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FTY720-Mitoxy reduces toxicity associated with MSA-like α-synuclein and oxidative stress by increasing trophic factor

Javier Vargas-Medrano1, Ismael Segura-Ulate1, Barbara Yang1

  • 1Department of Molecular and Translational Medicine, Graduate School of Biomedical Sciences, Center of Emphasis in Neurosciences, Texas Tech University Health Sciences Center El Paso, Paul L Foster School of Medicine, El Paso, TX, 79905, USA.

Neuropharmacology
|July 11, 2019
PubMed

Insights

Multiple system atrophy (MSA) involves alpha-synuclein (aSyn) damaging myelinating cells. FTY720-Mitoxy protects these cells from oxidative stress and promotes myelin repair, offering a potential therapy for MSA.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by alpha-synuclein (aSyn) aggregation in oligodendrocytes (OLGs), leading to demyelination and lack of effective treatments.
  • Aberrant neurotrophic factor expression, including BDNF and GDNF, is observed in MSA, and oxidative stress exacerbates OLG vulnerability.
  • The impact of oxidative stress on aSyn-accumulating OLGs and potential protective agents remain poorly understood.

Purpose of the Study:

  • To investigate the vulnerability of aSyn-expressing OLG cells to oxidative stress.
  • To evaluate the neuroprotective and myelin-supportive effects of novel FTY720 derivatives (FTY720-C2 and FTY720-Mitoxy) in an in vitro MSA model.
  • To explore the molecular mechanisms underlying the protective effects of FTY720-Mitoxy, focusing on trophic factor expression and myelin-associated glycoprotein (MAG) levels.

Main Methods:

  • Establishment of OLN-93 cell lines stably expressing wild-type or mutant aSyn.
  • Treatment of OLN-93 cells with FTY720, FTY720-C2, and FTY720-Mitoxy under varying oxidative stress conditions.
  • Assessment of cell viability, NGF, BDNF, and GDNF mRNA expression, histone 3 acetylation, ERK1/2 phosphorylation, and MAG levels.
  • Evaluation of the protective effects against oxidative-stress-induced cell death in both aSyn-expressing and non-expressing OLN-93 cells.

Main Results:

  • aSyn-expressing OLN-93 cells exhibited increased vulnerability to oxidative stress.
  • FTY720, FTY720-C2, and FTY720-Mitoxy maintained cell viability and stimulated NGF expression.
  • FTY720-Mitoxy uniquely increased BDNF and GDNF mRNA, alongside histone 3 acetylation and ERK1/2 phosphorylation, and elevated MAG levels.
  • FTY720-Mitoxy demonstrated specific protection against oxidative-stress-induced cell death in aSyn-expressing OLN-93 cells.

Conclusions:

  • FTY720-Mitoxy exhibits potent neuroprotective effects against oxidative stress in oligodendrocytes, particularly those expressing aSyn.
  • FTY720-Mitoxy promotes the expression of key trophic factors (NGF, BDNF, GDNF) and myelin-associated glycoprotein (MAG), suggesting a role in myelin repair.
  • These findings support FTY720-Mitoxy as a promising candidate for preclinical development as a disease-modifying therapy for Multiple System Atrophy.
Keywords:
BDNFGDNFMAGMSAMultiple system atrophyNGFOLN-93 cellsOligodendroglia

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