Peroxisome Proliferator-Activated Receptor γ Agonists Accelerate Oligodendrocyte Maturation and Influence Mitochondrial Functions and Oscillatory Ca2+ Waves

We have previously shown that natural (15-deoxy-Delta(12,14)-prostaglandin J(2)) and synthetic (pioglitazone) agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma) strengthen the intrinsic cellular mechanisms protecting oligodendrocyte (OL) progenitors (OPs) from oxidative insults and promote their differentiation. Here, we demonstrate that repeated administrations of PPAR-gamma agonists to OP cultures accelerate their differentiation to OLs, as indicated by increased numbers of O-4- and O-1-positive cells that show increased myelin basic protein expression, elaborated cholesterol-enriched membranes and have increased peroxisomes. Moreover, PPAR-gamma agonist-treated OLs show increased activity of the mitochondrial respiratory chain Complex IV and an increased ability to respond to environmental signals, such as adenosine diphosphate (ADP), with oscillatory Ca2+ waves; the latter closely correlated with the presence of mitochondria and were inhibited by the mitochondrial respiratory chain Complex I inhibitor rotenone. Because Ca2+ oscillations and mitochondrial respiratory chain activity play crucial roles in OL differentiation, these findings suggest that PPAR-gamma agonists could protect OLs and promote myelination through several mechanisms, including those involving mitochondrial functions. Our studies support the therapeutic potential of PPAR-gamma agonists in brain diseases in which mitochondrial alteration, oxidative stress, and demyelination occur and point to the need for a better understanding of the role of PPAR-gamma and its agonists in OL biology.