Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-κB transcription regulation and activating cAMP/CREB axis.
Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-κB transcription regulation and activating cAMP/CREB axis.
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发现用于治疗血管性痴呆的新型磷酸二酯酶-1抑制剂：通过阻断 NF-κB 转录调节和激活 cAMP/CREB 轴来抑制神经炎症。
DOI：
10.1016/j.apsb.2022.09.023
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发表时间：
2023-03
影响因子：
14.5
通讯作者：
Wu, Yinuo
中科院分区：
文献类型：
--
作者：
Zhou, Qian;Le, Meiling;Yang, Yiyi;Wang, Wenjuan;Huang, Yuqi;Wang, Quan;Tian, Yijing;Jiang, Meiyan;Rao, Yong;Luo, Hai-Bin;Wu, Yinuo
关键词：
血管性痴呆（VaD）是目前缺乏有效治疗的第二常见痴呆类型。神经炎症是VaD的重要病理特征，与VaD的发生发展密切相关。为了验证PDE1抑制剂对VaD的治疗潜力，我们用一种强效、选择性的PDE1抑制剂4a在体外和体内评估了其抗神经炎症、记忆和认知改善的作用。并系统探讨了4a在改善神经炎症和VaD中的作用机制。此外，为了优化4a的类药物性质，特别是代谢稳定性，我们设计并合成了15个衍生物。因此，候选5f对PDE1C的IC50值为4.5 nmol/L，对PDEs的选择性高，代谢稳定性好，可通过抑制NF-κB转录调节和激活cAMP/CREB轴，有效改善VaD小鼠模型的神经元变性、认知和记忆障碍。这些结果进一步证实PDE1抑制可作为治疗VaD的一种新的治疗策略。靶向抑制PDE1通过抑制NF-κB转录调控和激活cAMP/CREB轴改善血管性痴呆（VaD）小鼠的认知和记忆障碍。
Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC50 value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD. Targeting inhibition of PDE1 improved cognitive and memory impairment in vascular dementia (VaD) mice by suppressing NF-κB transcription regulation and activating cAMP/CREB axis.
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影响因子：
11
作者：
Delhaye S;Bardoni B
通讯作者：
Bardoni B
DOI：
10.1016/j.mcn.2019.103449
发表时间：
2020-01
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
O'Brien JJ;O'Callaghan JP;Miller DB;Chalgeri S;Wennogle LP;Davis RE;Snyder GL;Hendrick JP
通讯作者：
Hendrick JP
影响因子：
5.3
作者：
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通讯作者：
Sun MK
影响因子：
5.7
作者：
Plassman, B. L.;Langa, K. M.;Wallace, R. B.
通讯作者：
Wallace, R. B.
影响因子：
16.2
作者：
Iadecola C
通讯作者：
Iadecola C