Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury.
Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury.
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辛伐他汀通过激活脊髓损伤后 Wnt/β-catenin 信号通路抑制神经细胞凋亡并促进运动恢复
DOI：
10.1111/jnc.13382
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发表时间：
2016-07
影响因子：
4.7
通讯作者：
Mei X
中科院分区：
文献类型：
--
作者：
Gao K;Shen Z;Yuan Y;Han D;Song C;Guo Y;Mei X
他汀类药物在脊髓损伤（SCI）后表现出神经保护作用。然而，这些影响的分子机制仍然未知。这项研究表明，羟甲基戊二酰辅酶A还原酶抑制剂辛伐他汀（Simv）通过激活Wnt/β-catenin信号通路，对大鼠SCI模型中的神经元凋亡具有神经保护作用，并支持功能恢复。具体而言，SCI后给予Simv显著上调了低密度脂蛋白受体相关蛋白6磷酸化和β-连环蛋白的表达，增加了淋巴增强因子-1和T细胞因子-1的mRNA表达，并抑制了脊髓神经元中β-连环蛋白磷酸化的表达。Simv可提高脊髓前角运动神经元的存活率，减轻脊髓组织损伤。脊髓损伤后给予Simv还明显降低了脊髓神经元中Bax、活性caspase-3和活性caspase-9的表达水平以及转移酶UTP缺口末端标记（TUNEL）阳性神经元细胞的比例，但增加了脊髓神经元中Bcl-2的表达水平。然而，在脂多糖诱导的模型中，当Wnt/β-catenin信号通路被抑制时，Simv在培养的脊髓神经细胞中的抗凋亡作用降低。此外，Basso、Beattie和Bresnahan评分表明Simv治疗显著改善了SCI后大鼠的运动功能。这项研究首次报道Simv通过减少神经元凋亡发挥神经保护作用，并通过激活Wnt/β-catenin信号通路促进SCI后功能和病理恢复。 我们证实了辛伐他汀在脊髓损伤（SCI）后的神经保护作用。辛伐他汀通过激活Wnt/β-catenin信号通路减少神经元凋亡，促进神经元功能和病理的恢复，而辛伐他汀抑制Wnt/β-catenin信号通路后，其抗凋亡作用被逆转。这些结果为辛伐他汀治疗脊髓损伤提供了临床价值。
Statins exhibit neuroprotective effects after spinal cord injury (SCI). However, the molecular mechanism underlying these effects remains unknown. This study demonstrates that the hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin (Simv) exhibits neuroprotective effects on neuronal apoptosis and supports functional recovery in a rat SCI model by activating the Wnt/β‐catenin signaling pathway. In specific, Simv administration after SCI significantly up‐regulated the expression of low density lipoprotein receptor‐related protein 6 phosphorylation and β‐catenin protein, increased the mRNA expression of lymphoid enhancer factor‐1 and T‐cell factor‐1, and suppressed the expression of β‐catenin phosphorylation in the spinal cord neurons. Simv enhanced motor neuronal survival in the spinal cord anterior horn and decreased the lesion of spinal cord tissues after SCI. Simv administration after SCI also evidently reduced the expression levels of Bax, active caspase‐3, and active caspase‐9 in the spinal cord neurons and the proportion of transferase UTP nick end labeling (TUNEL)‐positive neuron cells, but increased the expression level of Bcl‐2 in the spinal cord neurons. However, the anti‐apoptotic effects of Simv were reduced in cultured spinal cord nerve cells when the Wnt/β‐catenin signaling pathway was suppressed in the lipopolysaccharide‐induced model. Furthermore, the Basso, Beattie, and Bresnahan scores indicated that Simv treatment significantly improved the locomotor functions of rats after SCI. This study is the first to report that Simv exerts neuroprotective effects by reducing neuronal apoptosis, and promoting functional and pathological recovery after SCI by activating the Wnt/β‐catenin signaling pathway. We verified the neuroprotective properties associated with simvastatin following spinal cord injury (SCI). Simvastatin reduced neuronal apoptosis, improved the functional and pathological recovery via activating Wnt/β‐catenin signal pathway, however, the anti‐apoptosis effects of simvastatin were reversed following suppressing Wnt/β‐catenin signaling pathway in primary spinal cord neurons. The significant findings may provide clinical therapeutic value of simvastatin for treating SCI.
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