Intranasal administration of ergothioneine improves memory in a mouse model of multiple system atrophy

No effective treatments have been established to delay or prevent the progression of multiple system atrophy (MSA), which is characterised by the accumulation of abnormal α-synuclein (α-Syn) species, including toxic α-Syn oligomers, in the central nervous system. In our previous study, we demonstrated that intranasal administration of trehalose reduces the levels of α-Syn oligomer by accelerating their conversion from toxic α-Syn oligomers to less harmful fibrils in a human α-Syn inducible MSA mouse model. This finding suggests that reducing α-Syn oligomers may be a crucial therapeutic strategy for MSA. The present study aimed to assess the potential of intranasal ergothioneine (ERG) administration in ameliorating MSA pathology within the MSA mouse model. A cognitive function test and electrophysiological analysis revealed that ERG administration significantly improved short-term spatial memory associated with hippocampal activity, with performance nearing normal levels. Immunohistochemical analysis showed that ERG treatment increased human α-Syn-positive areas within the dentate gyrus + dentate hilus regions of the hippocampus. By contrast, ERG treatment also led to a reduction in α-Syn phosphorylation in the cerebral cortex. Furthermore, immunoblotting confirmed that ERG treatment elevated expression levels of α-Syn monomer, while significantly reducing α-Syn dimer levels in the ERG-treated MSA model mice compared with untreated counterparts. Thus, the modification of α-Syn induced by ERG treatment may result in a reduction of α-Syn oligomers. Here, we demonstrate that intranasal administration of ERG improved short-term spatial memory in the MSA mouse model.