Pharmacological Characterizations of anti-Dementia Memantine Nitrate via Neuroprotection and Vasodilation in Vitro and in Vivo.,ACS Chemical Neuroscience

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Pharmacological Characterizations of anti-Dementia Memantine Nitrate via Neuroprotection and Vasodilation in Vitro and in Vivo.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-22 , DOI: 10.1021/acschemneuro.9b00242
Shinghung Mak _{1,

2} , Zheng Liu _{3,

4,

5} , Liangmiao Wu ₃ , Baojian Guo _{1,

3} , Fangcheng Luo _{3,

5} , Ziyan Liu ₃ , Shengquan Hu _{1,

2} , Jiajun Wang ₂ , Guozhen Cui ₆ , Yewei Sun ₃ , Yuqiang Wang ₃ , Gaoxiao Zhang ₃ , Yifan Han _{1,

2} , Zaijun Zhang _{3,

7}

Affiliation

We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO-cGMP pathway ex vivo. In the 2-vessel occlusion (2VO) rat model, MN-12 alleviated the impairments of spatial memory and motor dysfunction possibly via neuroprotection and improvement of the cerebral blood flow. Furthermore, the results of preliminary pharmacokinetic studies showed that MN-12 might quickly distribute to the major organs including the brain, indicating that MN-12 could penetrate the blood-brain barrier. Taken together, MN-12 might provide multifunctional therapeutic benefits for dementia associated with Alzheimer's disease, vascular dementia, and ischemic stroke, via neuroprotection and vessel dilation to improve the cerebral blood flow.

中文翻译：

硝酸美金刚通过体外和体内神经保护和血管舒张作用来抗痴呆的药理学特征。

我们之前设计并合成了一系列新型硝酸美金刚，其中一些已经表现出神经保护作用；然而，详细机制仍不清楚。在这项研究中，我们证明了 MN-12（硝酸美金刚之一）能够浓度依赖性地保护大鼠原代培养的小脑颗粒神经元 (CGN) 免受谷氨酸诱导的神经毒性。 Western blotting 分析显示，MN-12 可能通过同时抑制 ERK 通路和激活 PI3K/Akt 通路而具有神经保护作用。此外，MN-12 通过离体激活 NO-cGMP 途径，浓度依赖性地扩张预收缩的大鼠大脑中动脉。在2血管闭塞（2VO）大鼠模型中，MN-12可能通过神经保护和改善脑血流量减轻空间记忆和运动功能障碍。此外，初步药代动力学研究结果表明，MN-12可能会快速分布到包括大脑在内的主要器官，表明MN-12可以穿透血脑屏障。综上所述，MN-12 可能通过神经保护和血管扩张来改善脑血流量，为与阿尔茨海默病、血管性痴呆和缺血性中风相关的痴呆症提供多功能治疗益处。

更新日期：2020-01-23

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