PDF(Sci-hub)
Abstract：
BACKGROUND: Preclinical studies, clinical trials, and reviews suggest increasing 3\',5\'-cyclic adenosine monophosphate (cAMP) and 3\',5\'-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer\'s disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1α. PGC1α induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFκB and tau-phosphorylating GSK3β.
OBJECTIVE: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD.
RESULTS: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition.
CONCLUSIONS: Phosphodiesterase inhibitors may prevent and treat AD.
OBJECTIVE: We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD.
RESULTS: Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition.
CONCLUSIONS: Phosphodiesterase inhibitors may prevent and treat AD.
摘要：
背景：临床前研究，临床试验,和评论建议增加3\'，5'-环磷酸腺苷（cAMP）和3'，5'-环磷酸鸟苷(cGMP)与磷酸二酯酶抑制剂在阿尔茨海默病(AD)中具有疾病改善作用。cAMP/蛋白激酶A(PKA)和cGMP/蛋白激酶G(PKG)信号在AD中被破坏。cAMP/PKA和cGMP/PKG激活cAMP反应元件结合蛋白(CREB)。CREB结合线粒体和核DNA，诱导突触发生，记忆,和神经元存活基因(例如，脑源性神经营养因子）和过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC1α）。cAMP/PKA和cGMP/PKG激活Sirtuin-1，从而激活PGC1α。PGC1α诱导线粒体生物发生和抗氧化基因(例如，Nrf2）并抑制BACE1。cAMP和cGMP抑制BACE1诱导的NFκB和tau磷酸化GSK3β。
目的：我们回顾了疗效测试临床试验，流行病学,和荟萃分析，以严格调查磷酸二酯酶抑制剂是否预防或治疗AD。
结果：咖啡因和西洛他唑可能降低AD风险。丁苯茶碱和西地那非的临床试验是有希望的，但初步的和不确定的。PF-04447943和BI409,306无效。长春西汀,西洛他唑,尼麦角林的试验好坏参半.Deprinyl/司来吉兰试验仅显示短期益处。广谱磷酸二酯酶抑制剂propentofylline已在五项III期试验中显示可改善认知，痴呆严重程度，日常生活活动,以及对轻度至中度AD患者进行多尺度的全球评估，包括为期18个月的III期临床试验中的ADAS-CogandtheCIBIC-Plus。然而,根据MedScape文章声称的两本书，为期18个月的III期试验失败，所以propentofylline被停用了.现在,propentofylline用于治疗犬的认知功能障碍，which,像AD,涉及年龄相关的野生型Aβ沉积。
结论：磷酸二酯酶抑制剂可以预防和治疗AD。
目的：我们回顾了疗效测试临床试验，流行病学,和荟萃分析，以严格调查磷酸二酯酶抑制剂是否预防或治疗AD。
结果：咖啡因和西洛他唑可能降低AD风险。丁苯茶碱和西地那非的临床试验是有希望的，但初步的和不确定的。PF-04447943和BI409,306无效。长春西汀,西洛他唑,尼麦角林的试验好坏参半.Deprinyl/司来吉兰试验仅显示短期益处。广谱磷酸二酯酶抑制剂propentofylline已在五项III期试验中显示可改善认知，痴呆严重程度，日常生活活动,以及对轻度至中度AD患者进行多尺度的全球评估，包括为期18个月的III期临床试验中的ADAS-CogandtheCIBIC-Plus。然而,根据MedScape文章声称的两本书，为期18个月的III期试验失败，所以propentofylline被停用了.现在,propentofylline用于治疗犬的认知功能障碍，which,像AD,涉及年龄相关的野生型Aβ沉积。
结论：磷酸二酯酶抑制剂可以预防和治疗AD。
