Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation

The activation of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is known to exert anti-inflammatory and neuroprotective effects and PPAR-gamma agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-gamma agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-alpha by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-alpha is associated with i) increased mitochondrial superoxide production; ii) decreased mitochondrial membrane potential (mMP); and iii) decreased ADP-induced Ca2+ oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-alpha effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-alpha damage is mediated by mitochondrial function impairment. PPAR-gamma agonists protected OL progenitors against the inhibitory activities of both TNF-alpha and rotenone on mMP, mitochondrial ROS production, Ca2+ oscillations and OL differentiation. Finally, the PPAR-gamma agonist pioglitazone increased the expression of PGC-1 alpha (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS production), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-gamma agonist protection against INF-alpha damage. (C) 2015 Elsevier Inc. All rights reserved.