Abstract
Oligodendrocyte damage and loss are key features of multiple sclerosis (MS) pathology. Oligodendrocytes appear to be particularly vulnerable to reactive oxygen species (ROS) and cytokines, such as tumor necrosis factor-α (TNF), which induce cell death and prevent the differentiation of oligodendrocyte progenitor cells (OPCs). Here, we investigated the efficacy of sulforaphane (SFN), monomethyl fumarate (MMF) and Protandim to induce Nrf2-regulated antioxidant enzyme expression, and protect oligodendrocytes against ROS-induced cell death and ROS-and TNF-mediated inhibition of OPC differentiation. OLN-93 cells and primary rat oligodendrocytes were treated with SFN, MMF or Protandim resulting in significant induction of Nrf2-driven (antioxidant) proteins heme oygenase-1, nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 and p62/SQSTM1, as analysed by Western blotting. After incubation with the compounds, oligodendrocytes were exposed to hydrogen peroxide. Protandim most potently promoted oligodendrocyte cell survival as measured by live/death viability assay. Moreover, OPCs were treated with Protandim or vehicle control prior to exposing them to TNF or hydrogen peroxide for five days, which inhibited OPC differentiation. Protandim significantly promoted OPC differentiation under influence of ROS, but not TNF. Protandim, a combination of five herbal ingredients, potently induces antioxidants in oligodendrocytes and is able to protect oligodendrocytes against oxidative stress by preventing ROS-induced cell death and promoting OPC differentiation.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS).Histopathological hallmarks include focal demyelinated lesions characterized by oligodendrocyte (OL) cell death, axonal damage, gliosis, microglial activation, and infiltration of lymphocytes and macrophages [1,2]
OLN-93 cells most closely resemble 5-day to 10-day old cultured rat brain oligodendrocytes in terms of their morphological features and antigenic properties
The concentrations used were based on prior publications with the compounds [37,54,55] and dose-ranging experiments we performed in OLN-93 cells
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Histopathological hallmarks include focal demyelinated lesions characterized by oligodendrocyte (OL) cell death, axonal damage, gliosis, microglial activation, and infiltration of lymphocytes and macrophages [1,2]. In chronic demyelinating lesions in advanced stages of the disease, OL loss is extensive and widespread [3,4,5]. As oligodendrocyte progenitor cells (OPCs) were detected in chronic lesions [5,6], it appears that premyelinating OLs fail to differentiate and ensheath the axon with myelin in chronic MS. Studies have shown that ROS-induced oxidative damage to cells in the CNS significantly contribute to demyelination and neurodegeneration in MS [7,8,9]. Markers of lipid and Antioxidants 2016, 5, 30; doi:10.3390/antiox5030030 www.mdpi.com/journal/antioxidants
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