Memantine exerts neuroprotective effects by modulating alpha-synuclein transmission in a parkinsonian model

Abstract

Ample evidence has demonstrated that alpha-Synuclein can propagate from one area of the brain to others via cell-tocell transmission, which might be the underlying mechanism for pathological propagation and the disease progression of Parkinson's disease (PD). Recent reports have demonstrated cell surface receptor-mediated cell-tocell transmission of alpha-synuclein. Memantine decreased the levels of internalized cytosolic alpha-synuclein and led to attenuation in alpha-synuclein-induced cell death. Specifically, memantine attenuated alpha-synuclein-induced expression of clathrin and EEA1, and increased expression of NR2A subunits. Moreover, memantine inhibited propagation of extracellular alpha-synuclein and thus, decreased the expression of the phosphorylated form of alpha-synuclein in dopaminergic neurons of the substantia nigra, which was accompanied by increased survival of dopaminergic neurons with functional improvement of motor deficits. The present study demonstrated that memantine modulates extracellular alpha-synuclein propagation by inhibiting interactions between alpha-synuclein and NR2A subunits, which leads to neuroprotective effects on nigral dopaminergic neurons against alpha-synuclein-enriched conditions. The repositioning use of memantine in alpha-synuclein propagation needs to be further evaluated in patients with alpha-synucleinopathies as an effective therapeutic approach.