Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease.
Liangmiao WuXinhua ZhouYiwan CaoShing Hung MakLing ZhaNing LiZhiyang SuYifan HanYuqiang WangMaggie Pui Man HoiYewei SunGaoxiao ZhangZai-Jun ZhangXi-Fei YangPublished in: Aging cell (2021)
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.
Keyphrases
- pi k akt
- blood brain barrier
- signaling pathway
- room temperature
- transition metal
- nitric oxide
- cerebral ischemia
- cerebral blood flow
- cell proliferation
- metal organic framework
- drinking water
- cell cycle arrest
- cognitive decline
- mild cognitive impairment
- high glucose
- type diabetes
- metabolic syndrome
- middle aged
- high fat diet induced
- drug induced
- skeletal muscle
- diabetic rats
- cell death
- cognitive impairment
- stress induced