Open AccessTherapeutic efficacy of novel memantine nitrate MN‐08 in animal models of Alzheimer’s disease
Author(s) -
Wu Liangmiao,
Zhou Xinhua,
Cao Yiwan,
MAK Shing Hung,
Zha Ling,
Li Ning,
Su Zhiyang,
Han Yifan,
Wang Yuqiang,
Man Hoi Maggie Pui,
Sun Yewei,
Zhang Gaoxiao,
Zhang Zaijun,
Yang Xifei
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13371
Subject(s) - memantine , nmda receptor , pharmacology , glutamate receptor , alzheimer's disease , neuroprotection , biology , medicine , neuroscience , receptor , disease
Alzheimer's disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over‐activation of N‐methyl‐D‐aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN‐08, a novel memantine nitrate, was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in 2‐month‐old APP/PS1 transgenic mice (for a 6‐month preventative course) and in the 8‐month‐old triple‐transgenic (3×Tg‐AD) mice (for a 4‐month therapeutic course). In vitro, MN‐08 could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3β pathway, subsequently preventing glutamate‐induced neuronal loss. In addition, MN‐08 had favorable pharmacokinetics, blood‐brain barrier penetration, and safety profiles in rats and beagle dogs. These findings suggest that the novel memantine nitrate MN‐08 may be a useful therapeutic agent for AD.