Journal
AGING CELL
Volume 20, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/acel.13371
Keywords
Alzheimer’ s disease; cognitive deficits; memantine nitrate; nitric oxide; N‐ methyl‐ D‐ aspartate (NMDA) receptors
Categories
Funding
- Natural National Science Foundation of China [NSFC 82061160374]
- Macau Science and Development Fund [FDCT 0023/2020/AFJ]
- NSFC [81603106, 31861163001]
- National Science and Technology Innovative Drug Project of China [2019ZX09301172]
- China Postdoctoral Science Foundation [2020M683207]
- Guangdong Research And Development Project [2020A1515011061, 2020A1515011060, 2020A1515111207, 2017A030313742]
- Guangzhou Research Project [201804010495]
- Guangdong Medical Research Project [A2017554]
- Foshan Research Project [2017IT100153]
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The novel compound MN-08 was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and improve cognitive deficits in mouse models of AD. MN-08 also demonstrated the ability to antagonize NMDA receptors and prevent neuronal loss in vitro. These findings suggest that MN-08 could be a promising therapeutic agent for AD.
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 beta (A beta) 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 A beta 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 (3xTg-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/GSK3 beta 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.
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