Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's 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.
['Wu|Liangmiao|L|', 'Zhou|Xinhua|X|', 'Cao|Yiwan|Y|', 'Mak|Shing Hung|SH|', 'Zha|Ling|L|', 'Li|Ning|N|', 'Su|Zhiyang|Z|', 'Han|Yifan|Y|', 'Wang|Yuqiang|Y|', 'Man Hoi|Maggie Pui|MP|', 'Sun|Yewei|Y|', 'Zhang|Gaoxiao|G|', 'Zhang|Zaijun|Z|0000-0002-0690-1673', 'Yang|Xifei|X|0000-0002-9000-7016']
memantine nitrate N-methyl-D-aspartate (NMDA) receptors cognitive deficits Alzheimer’s disease nitric oxide