丹参酮ⅡA抑制焦亡通路改善糖尿病周围神经病变的分子机制研究

doi:10.3877/cma.j.issn.2095-123X.2025.03.002

目的

探讨丹参酮ⅡA（TIIA）通过调控焦亡通路改善糖尿病周围神经病变（DPN）的作用机制。

方法

（1）通过高脂饮食联合链脲佐菌素（STZ）构建2型糖尿病（T2DM）-DPN小鼠模型，将小鼠随机分为3组：空白组、模型组（给予110 mg/kg STZ）、TIIA组（DPN模型+20 mg/kg TIIA磺酸钠注射液），每组10只；（2）疼痛行为学评估：采用Von Frey纤维丝测痛实验及Hargreaves试验的行为学测试评估3组小鼠的机械痛觉敏感性及热痛觉敏感性；（3）将小鼠的坐骨神经通过HE染色、LFB髓鞘染色和透射电子显微镜（TEM）观察髓鞘轴突的组织学变化；（4）通过免疫荧光染色观察神经元标志物PGP9.5在3组小鼠足底皮肤表皮内神经纤维（IENF）的表达；（5）通过Western blot实验和免疫荧光实验方法检测3组小鼠的坐骨神经的核苷酸结合域样受体蛋白3（NLRP-3）、凋亡相关颗粒样蛋白（ASC）、Gasdermin-D（GSDMD）、半胱天冬酶-1（Caspase-1）和白介素-1β（IL-1β）蛋白的表达；（6）体外培养RSC96细胞并构建高糖损伤模型；（7）通过乳酸脱氢酶（LDH）细胞毒性实验测定不同药物浓度（5、10、20和40 µmol/L）对细胞活性的影响，并筛选最佳药物浓度；（8）将细胞系分为3组：空白组（5.5 mmol/L葡萄糖培养）、模型组（50 mmol/L葡萄糖培养）和TIIA组（50 mmol/L葡萄糖+20 µmol/L TIIA）；（9）通过流式细胞术检测3组细胞内的荧光探针DCFH-DA标记的活性氧（ROS）水平；（10）通过Western blot实验检测3组细胞的NLRP-3、ASC、GSDMD、Caspase-1和IL-1β蛋白的表达水平。

结果

（1）TIIA能够逆转长期高血糖所造成的周围神经损伤，髓鞘结构病理性改变；（2）TIIA药物治疗能够改善DPN模型小鼠IENF的缺失；（3）TIIA能够抑制高葡萄糖处理的RSC96细胞中的ROS的生成；（4）TIIA通过抑制NLRP3炎症小体组装、阻断Caspase-1/GSDMD依赖性焦亡通路，减少IL-1β等促炎因子释放，从而减轻长期高血糖所致的周围神经病理性损伤。

结论

TIIA通过减少高糖所致的细胞内异常增高的ROS水平，从而抑制焦亡信号通路改善DPN所致的周围神经损伤。

关键词: 糖尿病周围神经病变, 丹参酮ⅡA, 活性氧自由基, 焦亡信号通路

Objective

To investigate the mechanism of tanshinone ⅡA (TIIA) in improving diabetic peripheral neuropathy (DPN) by regulating pyroptosis pathway.

Methods

(1) Type 2 diabetes mellitus (T2DM)-DPN mouse models was established through high-fat diet feeding combined with intraperitoneal streptozotocin (STZ). The experimental animals were randomly divided into three groups: control group, model group (110 mg/kg STZ-induced), TIIA group (DPN model+20 mg/kg TIIA sodium sulfonate injection), with 10 mice in each group; (2) Pain behavioral assessments were conducted using Von Frey filaments for mechanical allodynia and the hot plate test to quantify thermal hyperalgesia thresholds; (3) Sciatic nerve sections underwent hematoxylin-eosin (HE) staining and Luxol fast blue (LFB) staining for myelin integrity, and transmission electron microscopy (TEM) to evaluate ultrastructural alterations in myelin-axon units; (4) Epidermal nerve fiber density in plantar skin specimens was quantified through immunofluorescence staining using anti-PGP9.5 antibodies; (5) Protein expression levels of nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), cysteinyl aspartate specific proteinase-1 (Caspase-1), gasdermin-D (GSDMD), and interleukin-1β (IL-1β) in sciatic nerves were quantitatively analyzed through Western blot combined with immunofluorescence assay; (6) RSC96 cells were cultured in vitro with hyperglycemic injury model established; (7) Cytotoxic effects of TIIA were assessed using lactate dehydrogenase (LDH) release assay across a concentration gradient (5, 10, 20, 40 μmol/L), with dose-response analysis identifying 20 μmol/L as the optimal therapeutic concentration for subsequent experiments; (8) Schwann cell were divided into three groups: control group (5.5 mmol/L glucose), hyperglycemic injury model group (50 mmol/L glucose), and pharmacological intervention (50 mmol/L glucose + 20 μmol/L TIIA); (9) Intracellular reactive oxygen species (ROS) levels were quantified via flow cytometry using DCFH-DA fluorescent probe; (10) The protein expression levels of NLRP-3, ASC, GSDMD, Caspase-1, and IL-1β in each group were analyze by Western blot.

Results

(1) TIIA ameliorated chronic hyperglycemia-induced myelin sheath structural pathology and neuropathic progression; (2) TIIA treatment significantly ameliorated the loss of intraepidermal nerve fibers density in DPN model mice; (3) TIIA inhibited hyperglycemia-induced ROS overproduction in RSC96 cells; (4) TIIA ameliorates chronic hyperglycemia-induced peripheral neuropathy through inhibiting suppression of NLRP3 inflammasome assembly, Caspase-1-mediated GSDMD cleavage, and subsequent IL-1β secretion, effectively disrupting the pyroptosis-inflammation axis.

Conclusions

TIIA alleviates hyperglycemia-induced peripheral neuropathic damage by scavenging intracellular ROS overaccumulation, thereby blocking NLRP3 inflammasome activation and subsequent Caspase-1/GSDMD-mediated pyroptosis in Schwann cells, ultimately preserving myelin-axon structural integrity.

Key words: Diabetic peripheral neuropathy, Tanshinone ⅡA, Reactive oxygen species, Pyroptosis signaling pathway

图1 3组小鼠DPN症状表型的比较A：体质量；B：血糖水平；C：机械痛撤爪阈值；D：热痛反应时间；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；DPN：糖尿病周围神经病变；TIIA：丹参酮ⅡA

Fig.1 Comparison of DPN symptom phenotypes among 3 groups of mice

图2 3组小鼠坐骨神经病理改变的HE染色和LFB染色评估A：HE染色；B：LFB染色

Fig.2 Histopathological evaluation of sciatic nerve alterations in 3 groups using HE and LFB staining techniques

图3 3组小鼠坐骨神经髓鞘TEM超微结构的改变A：3组小鼠坐骨神经髓鞘TEM超微结构；B：异常轴突髓鞘崩解率；C：髓鞘直径；D：轴突直径；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；TEM：透射电子显微镜；TIIA：丹参酮ⅡA

Fig.3 TEM ultrastructural changes of sciatic nerve myelin sheath in 3 groups of mice

图4 3组小鼠足底皮肤组织PGP9.5的免疫荧光染色图A：空白组；B：模型组；C：TIIA组；TIIA：丹参酮ⅡA

Fig.4 Immunofluorescence staining of PGP9.5 in the plantar skin tissue of the 3 groups of mice

图5 3组小鼠TIIA干预2周后坐骨神经焦亡相关蛋白表达水平Western blot检测结果A：NLRP3、ASC、Caspase-1、IL-1β、GSDMD的Western blot条带图；B~F：NLRP3（B）、ASC（C）、Caspase-1（D）、IL-1β（E）、GSDMD（F）的蛋白表达水平；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；TIIA：丹参酮ⅡA；NLRP3：核苷酸结合域样受体蛋白3；ASC：凋亡相关颗粒样蛋白；Caspase-1：半胱天冬酶-1；IL：白介素；GSDMD：gasdermin-D

Fig.5 Expression levels of pyroptosis related proteins in sciatic nerve of three groups of mice after 2 weeks of TIIA intervention by Western blot

图6 3组小鼠TIIA干预2周后坐骨神经焦亡相关蛋白表达水平免疫荧光检测结果A~E：NLRP3（A）、ASC（B）、Caspase-1（C）、GSDMD（D）、IL-1β（E）的荧光染色图；F~J：NLRP3（F）、ASC（G）、Caspase-1（H）、GSDMD（I）、IL-1β（J）的蛋白表达水平；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；TIIA：丹参酮ⅡA；NLRP3：核苷酸结合域样受体蛋白3；ASC：凋亡相关颗粒样蛋白；Caspase-1：半胱天冬酶-1；GSDMD：gasdermin-D；IL：白介素

Fig.6 Expression levels of pyroptosis related proteins in sciatic nerve of three groups of mice after 2 weeks of TIIA intervention by immunofluorescence

图7 不同浓度TIIA对高糖诱导的RSC96细胞LDH释放的影响与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；LDH：乳酸脱氢酶；TIIA：丹参酮ⅡA

Fig.7 Effect of different concentrations of TIIA on LDH release induced by high glucose in RSC96 cells

图8 3组RSC96细胞处理48 h后ROS水平比较A：3组RSC96细胞内ROS流式细胞术检测图；B：3组RSC96细胞内ROS水平统计结果；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；TIIA：丹参酮ⅡA；ROS：活性氧

Fig.8 Comparison of intracellular ROS levels in three groups of RSC96 cells after 48 h treatment

图9 3组RSC96细胞焦亡通路相关蛋白Western blot结果A：NLRP3、ASC、Caspase-1、IL-1β、GSDMD的Western blot条带图；B~F：NLRP3（B）、ASC（C）、Caspase-1（D）、IL-1β（E）、GSDMD（F）的蛋白表达水平；与空白组比较，^aP<0.05；与模型组比较，^bP<0.05；TIIA：丹参酮ⅡA；NLRP3：核苷酸结合域样受体蛋白3；ASC：凋亡相关颗粒样蛋白；Caspase-1：半胱天冬酶-1；IL：白介素；GSDMD：gasdermin-D

Fig.9 Representative Western blot images of pyroptosis-associated proteins in RSC96 cells in three groups

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Tanshinone ⅡA ameliorates diabetic peripheral neuropathy via suppressing NLRP3 inflammasome-mediated pyroptosis

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Tanshinone ⅡA ameliorates diabetic peripheral neuropathy via suppressing NLRP3 inflammasome-mediated pyroptosis