Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.

Keywords: Alzheimer's disease; Memory impairment; Neuroinflammation; P301S; PDE5 inhibitors; Pyrazolines; Tau.

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磷酸二酯酶-5（PDE5）抑制剂主要用于治疗勃起功能障碍和肺动脉高压，但也被报道可能对阿尔茨海默病（AD）的治疗具有潜在疗效。这可能是通过刺激一氧化氮（NO）/环磷酸鸟苷（cGMP）信号通路来实现的，因为cGMP是参与神经可塑性过程中的第二信使。在本研究中，我们使用P301S tauopathy小鼠模型评估了一种新型PDE5抑制剂RF26的有效性。大量实验证据表明，tau包涵体的发展会导致包括AD、额颞痴呆（FTD）、进行性核上性麻痹和其他疾病在内的tau病的神经退行性变。RF26成功靶向NO/cGMP信号通路，并通过Morris水迷宫和T形迷宫测试显著改善了P301S小鼠的空间记忆任务表现。此外，接受RF26治疗的小鼠表现出磷酸化tau包涵体负载、星形胶质细胞增生的显著减少以及促炎性细胞因子下调。所呈现的数据支持RF26作为一种有效的PDE5抑制剂，并呼吁进一步研究其作为阿尔茨海默病及其他tau相关神经退行性疾病潜在治疗药物的可能性。

关键词：阿尔茨海默病；记忆障碍；神经炎症；P301S；PDE5抑制剂；吡唑啉