Bisperoxovanadium Mediates Neuronal Protection through Inhibition of PTEN and Activation of PI3K/AKT-mTOR Signaling after Traumatic Spinal Injuries
Bisperoxovanadium Mediates Neuronal Protection through Inhibition of PTEN and Activation of PI3K/AKT-mTOR Signaling after Traumatic Spinal Injuries
复制标题
双过氧钒通过抑制PTEN和激活PI 3 K/AKT-mTOR信号通路对脊髓损伤后神经元的保护作用
DOI：
10.1089/neu.2018.6294
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发表时间：
2019-03-28
影响因子：
4.2
通讯作者：
Xu, Xiao-Ming
中科院分区：
文献类型：
--
作者：
Walker, Chandler L.;Wu, Xiangbing;Xu, Xiao-Ming
虽然脊髓损伤（SCI）中细胞死亡进展的机制已被广泛研究，但很少有明确的目标转化为临床应用。SCI中细胞存活的最好理解的机制之一是磷脂酰肌醇-3-激酶（PI 3 K）/Akt和相关的下游信号传导。被称为双过氧钒（bpV）的磷酸酶和张力蛋白同源物（PTEN）抑制剂在SCI、创伤性脑损伤、中风和其他神经系统疾病模型中在神经保护和功能恢复方面显示出明确的治疗功效。本研究的目的是阐明bpV活性在体外和体内SCI模型中对神经元存活的机制影响。与未处理的受损神经元相比，用100 nM bpV（pic）处理减少体外原代脊髓神经元损伤模型中的细胞死亡（p < 0.05），并上调Akt和核糖体蛋白S6（pS 6）活性（p < 0.05）。用PI 3 K抑制剂LY 294002或哺乳动物雷帕霉素靶标（mTOR）抑制剂雷帕霉素预处理脊髓神经元分别阻断Akt和核糖体蛋白S6活性的bpV活化。bpV处理增加了体外划痕损伤后细胞外信号相关激酶（Erk）的活性，雷帕霉素降低了bpV对Erk磷酸化的影响。在颈部半挫伤性SCI后，通过蛋白质印迹分析，Akt磷酸化在整个组织中减少（p < 0.01），并且在损伤后第一周内在半暗带腹角运动神经元中减少（p < 0.05）。相反，在此期间，PTEN活性似乎增加。如在体外观察到的，bpV还增加SCI后的Erk活性（p < 0.05）。我们的研究结果表明，PI 3 K/Akt信号转导可能是bpV介导损伤脊髓神经元神经保护作用的主要机制。
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 in vitro and in vivo models of SCI. Treatment with 100 nM bpV(pic) reduced cell death in a primary spinal neuron injury model (p < 0.05) in vitro, and upregulated both Akt and ribosomal protein S6 (pS6) activity (p < 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 in vitro, and rapamycin reduced influence by bpV on Erk phosphorylation. After a cervical hemicontusive SCI, Akt phosphorylation decreased in total tissue via Western blot analysis (p < 0.01) as well as in penumbral ventral horn motor neurons throughout the first week post-injury (p < 0.05). Conversely, PTEN activity appeared to increase over this period. As observed in vitro, bpV also increased Erk activity post-SCI (p < 0.05). Our results suggest that PI3K/Akt signaling is the likely primary mechanism of bpV action in mediating neuroprotection in injured spinal neurons.