Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.
Simvastatin prevents dopaminergic neurodegeneration in experimental parkinsonian models: the association with anti-inflammatory responses.
复制标题
DOI：
10.1371/journal.pone.0020945
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Yan J;Xu Y;Zhu C;Zhang L;Wu A;Yang Y;Xiong Z;Deng C;Huang XF;Yenari MA;Yang YG;Ying W;Wang Q
除了最初用于降低胆固醇外，他汀类药物还显示出多种神经保护作用。n -甲基- d -天冬氨酸（NMDA）受体与多巴胺能系统密切相互作用，并与帕金森病（PD）的治疗模式密切相关。本研究旨在探讨辛伐他汀通过调节NMDA受体对实验性帕金森模型的影响。通过给予辛伐他汀3周，观察6-羟多巴胺损伤单侧内侧前脑束后大鼠脑内NMDA受体的区域变化和抗焦虑样活性。采用[3H]MK-801（地佐西平）结合放射自显影法检测死后大鼠脑内NMDA受体的改变。应用6-羟多巴胺处理PC12，研究辛伐他汀的神经保护作用、与NMDA受体的关联以及抗炎作用。在6-羟多巴胺损伤大鼠中，观察到6-羟多巴胺诱导的焦虑和海马、CA1区、杏仁核和尾状壳核中NMDA受体的下调，而辛伐他汀显著改善了焦虑样活动，恢复了NMDA受体在检查脑区的表达。在服用辛伐他汀后，焦虑样活性与海马、杏仁核和CA1中NMDA受体表达的恢复呈显著正相关。辛伐他汀在6-羟多巴胺损伤的大鼠脑和6-羟多巴胺处理的PC12中发挥神经保护作用，部分通过调节NMDA受体、MMP9（基质金属蛋白酶-9）和TNF-a（肿瘤坏死因子- α）。我们的研究结果提供了强有力的证据，辛伐他汀治疗后NMDA受体的调节可以部分解释其在实验性帕金森模型中的抗焦虑样活性和抗炎机制。这些发现有助于更好地理解辛伐他汀通过NMDA受体治疗PD的关键作用。
In addition to their original applications to lowering cholesterol, statins display multiple neuroprotective effects. N-methyl-D-aspartate (NMDA) receptors interact closely with the dopaminergic system and are strongly implicated in therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate how simvastatin impacts on experimental parkinsonian models via regulating NMDA receptors. Regional changes in NMDA receptors in the rat brain and anxiolytic-like activity were examined after unilateral medial forebrain bundle lesion by 6-hydroxydopamine via a 3-week administration of simvastatin. NMDA receptor alterations in the post-mortem rat brain were detected by [3H]MK-801(Dizocilpine) binding autoradiography. 6-hydroxydopamine treated PC12 was applied to investigate the neuroprotection of simvastatin, the association with NMDA receptors, and the anti-inflammation. 6-hydroxydopamine induced anxiety and the downregulation of NMDA receptors in the hippocampus, CA1(Cornu Ammonis 1 Area), amygdala and caudate putamen was observed in 6-OHDA(6-hydroxydopamine) lesioned rats whereas simvastatin significantly ameliorated the anxiety-like activity and restored the expression of NMDA receptors in examined brain regions. Significant positive correlations were identified between anxiolytic-like activity and the restoration of expression of NMDA receptors in the hippocampus, amygdala and CA1 following simvastatin administration. Simvastatin exerted neuroprotection in 6-hydroxydopamine-lesioned rat brain and 6-hydroxydopamine treated PC12, partially by regulating NMDA receptors, MMP9 (matrix metalloproteinase-9), and TNF-a (tumour necrosis factor-alpha). Our results provide strong evidence that NMDA receptor modulation after simvastatin treatment could partially explain its anxiolytic-like activity and anti-inflammatory mechanisms in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD via NMDA receptors.
登录
查看更多内容
影响因子：
5.6
作者：
Araki, T;Tanji, H;Itoyama, Y
通讯作者：
Itoyama, Y
影响因子：
3.7
作者：
Byrnes, Elizabeth M.;Bridges, Robert S.
通讯作者：
Bridges, Robert S.
影响因子：
5.3
作者：
Hallett, PJ;Spoelgen, R;Dunah, AW
通讯作者：
Dunah, AW
影响因子：
9.9
作者：
Cramer, C.;Haan, M. N.;Kalbfleisch, J. D.
通讯作者：
Kalbfleisch, J. D.
DOI：
10.1523/jneurosci.4144-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ghosh A;Roy A;Matras J;Brahmachari S;Gendelman HE;Pahan K
通讯作者：
Pahan K