiment license is 20150304-004.
二、脊髓组织免疫荧光染色及纤维疤痕面积测量2. Immunofluorescence staining of spinal cord tissue and measurement of fibrous scar area
8周后，4％多聚甲醛灌注。再经4％多聚甲醛后固定12小时。弃掉多聚甲醛后，PBS洗三遍，每遍10min。剥离椎板，暴露脊髓，尽量保持脊髓完整性。取出的脊髓组织，收集损伤位点前后1.5mm距离的脊髓，经30％蔗糖脱水后，OCT包埋，冰冻切片厚度为10μm。加入免疫组化封闭液，室温封闭1h。用免疫组化一抗稀释液稀释一抗anti-CD31 antibody(R&D,goat 1:50)和anti-CD68 antibody(NOVUS Biological,Mouse 1:100)。加好一抗后，4℃过夜。弃掉一抗，PBS洗3遍，每遍5min。用免疫组化二抗稀释液稀释荧光二抗Alexa
Figure PCTCN2022131056-appb-000003
488 AffiniPure Sheep Anti-goat IgG(1：400，Sigma)和Alexa
Figure PCTCN2022131056-appb-000004
555 AffiniPure Sheep Anti--mouse IgG(1：400，Sigma)，加好二抗后，避光室温2h。弃掉二抗，PBS洗3遍，每遍5min。加入适量荧光封片剂，ZEISS正置荧 光显微镜下观察，拍照。观察损伤位点再生血管内皮细胞的标记物CD31分布情况，拍照并统计各组疤痕区再生血管的数量和长度。 After 8 weeks, 4% paraformaldehyde was perfused. Then fixed with 4% paraformaldehyde for 12 hours. After discarding the paraformaldehyde, wash three times with PBS for 10 minutes each time. The lamina is peeled off, the spinal cord is exposed, and the integrity of the spinal cord is preserved as much as possible. The spinal cord tissue was taken out, and the spinal cord at a distance of 1.5 mm before and after the injury site was collected. After dehydration with 30% sucrose, it was embedded in OCT and the frozen section thickness was 10 μm. Add immunohistochemistry blocking solution and block at room temperature for 1 hour. Dilute the primary antibodies anti-CD31 antibody (R&D, goat 1:50) and anti-CD68 antibody (NOVUS Biological, Mouse 1:100) with immunohistochemistry primary antibody diluent. After adding the primary antibody, incubate at 4°C overnight. Discard the primary antibody and wash 3 times with PBS, 5 minutes each time. Dilute fluorescent secondary antibody Alexa with immunohistochemistry secondary antibody diluent
Figure PCTCN2022131056-appb-000003
488 AffiniPure Sheep Anti-goat IgG (1:400, Sigma) and Alexa
Figure PCTCN2022131056-appb-000004
555 AffiniPure Sheep Anti-mouse IgG (1:400, Sigma), after adding the secondary antibody, keep in the dark at room temperature for 2 hours. Discard the secondary antibody and wash 3 times with PBS, 5 minutes each time. Add an appropriate amount of fluorescent mounting medium, observe and take photos under a ZEISS upright fluorescence microscope. The distribution of CD31, a marker of regenerated vascular endothelial cells at the injury site, was observed, and the number and length of regenerated blood vessels in the scar area of each group were counted.
请参阅图4，图4中A:小鼠脊髓T10半切模型实验设计流程，经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升及对照PBS 100微升，维持8周。B:8周后，取各组包含疤痕的约3mm长一段脊髓，纵切后，使用CD31标记再生的血管内皮细胞，CD68标记疤痕区小胶质细胞，检测各组血管再生情况。Bar＝200μm。C:通过比较各组CD31荧光强度，发现CD36抑制剂丹酚酸B(100μg/ml和200μg/ml)显著促进脊髓损伤疤痕区血管再生。*P<0.05，**P<0.01。Please refer to Figure 4. A in Figure 4: Experimental design process of mouse spinal cord T10 hemisection model. Three doses of CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml) 100 μl and control PBS 100 μl were injected intraperitoneally. Lasts for 8 weeks. B: After 8 weeks, an approximately 3 mm long section of the spinal cord containing scars from each group was taken. After longitudinal sectioning, CD31 was used to mark regenerated vascular endothelial cells and CD68 was used to mark microglia in the scar area to detect the vascular regeneration in each group. Bar=200μm. C: By comparing the CD31 fluorescence intensity in each group, it was found that the CD36 inhibitor salvianolic acid B (100 μg/ml and 200 μg/ml) significantly promoted vascular regeneration in the scar area of spinal cord injury. *P<0.05, **P<0.01.
结果显示，每天腹腔注射100μl CD36抑制剂丹酚酸B(100μg/ml和200μg/ml)显著促进脊髓损伤区再生血管穿过疤痕区。The results showed that daily intraperitoneal injection of 100 μl of the CD36 inhibitor salvianolic acid B (100 μg/ml and 200 μg/ml) significantly promoted the regeneration of blood vessels in the spinal cord injury area through the scar area.
本研究以能通过血脑屏障的CD36抑制剂丹酚酸B作为药物，抑制中枢脊髓损伤后局部胶质疤痕的形成，同时促进血管再生。This study uses salvianolic acid B, a CD36 inhibitor that can pass through the blood-brain barrier, as a drug to inhibit the formation of local glial scars after central spinal cord injury and at the same time promote vascular regeneration.
本发明利用脊髓T10半切模型，经腹腔注射三种剂量CD36抑制剂丹酚酸B(50,100和200μg/ml)100微升，8周后，发现可以显著抑制损伤局部成纤维细胞聚集形成的纤维疤痕，同时，也促进损伤局部血管再生。这有助于更好地理解植物提取物在神经损伤修复过程中的重要作用，并为神经损伤后的治疗提供新的靶点。The present invention uses the spinal cord T10 hemisection model to intraperitoneally inject 100 microliters of three doses of the CD36 inhibitor salvianolic acid B (50, 100 and 200 μg/ml). After 8 weeks, it is found that the fibrous scar formed by the accumulation of fibroblasts in the injured area can be significantly inhibited. , at the same time, it also promotes the regeneration of local blood vessels after injury. This helps to better understand the important role of plant extracts in the repair process of nerve injury and provides new targets for treatment after nerve injury.
以上所述仅为本发明的实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的权利要求范围。The above are only examples of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of the claims of the present invention.

Claims (7)

  1. CD36抑制剂在修复神经损伤药物中的应用。The application of CD36 inhibitors as drugs to repair nerve damage.
  2. 根据权利要求1所述的CD36抑制剂在修复神经损伤药物中的应用，其特征在于：所述CD36抑制剂包括丹酚酸B。The application of CD36 inhibitor in medicine for repairing nerve damage according to claim 1, characterized in that: the CD36 inhibitor includes salvianolic acid B.
  3. 根据权利要求2所述的CD36抑制剂在修复神经损伤药物中的应用，其特征在于：所述丹酚酸B用于抑制脊髓损伤区成纤维细胞形成纤维疤痕。The application of CD36 inhibitor in medicine for repairing nerve damage according to claim 2, characterized in that: the salvianolic acid B is used to inhibit the formation of fibrous scars by fibroblasts in the spinal cord injury area.
  4. 根据权利要求2所述的CD36抑制剂在修复神经损伤药物中的应用，其特征在于：所述丹酚酸B用于促进脊髓损伤区星型胶质细胞穿过纤维疤痕区。The application of CD36 inhibitor in medicine for repairing nerve damage according to claim 2, characterized in that: the salvianolic acid B is used to promote astrocytes in the spinal cord injury area to pass through the fibrous scar area.
  5. 根据权利要求2所述的CD36抑制剂在修复神经损伤药物中的应用，其特征在于：所述丹酚酸B用于促进脊髓损伤区的血管再生。The application of CD36 inhibitor in medicine for repairing nerve damage according to claim 2, characterized in that: the salvianolic acid B is used to promote vascular regeneration in the spinal cord injury area.
  6. 一种神经损伤修复药物，其特征在于：包含CD36抑制剂。A nerve damage repair drug, characterized by: containing a CD36 inhibitor.
  7. 根据权利要求6所述的神经损伤修复药物，其特征在于：所述CD36抑制剂包括丹酚酸B。The nerve damage repair medicine according to claim 6, characterized in that: the CD36 inhibitor includes salvianolic acid B.
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