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

Ji Eun Lee, Ha Na Kim, Dong Yeol Kim, Yu Jin Shin, Jin Young Shin, Phil Hyu Lee

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4 Citations (Scopus)


Ample evidence has demonstrated that α-Synuclein can propagate from one area of the brain to others via cell-to-cell 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-to-cell transmission of α-synuclein. Memantine decreased the levels of internalized cytosolic α-synuclein and led to attenuation in α-synuclein-induced cell death. Specifically, memantine attenuated α-synuclein-induced expression of clathrin and EEA1, and increased expression of NR2A subunits. Moreover, memantine inhibited propagation of extracellular α-synuclein and thus, decreased the expression of the phosphorylated form of α-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 α-synuclein propagation by inhibiting interactions between α-synuclein and NR2A subunits, which leads to neuroprotective effects on nigral dopaminergic neurons against α-synuclein-enriched conditions. The repositioning use of memantine in α-synuclein propagation needs to be further evaluated in patients with α-synucleinopathies as an effective therapeutic approach.

Original languageEnglish
Article number113810
JournalExperimental Neurology
Publication statusPublished - 2021 Oct

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning ( NRF2019R1A2C2085462 ), and the Brain Korea 21 PLUS Project for Medical Science, Yonsei University .

Publisher Copyright:
© 2021

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience


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