Borrajo Ana, Rodriguez-Perez Ana I, Villar-Cheda Begoña, Guerra Maria J, Labandeira-Garcia Jose L
Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
Neuropharmacology. 2014 Oct;85:1-8. doi: 10.1016/j.neuropharm.2014.05.021. Epub 2014 May 27.
Several recent studies have shown that activation of the RhoA/Rho-associated kinase (ROCK) pathway is involved in the MPTP-induced dopaminergic cell degeneration and possibly in Parkinson's disease. ROCK inhibitors have been suggested as candidate neuroprotective drugs for Parkinson's disease. However, the mechanism responsible for the increased survival of dopaminergic neurons after treatment with ROCK inhibitors is not clear. We exposed primary (neuron-glia) mesencephalic cultures, cultures of the MES 23.5 dopaminergic neuron cell line and primary mesencephalic cultures lacking microglial cells to the dopaminergic neurotoxin MPP+ and the ROCK inhibitor Y-27632 in order to study the effects of ROCK inhibition on dopaminergic cell loss and the length of neurites of surviving dopaminergic neurons. In primary (neuron-glia) cultures, simultaneous treatment with MPP+ and the ROCK inhibitor significantly reduced the loss of dopaminergic neurons. In the absence of microglia, treatment with the ROCK inhibitor did not induce a significant reduction in the dopaminergic cell loss. Treatment with the ROCK inhibitor induced a significant decrease in axonal retraction in primary cultures with and without microglia and in cultures of the MES 23.5 neuron cell line. In conclusion, inhibition of microglial ROCK is essential for the neuroprotective effects of ROCK inhibitors against cell death induced by the dopaminergic neurotoxin MPP+. In addition, ROCK inhibition induced a direct effect against axonal retraction in surviving neurons. However, the latter effect was not sufficient to cause a significant increase in the survival of dopaminergic neurons after treatment with MPP+.
最近的几项研究表明，RhoA/ Rho相关激酶（ROCK）信号通路的激活与MPTP诱导的多巴胺能细胞变性有关，并且可能与帕金森病有关。ROCK抑制剂已被认为是帕金森病潜在的神经保护药物。然而，ROCK抑制剂治疗后多巴胺能神经元存活率增加的机制尚不清楚。我们将原代（神经元-胶质细胞）中脑培养物、MES 23.5多巴胺能神经元细胞系培养物以及缺乏小胶质细胞的原代中脑培养物暴露于多巴胺能神经毒素MPP +和ROCK抑制剂Y-27632中，以研究ROCK抑制对多巴胺能细胞丢失以及存活的多巴胺能神经元神经突长度的影响。在原代（神经元-胶质细胞）培养物中，MPP +与ROCK抑制剂同时处理可显著减少多巴胺能神经元的丢失。在没有小胶质细胞的情况下，用ROCK抑制剂处理并没有显著减少多巴胺能细胞的丢失。ROCK抑制剂处理可显著减少有或没有小胶质细胞的原代培养物以及MES 23.5神经元细胞系培养物中的轴突回缩。总之，抑制小胶质细胞ROCK对于ROCK抑制剂对多巴胺能神经毒素MPP +诱导的细胞死亡的神经保护作用至关重要。此外，ROCK抑制对存活神经元的轴突回缩有直接作用。然而，后一种作用不足以导致MPP +处理后多巴胺能神经元的存活率显著增加。
