目的 探讨AKT激动剂SC79对小鼠坐骨神经挤压伤后轴突再生及功能恢复的作用。 方法 建立小鼠坐骨神经挤压伤模型，随机分为对照组与SC79组（40 mg/kg，腹腔注射）。同时构建背根神经节（DRG）外植体轴突切断模型，在培养基内加入SC79（4 mg/mL）。采用Western blot检测AKT信号通路激活情况；免疫荧光评估轴突再生、施万细胞增殖及髓鞘再生；结合霍乱毒素B（Chorea toxin subunit B, CTB）逆行示踪、神经肌肉接头染色、腓肠肌形态学分析及坐骨神经功能指数（SFI）评价神经环路重建与功能恢复。 结果 坐骨神经挤压伤后第3 d，SC79组坐骨神经及腰骶段脊髓中p-AKT/AKT比值显著高于对照组（P<0.05）。术后7 d，SC79组远端再生轴突密度显著升高，S-100β/Ki67双阳性施万细胞比例显著增加（P<0.001）。术后30 d，SC79组轴突横截面积及髓鞘厚度显著增大，CTB阳性脊髓前角神经元数量明显增加（P<0.001）。体外实验中，SC79显著促进DRG轴突再生长度（P<0.001），并部分逆转生长锥塌陷。功能学评估显示，SC79组神经肌肉接头再支配率显著提高，腓肠肌湿重比增加，SFI显著改善（P<0.05）。 结论 SC79 可通过激活 AKT 通路，促进小鼠坐骨神经挤压伤后轴突再生、神经环路重建及功能恢复，即时给药效果最优，有望成为周围神经损伤修复的潜在药物。
Abstract
Objective To investigate the effect of SC79, an AKT activator, on axonal regeneration and functional recovery following sciatic nerve crush injury in mice. Methods Mouse models of sciatic nerve crush injury were established and randomly divided into a control group and an SC79 group (40 mg/kg, intraperitoneal injection). Dorsal root ganglion (DRG) explant axotomy models were also established, and SC79 (4 mg/ml) was added to the culture medium. Western blot was used to detect the activation of the AKT signaling pathway. Immunofluorescence was applied to evaluate axonal regeneration, Schwann cell proliferation, and myelin regeneration. Neural circuit reconstruction and functional recovery were assessed by cholera toxin subunit B (CTB) retrograde tracing, neuromuscular junction staining, gastrocnemius morphological analysis, and the sciatic functional index (SFI). Results At 3 days after sciatic nerve crush injury, the p-AKT/AKT ratio in the sciatic nerve and lumbosacral spinal cord was significantly higher in the SC79 group than in the control group (P<0.05). At 7 days post-injury, SC79 significantly increased the density of distal regenerated axons and the proportion of S-100β/Ki67 double-positive Schwann cells (P<0.001). At 30 days post-injury, SC79 markedly increased axonal cross-sectional area, myelin thickness, and the number of CTB-positive spinal anterior horn neurons (P<0.001). In vitro, SC79 significantly promoted DRG axonal regeneration (P<0.001) and partially reversed growth cone collapse. Functional assessments showed that SC79 significantly improved neuromuscular junction reinnervation, gastrocnemius wet weight ratio, and SFI (P<0.05). Conclusion SC79 promotes axonal regeneration, neural circuit reconstruction, and functional recovery after sciatic nerve crush injury in mice by activating the AKT pathway. Immediate administration yields the optimal effect, indicating that SC79 is a promising candidate for peripheral nerve injury repair.
关键词
AKT激动剂； /
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SC79； /
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坐骨神经挤压伤； /
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轴突再生
Key words
AKT agonist; /
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SC79; /
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sciatic nerve crush injury; /
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axonal regeneration
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基金
福建省自然科学基金联合资助项目（2024J011263）；福建省中青年教师教育科研项目（JAT210792）
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