BACKGROUND and purpose: In this study, we employed a multiple microinfarction (MMI) based vascular dementia (VaD) model in aged rats and tested the therapeutic effects of Sildenafil, a phosphodiesterase type 5 inhibitor, on cognitive decline, white matter damage, autophagy and inflammatory response associated with VaD. METHODS Male, aged (16-18 months) Wistar rats were subjected to MMI (800 ± 100, 70-100 μm cholesterol crystals injected into the internal carotid artery) and treated with or without Sildenafil (2 mg/kg, i.p) starting at 24 h after MMI daily for 28 days. Four experimental groups were employed: Sham control, Sham + Sildenafil, MMI, and MMI + Sildenafil. A battery of cognitive tests were performed and rats were sacrificed at 28 days after MMI for immunohistochemical evaluation and PCR assay. RESULTS Sildenafil treatment in aged MMI rats significantly improves short term memory evaluated by the novel object recognition test and improves spatial learning and memory in the Morris water maze test compared to aged control MMI rats. Sildenafil treatment of aged MMI rats significantly increases axon and myelin density in the corpus callosum and white matter bundles in the striatum, increases oligodendrocyte and oligodendrocyte progenitor cell number in the corpus callosum, cortex and striatum, and increases synaptic protein expression in the cortex and striatum compared to aged control MMI rats. In addition, Sildenafil treatment of MMI in aged rats significantly decreases Beclin1 expression and inflammatory factors Monocyte chemoattractant protein-1 and Interleukin-1β expression in brain. Sildenafil treatment in aged rats does not improve cognitive outcome compared to aged sham control rats. CONCLUSIONS Sildenafil treatment of MMI in aged rats significantly improves cognition and memory at 1 month after MMI. Sildenafil treatment increases axon and myelin density, increases Synaptophysin expression, decreases autophagic activity and exerts anti-inflammatory effects which in concert may contribute to cognitive improvement in aged rats subjected to MMI.

中文翻译：

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西地那非治疗老年大鼠血管性痴呆。

背景与目的：在本研究中，我们采用基于多发性微梗死（MMI）的老年大鼠血管性痴呆（VaD）模型，测试了 5 型磷酸二酯酶抑制剂西地那非对认知能力下降、白质损伤、自噬和自噬的治疗作用。与 VaD 相关的炎症反应。方法 雄性，年龄（16-18 个月）Wistar 大鼠接受 MMI（800 ± 100, 70-100 μm 胆固醇晶体注入颈内动脉），并用或不用西地那非（2 mg/kg，ip）治疗每天 MMI 后 24 小时，持续 28 天。采用了四个实验组：假手术对照组、假手术+西地那非、MMI 和MMI + 西地那非。进行了一系列认知测试，并在 MMI 后 28 天处死大鼠进行免疫组织化学评估和 PCR 测定。结果与老年对照MMI大鼠相比，老年MMI大鼠的西地那非治疗显着改善了新物体识别测试评估的短期记忆，并改善了Morris水迷宫测试中的空间学习和记忆力。西地那非治疗老年 MMI 大鼠显着增加胼胝体和纹状体白质束中的轴突和髓鞘密度，增加胼胝体、皮质和纹状体中的少突胶质细胞和少突胶质祖细胞数量，并增加皮质和纹状体中的突触蛋白表达与老年对照 MMI 大鼠相比。此外，西地那非治疗老年大鼠 MMI 显着降低脑中 Beclin1 表达和炎症因子单核细胞趋化蛋白 1 和白细胞介素 1β 表达。与老年假对照组大鼠相比，老年大鼠的西地那非治疗不会改善认知结果。结论 西地那非治疗老年大鼠 MMI 可显着改善 MMI 后 1 个月的认知和记忆力。西地那非治疗增加轴突和髓鞘密度，增加突触素表达，降低自噬活性并发挥抗炎作用，这可能有助于改善接受 MMI 的老年大鼠的认知能力。