Centro de Investigación y Desarrollo de Medicamentos (CIDEM), BioCubaFarma, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600 La Habana, Cuba.
Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, Department of Biochemistry, Ghent University, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
Brain Behav Immun. 2017 Aug;64:103-115. doi: 10.1016/j.bbi.2017.04.002. Epub 2017 Apr 6.
Stroke represents one of the first causes of mortality and morbidity worldwide. We evaluated the therapeutic potential of a novel semi-synthetic spirosteroid sapogenin derivative "S15" in a transient middle cerebral artery occlusion (tMCAO) focal ischemia model in rat. S15-treated rats had significantly reduced infarct volumes and improved neurological functions at 24h post-reperfusion, compared with ischemia. Corresponding gene expression changes in brain were characterized by mRNA sequencing and qPCR approaches. Next, we applied geneset, pathway and transcription factor motif enrichment analysis to identify relevant signaling networks responsible for neuronal damage upon ischemia-reperfusion or neuroprotection upon pretreatment with S15. As expected, ischemia-reperfusion brain damage strongly modulates transcriptional programs associated with immune responses, increased differentiation of immune cells as well as reduced (cat)ion transport and synaptic activity. Interestingly, S15-dependent neuroprotection regulates inflammation-associated genes involved in phagosome specific resolution of tissue damage, chemotaxis and anti-inflammatory alternative activation of microglia. Altogether our transcriptome wide RNA sequencing and integrated pathway analysis provides new clues in the neuroprotective properties of a novel spirosteroid S15 or neuronal damage in rat brains subjected to ischemia, which opens new perspectives for successful treatment of stroke.
中风是全球范围内导致死亡和发病的首要原因之一。我们评估了一种新型半合成甾体皂苷原代化合物“S15”在大鼠短暂性大脑中动脉闭塞（tMCAO）局灶性缺血模型中的治疗潜力。与缺血组相比，S15 治疗组大鼠在再灌注后 24 小时的梗死体积显著减小，神经功能明显改善。采用 mRNA 测序和 qPCR 方法对大脑中的相应基因表达变化进行了特征分析。接下来，我们应用基因集、通路和转录因子基序富集分析来确定与缺血再灌注引起的神经元损伤或 S15 预处理引起的神经保护相关的信号转导网络。正如预期的那样，缺血再灌注脑损伤强烈调节与免疫反应相关的转录程序，增加免疫细胞的分化，以及减少（cat）离子转运和突触活性。有趣的是，S15 依赖性神经保护调节与吞噬体特异性组织损伤、趋化和小胶质细胞抗炎替代激活相关的炎症相关基因。总的来说，我们的全转录组 RNA 测序和综合通路分析为新型甾体 S15 的神经保护特性或大鼠大脑缺血引起的神经元损伤提供了新的线索，为中风的成功治疗开辟了新的视角。
