FTY720-Mitoxy reduces toxicity associated with MSA-like α-synuclein and oxidative stress by increasing trophic factor expression and myelin protein in OLN-93 oligodendroglia cell cultures. (1st November 2019)

• Record Type: Journal Article
• Authors: Vargas-Medrano, Javier; Segura-Ulate, Ismael; Yang, Barbara; Chinnasamy, Ramesh; Arterburn, Jeffrey B.; Perez, Ruth G.
• Is Part Of: Neuropharmacology. Volume 158(2019)
• Publication Date: 2019-11-01
• Subjects: BDNF -- GDNF -- MAG -- Multiple system atrophy -- MSA -- NGF -- Oligodendroglia -- OLN-93 cells; AcH3 Acetylated histone 3 -- aSyn α-Synuclein -- BDNF brain-derived neurotrophic factor -- DLB Dementia with Lewy Bodies -- FDA Food and Drug Administration -- GCI glial cytoplasmic inclusions -- GDNF glial cell line derived neurotrophic factor -- H2O2 hydrogen peroxide -- LB Lewy bodies -- LN Lewy neurites -- MAG myelin associated glycoprotein -- MSA Multiple System Atrophy -- NGF nerve growth factor -- NR neutral red assays -- OLGs oligodendroglia cells -- PD Parkinson's disease -- S1PR sphingosine-1 phosphate receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2019.107701
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Multiple system atrophy (MSA) is a fatal demyelinating disorder lacking any disease-modifying therapies. MSA pathology stems from aggregated α-synuclein (aSyn) accumulation in glial cytosolic inclusions of oligodendroglial cell (OLGs), the myelinating cells of brain. In MSA brains and in MSA animal models with aSyn accumulation in OLGs, aberrant expression of brain-derived neurotrophic factor (BDNF) and glial-cell-line-derived neurotrophic factor (GDNF) occur. Nerve growth factor (NGF) expression can also be altered in neurodegenerative diseases. It is unclear if oxidative stress impacts the viability of aSyn-accumulating OLG cells. Here, we show that OLN-93 cells stably expressing human wild type aSyn or the MSA-associated-aSyn-mutants G51D or A53E, are more vulnerable to oxidative stress. In dose response studies we found that OLN-93 cells treated 48 h with 160 nM FTY720 or our new non-immunosuppressive FTY720-C2 or FTY720-Mitoxy derivatives sustained normal viability. Also, FTY720, FTY720-C2, and FTY720-Mitoxy all stimulated NGF expression at 24 h. However only FTY720-Mitoxy also increased BDNF and GDNF mRNA at 24 h, an effect paralleled by increases in histone 3 acetylation and ERK1/2 phosphorylation. Myelin associated glycoprotein (MAG) levels were also increased in OLN-93 cells after 48 h treatment with FTY720-Mitoxy. FTY720, FTY720-C2, and FTY720-Mitoxy all prevented oxidative-stress-associated-cell-death of OLN-93 cells that lack any aSyn expression. However, only FTY720-Mitoxy protected MSA-like aSyn-expressing-OLN-93-cells against oxidative-cell-death. These data identify potent protective effects for FTY720-Mitoxy with regard to trophic factors as well as MAG expression by OLG cells. Testing of FTY720-Mitoxy in mice is thus a judicious next step for neuropharmacological preclinical development. Graphical abstract: Image 1 Highlights: All three FTY720s increase NGF mRNA, but only FTY720-Mitoxy also increases BDNF and GDNF mRNAs at 24 h in OLN-93 cells. Pretreating OLN-93 cells with all three FTY720s blocks 75 μM H2 O2 toxicity. aSyn expressing OLN-93 cells are more vulnerable to H2 O2 than cells lacking aSyn. Only FTY720-Mitoxy blocks 75 μM H2 O2 toxicity in MSA-like OLN-93 lines. Only FTY720-Mitoxy increases MAG, AcH3, and pERK1/2 protein in OLN-93 cells.