Abstract
Background: Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder, largely characterized with cognitive impairment. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist approved by FDA since 2003, indicated for the treatment of moderate to severe dementia of the Alzheimer's type. Our team has designed and synthesized a new nitro-derivative of memantine, MN-08, which could release free NO to dilate blood vessels. Our previous study indicated that the therapeutic efficacy of MN-08 was at least 2-fold greater than memantine in the vascular dementia rat model, and possess the functions of dilating the cerebral vessels and enhancing the blood flow, but not decreasing the peripheral blood pressure.
Methods: In this study, using behavioral, histological and biochemical methods, outcomes of triple-transgenic (3 Tg-AD) mice with differing levels of AD-like neuropathology (8 months) were treated for 4 months with different doses of MN-08.
Results: After the treatment, MN-08-treated mice had restored cognition and significantly reduced the levels of soluble and insoluble amyloid-beta (Fig 1. A-E). In particular, we found that MN-08 reduced Amyloid beta aggregation via promoting non-amyloidonegic amyloid precursor protein (APP) processing, by regulating APP-cleavage secretase expression (ADAM 10, sAPPa) in transgenic mice (Fig 1. F).
Conclusions: These results suggest that the MN-08 could be a novel promising disease modification and prevention therapeutic strategy for the treatment of VD and AD.
