Cilostazol Protects Against Brain White Matter Damage and Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion
Cilostazol Protects Against Brain White Matter Damage and Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion
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DOI：
10.1161/01.str.0000221783.08037.a9
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发表时间：
2006-06
期刊：
影响因子：
8.3
通讯作者：
Terubumi Watanabe;Ning Zhang;Meizi Liu;R. Tanaka;Y. Mizuno;T. Urabe
中科院分区：
文献类型：
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作者：
Terubumi Watanabe;Ning Zhang;Meizi Liu;R. Tanaka;Y. Mizuno;T. Urabe
背景与目的-脑卒中后患者脑白质病变导致认知障碍。本研究旨在通过大鼠慢性脑低灌注模型，评估西洛他唑（III型磷酸二酯酶的有效抑制剂）通过激活转录因子camp -响应元件结合蛋白（CREB）磷酸化的信号通路的神经保护机制。方法：大鼠双侧颈总动脉结扎。将患者分为西洛他唑组（n=80）和载体组（n=80）。在基线和低灌注后3、7、14、21和28天分析4-羟基-2-壬烯醛（HNE）、谷胱甘肽- s -转移酶（GST-pi）、离子钙结合受体分子1、磷酸化CREB （p-CREB）、Bcl-2和环氧化酶2 （COX-2）在Morris水迷宫任务中的表现和免疫组化。结果-西洛他唑显著改善低灌注后7天的空间学习记忆（6.8±2.3秒；P<0.05）。西洛他唑显著抑制低灌注后早期脑白质中ne修饰蛋白的积累和gst -pi阳性少突胶质细胞的损失（P<0.05）。西洛他唑上调P - creb和Bcl-2 (P<0.05)，增加COX-2表达，降低低灌注早期小胶质细胞活化。结论-我们的研究结果表明，西洛他唑通过CREB磷酸化途径发挥脑保护作用，导致Bcl-2和COX-2表达上调，表明西洛他唑可能对脑卒中后患者的认知功能障碍有潜在的治疗作用。
Background and Purpose— White matter lesions contribute to cognitive impairment in poststroke patients. The present study was designed to assess the neuroprotective mechanisms of cilostazol, a potent inhibitor of type III phosphodiesterase, through signaling pathways that lead to activation of transcription factor cAMP-responsive element binding protein (CREB) phosphorylation using rat chronic cerebral hypoperfusion model. Methods— Rats underwent bilateral common carotid artery ligation. They were divided into the cilostazol group (n=80) and the vehicle (control) group (n=80). Performance at the Morris water maze task and immunohistochemistry for 4-hydroxy-2-nonenal (HNE), glutathione-S-transferase-pi (GST-pi), ionized calcium-binding adaptor molecule 1, phosphorylated CREB (p-CREB), Bcl-2, and cyclooxygenase-2 (COX-2) were analyzed at baseline and at 3, 7, 14, 21, and 28 days after hypoperfusion. Result— Cilostazol significantly improved spatial learning memory (6.8±2.3 seconds; P<0.05) at 7 days after hypoperfusion. Cilostazol markedly suppressed accumulation of HNE-modified protein and loss of GST-pi–positive oligodendrocytes in the cerebral white matter during the early period after hypoperfusion (P<0.05). Cilostazol upregulated p-CREB and Bcl-2 (P<0.05), increased COX-2 expression, and reduced microglial activation in the early period of hypoperfusion. Conclusion— Our results indicate that cilostazol exerts a brain-protective effect through the CREB phosphorylation pathway leading to upregulation of Bcl-2 and COX-2 expressions and suggest that cilostazol is potentially useful for the treatment of cognitive impairment in poststroke patients.