Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease and vascular dementia
10.3867/j.issn.1000-3002.2023.07.028
- Author:
Miao LIANG
1
;
Xinghua ZHOU
;
Yuqiang WANG
;
PM Mag-gie HOI
;
Zaijun ZHANG
Author Information
1. Institute of New Drug Research,College of Pharmacy,Ji-nan University,Guangzhou 510632,China
- Keywords:
Alzheimer's disease;
vascular dementia;
NMDA receptor;
nitric oxide;
memantine nitrate MN-08
- From:
Chinese Journal of Pharmacology and Toxicology
2023;37(7):492-493
- CountryChina
- Language:Chinese
-
Abstract:
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-methyl-D-aspartate(NMDA)receptors,decreased cerebral blood flow,and subsequent pathological events,play signifi-cant 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 a 4-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 dysregula-tions of the ERK and PI3K/Akt/GSK3β pathway,subse-quently preventing glutamate-induced neuronal loss.Additionally,MN-08 exhibited favorable pharmacokinet-ics,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.
