金雀异黄素通过阻断 PTPN1 激活 IRS1/Akt/mTOR 信号通路抑制自噬从而改善脊髓损伤后的运动功能恢复。
Tenuigenin activates the IRS1/Akt/mTOR signaling by blocking PTPN1 to inhibit autophagy and improve locomotor recovery in spinal cord injury.
机构信息
Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China.
Department of Urology Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, Liaoning, PR China.
出版信息
J Ethnopharmacol. 2023 Dec 5;317:116841. doi: 10.1016/j.jep.2023.116841. Epub 2023 Jun 22.
ETHNOPHARMACOLOGICAL RELEVANCE
Tenuigenin (TEN) is a main pharmacologically active component of Polygala tenuifolia Willd. (Polygalaceae), which has shown neuroprotective functions in Alzheimer's disease. Moreover, TEN also demonstrated an anti-oxidative impact in an in vitro model of Parkinson's disease, reducing damage and loss of dopaminergic neurons.
AIM
This work focuses on the impact of TEN on locomotor recovery following spinal cord injury (SCI) and underpinning molecules involved.
METHODS
A rat model of SCI was generated, and the rats were treated with TEN, oe-PTPN1 (PTP non-receptor type 1), a protein kinase B (Akt)/mammalian target of rapamycin (mTOR) antagonist LY294002, or an autophagy inhibitor 3-methyladenine (3-MA). Subsequently, locomotor function was detected. Pathological changes and neuronal activity in the spinal cord tissues were analyzed by hematoxylin and eosin staining, Nissl staining, and TUNEL assays. Protein expression of Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3B)-II/LC3B-I, PTPN1, IRS1, mTOR, and phosphorylated Akt (p-Akt) was analyzed by western blot assays. The LC3B expression was further examined by immunofluorescence staining.
RESULTS
Treatment with TEN restored the locomotor function of SCI rats, reduced the cavity area and cell apoptosis, upregulated growth-associated protein 43 and neurofilament 200, and decreased the Beclin-1 and LC3B-II/LC3B-I levels in the spinal cord. TEN suppressed PTPN1 protein level, while PTPN1 suppressed IRS1 protein to reduce the p-Akt and mTOR levels. Either PTPN1 overexpression or LY294002 treatment blocked the promoting effect of TEN on SCI recovery. However, treatment with 3-MA suppressed autophagy, which consequently rescued the locomotor function and reduced neuron loss induced by PTPN1.
CONCLUSION
This study demonstrates that TEN suppresses autophagy to promote function recovery in SCI rats by blocking PTPN1 and rescuing the IRS1/Akt/mTOR signaling.
民族药理学相关性
远志皂苷元（TEN）是远志（远志科）的主要药理活性成分之一，在阿尔茨海默病中具有神经保护作用。此外，TEN 在帕金森病的体外模型中也表现出抗氧化作用，可减少多巴胺能神经元的损伤和丢失。
目的
本研究旨在探讨 TEN 对脊髓损伤（SCI）后运动功能恢复的影响及其作用机制。
方法
建立大鼠 SCI 模型，用 TEN、过表达 PTPN1（蛋白酪氨酸磷酸酶非受体型 1）、蛋白激酶 B（Akt）/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂 LY294002 或自噬抑制剂 3-甲基腺嘌呤（3-MA）处理大鼠。然后检测运动功能。通过苏木精-伊红染色、尼氏染色和 TUNEL 检测分析脊髓组织的病理变化和神经元活性。通过 Western blot 检测 Beclin-1 和微管相关蛋白 1 轻链 3β（LC3B）-II/LC3B-I、PTPN1、胰岛素受体底物 1（IRS1）、mTOR 和磷酸化 Akt（p-Akt）的蛋白表达。通过免疫荧光染色进一步检测 LC3B 的表达。
结果
TEN 治疗恢复了 SCI 大鼠的运动功能，减少了空洞面积和细胞凋亡，上调了生长相关蛋白 43 和神经丝 200，降低了脊髓中的 Beclin-1 和 LC3B-II/LC3B-I 水平。TEN 抑制了 PTPN1 蛋白水平，而 PTPN1 抑制了 IRS1 蛋白，降低了 p-Akt 和 mTOR 水平。过表达 PTPN1 或用 LY294002 处理均可阻断 TEN 对 SCI 恢复的促进作用。然而，用 3-MA 抑制自噬可抑制 PTPN1 诱导的运动功能和神经元丢失。
结论
本研究表明，TEN 通过抑制 PTPN1 并挽救 IRS1/Akt/mTOR 信号通路来抑制自噬，从而促进 SCI 大鼠的功能恢复。
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