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双过氧钒通过抑制 PTEN 和激活 PI3K/AKT-mTOR 信号通路介导创伤性脊髓损伤后的神经元保护。

Bisperoxovanadium Mediates Neuronal Protection through Inhibition of PTEN and Activation of PI3K/AKT-mTOR Signaling after Traumatic Spinal Injuries.

机构信息

Department of Biomedical and Applied Sciences, Indiana University School of Dentistry, Indianapolis, Indiana.

Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery and Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana.

出版信息

J Neurotrauma. 2019 Sep 15;36(18):2676-2687. doi: 10.1089/neu.2018.6294. Epub 2019 Mar 28.

Abstract

Although mechanisms involved in progression of cell death in spinal cord injury (SCI) have been studied extensively, few are clear targets for translation to clinical application. One of the best-understood mechanisms of cell survival in SCI is phosphatidylinositol-3-kinase (PI3K)/Akt and associated downstream signaling. Clear therapeutic efficacy of a phosphatase and tensin homologue (PTEN) inhibitor called bisperoxovanadium (bpV) has been shown in SCI, traumatic brain injury, stroke, and other neurological disease models in both neuroprotection and functional recovery. The present study aimed to elucidate mechanistic influences of bpV activity in neuronal survival in and models of SCI. Treatment with 100 nM bpV(pic) reduced cell death in a primary spinal neuron injury model ( < 0.05) , and upregulated both Akt and ribosomal protein S6 (pS6) activity ( < 0.05) compared with non-treated injured neurons. Pre-treatment of spinal neurons with a PI3K inhibitor, LY294002 or mammalian target of rapamycin (mTOR) inhibitor, rapamycin blocked bpV activation of Akt and ribosomal protein S6 activity, respectively. Treatment with bpV increased extracellular signal-related kinase (Erk) activity after scratch injury , and rapamycin reduced influence by bpV on Erk phosphorylation. After a cervical hemicontusive SCI, Akt phosphorylation decreased in total tissue via Western blot analysis ( < 0.01) as well as in penumbral ventral horn motor neurons throughout the first week post-injury ( < 0.05). Conversely, PTEN activity appeared to increase over this period. As observed , bpV also increased Erk activity post-SCI ( < 0.05). Our results suggest that PI3K/Akt signaling is the likely primary mechanism of bpV action in mediating neuroprotection in injured spinal neurons.

摘要

虽然脊髓损伤 (SCI) 中细胞死亡进展的相关机制已被广泛研究,但很少有明确的靶点可以转化为临床应用。在 SCI 中,细胞存活的机制之一是磷脂酰肌醇-3-激酶 (PI3K)/Akt 和相关的下游信号通路。一种名为双过氧钒 (bpV) 的磷酸酶和张力蛋白同系物 (PTEN) 抑制剂在 SCI、创伤性脑损伤、中风和其他神经疾病模型中的神经保护和功能恢复方面显示出明显的治疗效果。本研究旨在阐明 bpV 活性在 SCI 和 模型中神经元存活中的机制影响。用 100 nM bpV(pic) 处理可减少原代脊髓神经元损伤模型中的细胞死亡( < 0.05),与未处理的受伤神经元相比,Akt 和核糖体蛋白 S6(pS6) 的活性分别上调( < 0.05)。用 PI3K 抑制剂 LY294002 或雷帕霉素(mTOR 抑制剂)预处理脊髓神经元,分别阻断 bpV 对 Akt 和核糖体蛋白 S6 活性的激活。用 bpV 处理后,划痕损伤后细胞外信号调节激酶 (Erk) 的活性增加,雷帕霉素降低了 bpV 对 Erk 磷酸化的影响。在颈半挫伤性 SCI 后,Western blot 分析显示总组织中的 Akt 磷酸化减少( < 0.01),损伤后第一周脊髓腹角运动神经元的磷酸化减少( < 0.05)。相反,在这段时间内,PTEN 的活性似乎增加了。正如所观察到的,bpV 也增加了 SCI 后的 Erk 活性( < 0.05)。我们的结果表明,PI3K/Akt 信号通路可能是 bpV 介导损伤脊髓神经元神经保护的主要作用机制。

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本文引用的文献

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