Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer disease

OBJECTIVE Alzheimer 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. This study seeks to explore the efficacy and mechanism of action of MN-08, a novel memantine nitrate, in established animal models of AD. METHODS MN-08′s effectiveness as a preventative and therapeutic agent was tested in 2-to 8-month-old APP/PS1 transgenic mice and 9-to 12-month-old 3 × Tg-AD mice, respectively. The neuroprotective mechanism of MN-08 was tested in the glutamate cell model. The pharmacokinetics and safety of MN-08 in vivo were determined in normal rats and beagle dogs. For the behavioral test, Western blotting analysis, pathology, ELISA test and in vitro cell tests, investigators were blinded to the experimental grouping and drug treatment. RESULTS 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-monthold 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 PI3 K/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. CONCLUSION The novel memantine nitrate MN-08 may be a useful therapeutic agent for AD.