Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.
Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.
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辛伐他汀可保护听觉毛细胞免受庆大霉素诱导的毒性，并在体外激活Akt信号传导。
DOI：
10.1186/1471-2202-12-114
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发表时间：
2011-11-14
期刊：
影响因子：
2.4
通讯作者：
Bodmer D
中科院分区：
文献类型：
--
作者：
Brand Y;Setz C;Levano S;Listyo A;Chavez E;Pak K;Sung M;Radojevic V;Ryan AF;Bodmer D
3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂，称为他汀类药物，通常用作降胆固醇药物。在过去的十年中，有证据表明他汀类药物也具有神经保护作用。视网膜研究表明，常用的他汀类药物辛伐他汀可增加体内Akt磷酸化，这表明PI 3 K/Akt途径有助于实现保护作用。虽然关于神经保护作用的研究已经在几个系统中进行，但他汀类药物对内耳的影响在很大程度上是未知的。我们评估是否3-羟基-3-甲基戊二酰辅酶A还原酶是存在于大鼠耳蜗内，辛伐他汀是否能够保护听毛细胞从庆大霉素诱导的凋亡细胞死亡在体外小鼠模型。此外，我们评估了辛伐他汀是否增加Corti器官中Akt磷酸化。采用逆转录-聚合酶链反应（RT-PCR）检测Corti器、螺旋神经节和血管纹中3-羟基-3-甲基戊二酰辅酶A还原酶mRNA的表达。此外，我们观察到，与单独使用庆大霉素处理的样本相比，除了庆大霉素之外，还使用辛伐他汀处理的Corti器官中毛细胞损失呈剂量依赖性且显着减少。辛伐他汀的保护作用被逆转的甲羟戊酸，辛伐他汀阻断的下游代谢产物，证明了保护的特异性。最后，蛋白质印迹法显示辛伐他汀处理后Corti Akt磷酸化的器官在体外增加。这些结果表明他汀类药物在内耳中的神经保护作用，通过减少3-羟基-3-甲基戊二酰辅酶A还原酶代谢和Akt活化介导。
Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, are commonly used as cholesterol-lowering drugs. During the past decade, evidence has emerged that statins also have neuroprotective effects. Research in the retina has shown that simvastatin, a commonly used statin, increases Akt phosphorylation in vivo, indicating that the PI3K/Akt pathway contributes to the protective effects achieved. While research about neuroprotective effects have been conducted in several systems, the effects of statins on the inner ear are largely unknown. We evaluated whether the 3-hydroxy-3-methylglutaryl-coenzyme A reductase is present within the rat cochlea and whether simvastatin is able to protect auditory hair cells from gentamicin-induced apoptotic cell death in a in vitro mouse model. Furthermore, we evaluated whether simvastatin increases Akt phosphorylation in the organ of Corti. We detected 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in organ of Corti, spiral ganglion, and stria vascularis by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, we observed a dose-dependent and significant reduction of hair cell loss in organs of Corti treated with simvastatin in addition to gentamicin, as compared to samples treated with gentamicin alone. The protective effect of simvastatin was reversed by addition of mevalonate, a downstream metabolite blocked by simvastatin, demonstrating the specificity of protection. Finally, Western blotting showed an increase in organ of Corti Akt phosphorylation after simvastatin treatment in vitro. These results suggest a neuroprotective effect of statins in the inner ear, mediated by reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase metabolism and Akt activation.
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DOI：
10.1096/fj.02-1014fje
发表时间：
2003-05
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Greenwood J;Walters CE;Pryce G;Kanuga N;Beraud E;Baker D;Adamson P
通讯作者：
Adamson P
影响因子：
2.8
作者：
Bodmer, D;Brors, D;Ryan, AF
通讯作者：
Ryan, AF
影响因子：
1
作者：
Bodmer, D;Brors, D;Ryan, AF
通讯作者：
Ryan, AF
影响因子：
1.7
作者：
Okuda, T;Sugahara, K;Yamashita, H
通讯作者：
Yamashita, H
通过通过阿托伐他汀靶向Th1细胞，治疗实验性脑脊髓炎中的复发性麻痹。
影响因子：
15.3
作者：
Aktas, O;Waiczies, S;Smorodchenko, A;Dörr, J;Seeger, B;Prozorovski, T;Sallach, S;Endres, M;Brocke, S;Nitsch, R;Zipp, F
通讯作者：
Zipp, F