Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany.
PLoS One. 2013 Jul 31;8(7):e70124. doi: 10.1371/journal.pone.0070124. Print 2013.
The Sphingosine-1-phosphate (S1P) signaling pathway is known to influence pathophysiological processes within the brain and the synthetic S1P analog FTY720 has been shown to provide neuroprotection in experimental models of acute stroke. However, the effects of a manipulation of S1P signaling at later time points after experimental stroke have not yet been investigated. We examined whether a relatively late initiation of a FTY720 treatment has a positive effect on long-term neurological outcome with a focus on reactive astrogliosis, synapses and neurotrophic factors.
We induced photothrombotic stroke (PT) in adult C57BL/6J mice and allowed them to recover for three days. Starting on post-stroke day 3, mice were treated with FTY720 (1 mg/kg b.i.d.) for 5 days. Behavioral outcome was observed until day 31 after photothrombosis and periinfarct cortical tissue was analyzed using tandem mass-spectrometry, TaqMan®analysis and immunofluorescence.
FTY720 treatment results in a significantly better functional outcome persisting up to day 31 after PT. This is accompanied by a significant decrease in reactive astrogliosis and larger post-synaptic densities as well as changes in the expression of vascular endothelial growth factor α (VEGF α). Within the periinfarct cortex, S1P is significantly increased compared to healthy brain tissue.
Besides its known neuroprotective effects in the acute phase of experimental stroke, the initiation of FTY720 treatment in the convalescence period has a positive impact on long-term functional outcome, probably mediated through reduced astrogliosis, a modulation in synaptic morphology and an increased expression of neurotrophic factors.
鞘氨醇-1-磷酸（S1P）信号通路已知会影响大脑中的病理生理过程，并且已证明合成 S1P 类似物 FTY720 在急性中风的实验模型中提供神经保护作用。然而，实验性中风后 S1P 信号转导的相对晚期干预的效果尚未得到研究。我们研究了 FTY720 治疗的相对较晚开始是否对长期神经学结局产生积极影响，重点是反应性星形胶质细胞增生、突触和神经营养因子。
我们在成年 C57BL/6J 小鼠中诱导光血栓性中风（PT），并允许它们恢复三天。从中风后第 3 天开始，用 FTY720（1mg/kg b.i.d.）治疗 5 天。在光血栓形成后第 31 天观察行为结局，并使用串联质谱、TaqMan®分析和免疫荧光分析梗塞周围皮质组织。
FTY720 治疗可显著改善功能结局，持续至 PT 后第 31 天。这伴随着反应性星形胶质细胞增生的显著减少和更大的突触后密度以及血管内皮生长因子α（VEGFα）的表达变化。在梗塞周围皮质内，S1P 与健康脑组织相比显著增加。
除了在实验性中风的急性期已知的神经保护作用外，在恢复期开始 FTY720 治疗对长期功能结局有积极影响，可能通过减少星形胶质细胞增生、调节突触形态和增加神经营养因子表达来介导。
