Department of Neurology, The University of Tokyo Graduate School of Medicine, Japan.
Department of Neurology, The University of Tokyo Graduate School of Medicine, Japan.
Neurosci Lett. 2018 Jan 1;662:247-252. doi: 10.1016/j.neulet.2017.10.045. Epub 2017 Nov 5.
Cilostazol is known to alleviate white matter demyelination due to chronic cerebral hypoperfusion in rodent models, although their pharmacological mechanisms remain unclear. In this study, we investigated the protective effect of cilostazol in relation to gene expression profile. Bilateral common carotid artery stenosis (BCAS) mice were treated with oral administration of cilostazol or placebo starting from a week after the surgery. Demyelination of the cingulum was compared between the 2 groups 2, 6, and 10 weeks after initial drug administration. Also, to examine temporal gene expression change during demyelination, DNA microarray analysis was conducted using samples from the corpus callosum of 2nd and 6th week BCAS mice. For genes that showed more than 2-fold up-regulation, their increase was validated by qPCR. Finally, to determine the effect of cilostazol towards those genes, their expression in the corpus callosum of 6-week placebo-treated and cilostazol-treated BCAS mice was compared by qPCR. Amelioration of myelin loss was observed in cilostazol-treated group, showing significant difference with those observed in placebo group after 10-week treatment. Gene ontology analysis of the 17 up-regulated (FDR<0.01) genes showed that majority of the genes were related to cell development processes. Among the validated genes, expression of Btg2 was significantly promoted in the corpus callosum of BCAS mice by administration of cilostazol. Results of this study suggest that activation of Btg2 may be one of the key pharmacological effects of cilostazol towards the white matter during chronic ischemia.
西洛他唑已知可减轻因慢性大脑低灌注引起的啮齿动物模型的白质脱髓鞘，尽管其药理机制尚不清楚。在这项研究中，我们研究了西洛他唑与基因表达谱的关系。在手术后一周开始，通过口服给予西洛他唑或安慰剂治疗双侧颈总动脉狭窄（BCAS）小鼠。在初始药物给药后 2、6 和 10 周比较 2 组之间扣带回的脱髓鞘情况。此外，为了检查脱髓鞘过程中的时间基因表达变化，使用来自第 2 和第 6 周 BCAS 小鼠胼胝体的样本进行 DNA 微阵列分析。对于显示超过 2 倍上调的基因，通过 qPCR 验证其增加。最后，为了确定西洛他唑对这些基因的作用，通过 qPCR 比较 6 周安慰剂治疗和西洛他唑治疗的 BCAS 小鼠胼胝体中的基因表达。在西洛他唑治疗组中观察到髓鞘丢失的改善，在 10 周治疗后与安慰剂组观察到的显著差异。17 个上调（FDR<0.01）基因的基因本体分析表明，大多数基因与细胞发育过程有关。在验证的基因中，Btg2 在 BCAS 小鼠的胼胝体中的表达通过西洛他唑给药显著促进。这项研究的结果表明，Btg2 的激活可能是西洛他唑在慢性缺血期间对白质的关键药理作用之一。
