Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer′s disease and vascular dementia

OBJECTIVE Alzheimer′s disease (AD)and vascular dementia (VD)are the primary causes of dementia in elderly individuals,and therapeutic options for both conditions are limited.Overactivation of N-methylD-aspartate (NMDA) receptors,decreased cerebral blood flow,and subsequent pathological events,play significant roles in the progression of AD and VD.METHODS In this study,we investigated the therapeutic effects and underlying mechanisms of MN-08,a novel memantine nitrate,in mouse models of AD and rats with VD.RESULTS MN-08 was found to inhibit Aβ accumulation,prevent neuronal and dendritic spine loss,and attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice (following a 6-month preventative course) and in 8-month-old triple-transgenic (3×Tg-AD) mice (following a4-month therapeutic course),as well as in rat models of VD with preventive and therapeutic treatments.In vitro,MN-08 was shown to bind to and antagonize NMDA receptors,inhibit calcium influx,and reverse dysregulations of the ERK and PI3K/Akt/GSK3β pathway,subsequently preventing glutamate-induced neuronal loss.Additionally,MN-08 exhibited favorable pharmacokinetics,blood-brain barrier penetration,and safety profiles in rats and beagle dogs.CONCLUSION These findings suggest that the novel memantine nitrate MN-08 may be a useful therapeutic agent for AD and VD.