Nature Aging:PDE5抑制剂再现传奇,或可防治阿尔茨海默病

2021-12-07 生物世界 生物世界

目前,全球约有5000万人罹患阿尔茨海默病(Alzheimer's disease, AD),俗称“老年痴呆”,是最常见的神经退行性疾病。随着人类平均寿命增长,老年化社会加剧,

目前,全球约有5000万人罹患阿尔茨海默病(Alzheimer's disease, AD),俗称“老年痴呆”,是最常见的神经退行性疾病。随着人类平均寿命增长,老年化社会加剧,阿尔茨海默病的患病率也在不断上升,预计到2050年,阿尔茨海默病患者将增加至1.5亿以上,给社会造成了巨大且不断增加的经济和疾病负担。

阿尔茨海默病的病理特征是大脑中存在β-淀粉样蛋白(Aβ)和Tau淀粉样蛋白沉积,然而,现在针对Aβ和tau蛋白的阿尔茨海默病的药物对患者缺乏临床益处,大多数临床试验证实这类药物并不能改善这些患者的认知功能。

2021年12月6日,美国克利夫兰医学中心的程飞雄团队在 Nature 子刊 Nature Aging 发表了题为:Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease 的研究论文,研究发现老药,大家熟知的伟哥,学名叫西地那非,主要用于治疗肺动脉高压和男性勃起功能障碍,惊奇地发现与阿尔茨海默病发病风险显著降低有关。

陈雄飞团队利用一种计算方法整合了遗传学数据和其他生物学数据,构建了能展现阿尔茨海默病生物学特征的13个疾病“内表型模块”。研究团队将这些模块绘制成一个包含了351444种人类蛋白互作的大型网络,随后计算了1600种FDA批准药物的网络接近度分数,分数越高表示该药物在阿尔茨海默病相关模块中能与多种分子靶点(靶向Aβ和tau蛋白)进行物理相互作用。

结果显示,西地那非是得分最高的药物之一,而且之前有临床前研究表明西地那非可以显著改善认知和记忆,这提示了该药或能影响阿尔茨海默病。

这项研究中,为进行验证西地那非与阿尔茨海默病的关联,进一步分析了美国723万人的保险理赔数据,发现开处方药西地那非与随访6年后阿尔茨海默病确诊风险降低69%有关(HR:0.31, 95% CI 0.25–0.39, P < 1.0 × 10–8),这是惊人的效果,虽然这样的数据中存在很多偏倚

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由于西地那非主要用于治疗男性勃起功能障碍,所以性别因素显得尤其重要,因此,研究团队校正了性别、年龄这些潜在影响因素。校正后的数据表明,开处方药西地那非与男性随访6年后阿尔茨海默病确诊风险降低73%有关,与女性风险降低35%有关。与65-74岁年龄的人风险降低62%有关,与75岁及以上的人风险降低51%有关。

 

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这些结果表明,西地那非与真实世界患者数据中阿尔茨海默病发病率的降低有显著关系。

研究团队进一步使用来自阿尔茨海默病患者的诱导多能干细胞(iPSC)的人类小胶质细胞和神经元,进行体外实验,结果发现,西地那非能够增加神经轴突生长,并降低tau蛋白的异常磷酸化,从机制上支持了西地那非在降低阿尔茨海默病风险中的潜在有益作用。

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该研究的领导者程飞雄博士

这项研究结果意外发现了伟哥的神奇作用,事实上,也并不意外。梅斯医学小编认为:

其一,西地那非一直剑走偏峰。西地那非俗称“伟哥”,由美国辉瑞公司研发,最初作为治疗心血管疾病的5-磷酸二酯酶(PDE5)抑制剂而进行临床研究。然而,它并没有达到研究人员的预期的扩张血管、缓解心血管疾病的目的。1991年4月,西地那非的临床研究正式宣告失败。但意外发现它能治疗男性勃起功能障碍(ED),1998年西地那非获得FDA批准上市,用于治疗男性勃起功能障碍(ED),一度成为闻名全球的蓝色小药丸。

其二,当前的研究结果还不能论证西地那非与阿尔茨海默病风险存在因果关系。未来还需要开展随机对照试验进行证实。

其三,最近一些年,已有一些基础研究和临床研究提供了迹象。去年一项系统综述,全面概括了西地那非与阿尔茨海默病风险的关系,认为有很多机制可能是有效的。首先,一氧化氮/环磷酸鸟苷 (cGMP) 信号在阿尔茨海默病 (AD) 中受到损害,而降解 cGMP 的磷酸二酯酶 5 (PDE5) 则被上调。西地那非抑制 PDE5 并增加 cGMP 水平。低剂量西地那非可能会抑制 β-分泌酶 1 的表达和淀粉样蛋白-β (Aβ) 的生成,上调抗氧化酶,并诱导线粒体生物发生。其次,西地那非应增加脑灌注、胰岛素敏感性、长时程增强和神经发生,同时抑制神经细胞凋亡和炎症。

其四,这项研究不是心血来潮。事实上,最早2004年就有研究发现,西地那非能改善小鼠的学习记忆功能。2010年,Sabayan B首次提出可能用于治疗阿尔茨海默病。最近10年,又有大量的研究从不同角度发现西地那非具有潜在作用。

参考文献:

Fang, J., Zhang, P., Zhou, Y. et al. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nat Aging (2021). https://doi.org/10.1038/s43587-021-00138-z

Sanders O.Sildenafil for the Treatment of Alzheimer's Disease: A Systematic Review.J Alzheimers Dis Rep. 2020 Apr 22;4(1):91-106

Devan BD, Sierra-Mercado D Jr, Jimenez M, Bowker JL, Duffy KB, Spangler EL, Ingram DK.Phosphodiesterase inhibition by sildenafilcitrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.Pharmacol Biochem Behav. 2004 Dec;79(4):691-9

Sabayan B, Zamiri N, Farshchizarabi S, Sabayan B.Phosphodiesterase-5 inhibitors: novel weapons against Alzheimer'sdisease?Int J Neurosci. 2010 Dec;120(12):746-51

Liu L, Xu H, Ding S, Wang D, Song G, Huang X.Phosphodiesterase 5 inhibitors as novel agents for the treatment of Alzheimer's disease.Brain Res Bull. 2019 Nov;153:223-231

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  3. 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    2022-06-01 jklm09
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    2022-07-25 屋顶瞄爱赏月

    签到学习

    0

  6. 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  9. [GetPortalCommentsPageByObjectIdResponse(id=1885524, encodeId=109c18855249c, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Aug 12 07:04:04 CST 2022, time=2022-08-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818164, encodeId=2993181816468, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210606/e8b96fdba070433da10cd357c0646807/28bf16f46e314caaad8396c0c7df7a04.jpg, createdBy=adb15496357, createdName=仁术2021, createdTime=Tue Dec 07 12:26:45 CST 2021, time=2021-12-07, status=1, ipAttribution=)]
    2021-12-08 微风山谷smile

    老药新用

    0

  10. 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    2021-12-07 仁术2021

    不错,学习了。

    0

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检测阿尔茨海默病(AD)中淀粉样蛋白(Aβ)病理是生物标记物在临床治疗中实施的一个重大进步。某些基于高精度免疫沉淀-耦合质谱法的方法在检测脑Aβ病理时比大多数血浆Aβ42/40免疫分析方法表现更得更好

Alz Res Therapy:脑脊液tau蛋白,助力认知功能分组

脑脊液(CSF)中的高t-tau水平被认为反映了神经元的变性或损伤,在各种涉及神经元死亡的情况下,如急性中风后,CSF中可以发现高t-tau水平。越来越高的tau亚组的特点是MMSE下降更快,发展为A

JAMA Neurology:哌醋甲酯对阿尔茨海默病患者情感淡漠的影响--ADMET-2随机临床试验

淡漠是阿尔茨海默病(AD)患者最常见的神经精神症状之一。研究发现哌醋甲酯是一种安全有效的药物,可用于治疗阿尔茨海默病的冷漠。

JAMA Neurology:左乙拉西坦对伴有与不伴有癫痫样活动的阿尔茨海默病患者认知功能的影响

在这项随机临床试验中,左乙拉西坦的耐受性很好,尽管它没有改善主要结果,但在预先指定的分析中,左乙拉西坦改善了阿尔茨海默病(AD)和癫痫样活动患者的空间记忆和执行功能任务的表现。

Alz Res Therapy:胆碱酯酶抑制剂使用,或和认知功能变化无关

在有或没有淀粉样物质负担的患者中,使用或不使用CEI与1年的随访中的认知变化无关