Blood–Brain Barrier Permeable and NO-Releasing Multifunctional Nanoparticles for Alzheimer’s Disease Treatment: Targeting NO/cGMP/CREB Signaling Pathways,Journal of Medicinal Chemistry

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Blood–Brain Barrier Permeable and NO-Releasing Multifunctional Nanoparticles for Alzheimer’s Disease Treatment: Targeting NO/cGMP/CREB Signaling Pathways
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-13 , DOI: 10.1021/acs.jmedchem.1c01240
Zhikun Liu _{1,

2} , Qingqing Liu _{1,

2} , Bin Zhang _{1,

2} , Qiao Liu _{1,

2} , Lei Fang _{1,

2} , Shaohua Gou _{1,

2}

Affiliation

The development of novel therapeutic strategies for combating Alzheimer’s disease (AD) is challenging but imperative. Multifunctional nanoparticles are promising tools for regulating complex pathological dysfunctions for AD treatment. Herein, we constructed multifunctional nanoparticles consisting of regadenoson (Reg), nitric oxide (NO) donor, and YC-1 in a single molecular entity that can spontaneously self-assemble into nanoparticles and load donepezil to yield Reg-nanoparticles (Reg-NPs). The Reg moiety enabled the Reg-NPs to effectively regulate tight junction-associated proteins in the blood–brain barrier, thus facilitating the permeation of donepezil through the barrier and its accumulation in the brain. Moreover, the released NO and YC-1 activated the NO/cGMP/CREB signaling pathway by stimulating soluble guanylyl cyclase and inhibiting phosphodiesterase activity, which finally reduced cytotoxicity induced by aggregated Aβ in the neurons and was beneficial for synaptic plasticity and memory formation.

中文翻译：

用于治疗阿尔茨海默病的血脑屏障可渗透且释放 NO 的多功能纳米颗粒：针对 NO/cGMP/CREB 信号通路

开发对抗阿尔茨海默病（AD）的新型治疗策略具有挑战性，但势在必行。多功能纳米粒子是调节 AD 治疗中复杂病理功能障碍的有前途的工具。在此，我们在单个分子实体中构建了由热加腺苷（Reg）、一氧化氮（NO）供体和YC-1组成的多功能纳米颗粒，该纳米颗粒可以自发自组装成纳米颗粒并负载多奈哌齐以产生Reg-纳米颗粒（Reg-NPs）。 Reg部分使Reg-NPs能够有效调节血脑屏障中的紧密连接相关蛋白，从而促进多奈哌齐穿过血脑屏障并在大脑中积聚。此外，释放的NO和YC-1通过刺激可溶性鸟苷酸环化酶、抑制磷酸二酯酶活性，激活NO/cGMP/CREB信号通路，最终降低神经元内聚集的Aβ诱导的细胞毒性，有利于突触可塑性和记忆形成。

更新日期：2021-09-23

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