The multifunctional memantine nitrate MN-08 ameliorates neuropathology and motor deficits in Huntington’s disease models

Huntington’s disease (HD) is a neurodegenerative disorder caused by a mutation in the Huntingtin (HTT) gene. Abnormal aggregation and accumulation of mutant HTT protein (mHTT) ultimately results in the death of striatal neurons and choreiform movements in patients. Currently, treatment for HD is primarily symptomatic, with no curative drug available. MN-08, a memantine nitrate derivative, acts as a dual-functional N-methyl-D-aspartic acid receptor (NMDAR) antagonist and releases nitric oxide (NO) in the brain, both of which exert effects in the central nervous system. Previous studies have demonstrated that MN-08 exhibits neuroprotective effects in various neurodegenerative diseases. The aim of this study was to evaluate the efficacy and mechanism of MN-08 in HEK-293T 120Q cell lines, brain slices (from Macaca fascicularis), and HD mouse models. In the 120Q HD cell line, MN-08 reduced mHTT in a time- and concentration-dependent manner. In both 109Q virus-induced monkey brain slices and the HD mouse models, MN-08 decreased mHTT aggregates and ameliorated neuropathology. Additionally, MN-08 alleviated motor impairments in HD mice (one month treatment in 109Q mice and 7-week treatment in R6/1 mice), outperforming the positive control drug tetrabenazine (TBZ). Mechanistically, as a nitrate derivative of memantine, MN-08 antagonized NMDA receptors and released NO, activating the cGMP/PKG pathway to promote ubiquitin-mediated degradation of mHTT, accompanied by a reduction in neuroinflammation. Overall, our findings demonstrate that MN-08 exhibits promising efficacy in both in vitro and in vivo models of HD through its multifunctional actions, offering a promising preclinical candidate for multi-target therapy in HD treatment.