NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

Abstract

An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.

GPR43 regulation of mitochondrial damage to alleviate inflammatory reaction in sepsis

“…PPARγ can regulate the transcription of target genes, inhibit the activation of immune cells and the expression of inflammatory factors, thus alleviating airway inflammation [ 40 ]. Recently, a large number of studies have shown that PPARγ has important antioxidant protection [ 41 ]. In addition, PPARγ activation can directly inhibit the production of ROS and promote the expression of antioxidant genes such as GST and SOD, thus antagonizing antioxidant stress [ 42 ].…”

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

“…Nuclear factor erythroid-2-related factor 2 (Nrf2) is involved in the maintenance of cellular redox homeostasis through the up-regulation of antioxidant enzymes. Different studies suggest that Nrf2 is an effective modulator of stem cell self-renewal and differentiation [ 32 , 33 , 34 ]. Apurinic/apyrimidinic endonuclease 1 (APE1), also called Redox Factor-1 [ 1 ], is a pleiotropic protein that regulates various cellular functions including oxidative stress and has a role in the maintenance of the stem cell pool and differentiation by modulating intracellular redox homeostasis [ 35 , 36 , 37 ].…”

PPAR Gamma and Viral Infections of the Brain

“…Pioglitazone has been shown to inhibit, significantly for all, albeit moderately for some, the decrease in total thiol, SOD and catalase levels and the increase in malondialdehyde (MDA, a marker of PUFA peroxidation) levels in hippocampal and cortical extracts, in a rat model of hypothyroidism, a phenotype known to cause neurological damage [48]. Pioglitazone has also been shown to induce expression of TFAM and PGC-1α along with increased mitochondrial biogenesis and to restore mitochondrial membrane potential after challenge with rotenone, an inhibitor of the mitochondrial transport chain complex 1, in rat oligodendrocyte cultures [49]. Recent reports also documented a similar role of PPARγ and agonists in non brain tissues or cells.…”

“…A wealth of studies recently reviewed in [69] showed that PPARγ supports NSC growth, survival and stemness maintenance and positively regulates neuronogenesis and neurite outgrowth in maturing neurons. More recently, pioglitazone was shown to promote differentiation of rat primary oligodendrocytes [49].…”