Multi-functional memantine nitrate attenuated cognitive impairment in models of vascular dementia and Alzheimer's disease through neuroprotection and increased cerebral blood flow

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-03-11 DOI:10.1016/j.neuropharm.2025.110410

Guangying Chen , Kexin Zhang , Minghua Sun , Ningqing Xie , Liangmiao Wu , Guiliang Zhang , Baojian Guo , Chunhui Huang , Maggie Pui Man Hoi , Gaoxiao Zhang , Changzheng Shi , Yewei Sun , Zaijun Zhang , Yuqiang Wang

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引用次数: 0

Abstract

Alzheimer's disease (AD) and vascular dementia (VaD) are two prevalent forms of dementia. VaD is linked to cerebrovascular lesions, such as those from white matter ischemia and chronic cerebral hypoperfusion, which can also occur in AD. Nitric oxide (NO) regulates cerebral blood flow (CBF) in the central nervous system. Memantine is an NMDA receptor antagonist approved for AD treatment. This study investigated the efficacy and molecular mechanism of MN-08, a novel memantine nitrate, in one VaD model (2VO) and two AD models (APP/PS1 mice and Aβ1-42-induced mice). MN-08 increased CBF, ameliorated cognitive and memory functions in VaD and AD, and was more effective than memantine. MN-08 increased the survival rate of CA1 neurons and mitigated white matter lesions and axonal damage. Moreover, MN-08 protected neurons from OGD-induced loss and promoted axonal outgrowth in the hippocampus by upregulating phosphorylated Akt (p-Akt), glycogen synthase kinase-3β (p-GSK3β), and high-molecular-weight neurofilaments (p-NFH). The beneficial effects of MN-08 were attenuated by carboxy-PTIO, a potent NO scavenger, suggesting that MN-08-derived NO may alleviate cognitive impairment from cerebral hypoperfusion. Taken together, our studies demonstrate that MN-08 is a promising therapeutic agent for the treatment of dementia including VaD and AD.

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多功能硝酸美金刚通过神经保护和增加脑血流量减轻血管性痴呆和阿尔茨海默病模型的认知障碍。

阿尔茨海默病（AD）和血管性痴呆（VaD）是痴呆的两种常见形式。VaD与脑血管病变有关，如白质缺血和慢性脑灌注不足，这也可能发生在AD中。一氧化氮（NO）调节中枢神经系统的脑血流（CBF）。美金刚是一种被批准用于阿尔茨海默病治疗的NMDA受体拮抗剂。本研究探讨了新型硝酸美金刚MN-08在1种VaD模型（2VO）和2种AD模型（APP/PS1小鼠和a - β1-42诱导小鼠）中的作用及其分子机制。MN-08增加脑血流，改善VaD和AD患者的认知和记忆功能，效果优于美金刚。MN-08可提高CA1神经元的存活率，减轻脑白质损伤和轴突损伤。此外，MN-08通过上调磷酸化Akt （p-Akt）、糖原合成酶激酶3β (p-GSK3β)和高分子量神经丝（p-NFH），保护神经元免受ogd诱导的损失，促进海马轴突生长。MN-08的有益作用被强效NO清除剂羧基ptio减弱，提示MN-08衍生的NO可能减轻脑灌注不足引起的认知障碍。综上所述，我们的研究表明MN-08是一种治疗包括VaD和AD在内的痴呆的有前景的治疗剂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).