Peroxisome Proliferator-Activated Receptor-γ Agonists Promote Differentiation and Antioxidant Defenses of Oligodendrocyte Progenitor Cells

Abstract

Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists may control brain inflammation and, therefore, may be useful for the treatment of human CNS inflammatory conditions. The PPAR-gamma agonists delay the onset and ameliorate clinical manifestations in animal demyelinating disease models, in which the beneficial effects are thought to be mainly related to anti-inflammatory effects on peripheral and brain immune cells. Direct effects on neurons, oligodendrocytes, and other CNS resident cells cannot be excluded, however. To analyze potential direct actions of PPAR-gamma agonists on oligodendrocytes, we investigated the effects of both natural (15-deoxy Delta prostaglandin J2) and synthetic (pioglitazone) PPAR-gamma agonists in primary cultures of rat oligodendrocyte progenitor cells. The PPAR-gamma agonists promoted oligodendrocyte progenitor cell differentiation and enhanced their antioxidant defenses by increasing levels of catalase and copper-zinc superoxide dismutase while maintaining the overall homeostasis of the glutathione system. Protective effects were abolished in the presence of the specific PPAR-gamma antagonist GW9662, indicating that they are specifically dependent on PPAR-gamma. These observations suggest that in addition to their known anti-inflammatory effects, PPAR-gamma agonists may protect oligodendrocyte progenitor cells by preserving their integrity and favoring their differentiation into myelin-forming cells. Thus, PPAR-gamma may promote recovery from demyelination by direct effects on oligodendrocytes.

Hyperforin promotes mitochondrial function and development of oligodendrocytes

“…PPAR-γ agonists are found to promote the differentiation of cultured spinal cord oligodendrocytes by the increasing percentage of cells expressing MBP (Roth et al, 2003). In another study, PPAR-γ agonists not only promote the differentiation of primary rat OPCs but also enhance their antioxidant defenses by increasing the levels of catalase and superoxide dismutase (Bernardo et al, 2009;Sim et al, 2008). A novel thiadiazolidinone, a PPAR-γ agonist, has shown antidepressant effects in the forced swimming test, and this effect is inhibited by PPAR-γ antagonists (Rosa et al, 2008).…”

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

“…Purified cultures of OPs were obtained as previously described (Bernardo et al, 2009), and in accordance with the European Communities Council Directive N. 2010/63/EU. Forebrains from postnatal day 1 Wistar rats (Harlan, Milan, Italy) were mechanically dissociated, and the cells obtained were grown for 10 days in Dulbecco's modified Eagle's medium (DMEM with high glucose,) supplemented with 10% foetal bovine serum on poly-L-lysine coated 60-mm-diameter culture dishes.…”

“…catalase, Cu/Zn SOD), and of those encoding for the mitochondrial uncoupling protein 2 (UCP2) and PGC-1α (Bernardo et al, 2009;Shimokawa et al, 1998). UCP2 is a member of the uncoupling protein family whose precursor, UCP1, is expressed in brown adipose tissue where it is responsible for thermogenesis.…”

“…Other members of the family are known for their role in controlling superoxide production by mitochondria. In previous reports we and others showed that PPAR-γ agonists applied to OP cultures promote the intrinsic mechanisms of defense toward oxidative stress, protect from mitochondrial insult and accelerate OL differentiation (Bernardo et al, 2009;De Nuccio et al, 2011;Roth et al, 2003). With the intent of further addressing the potential of PPAR-γ agonists to promote myelination, we investigated their ability to protect OP cultures against the deleterious effects of TNF-α, used to mimic an inflammatory challenge, typical of demyelinating diseases such as MS. To this aim we focused our analyses on OP differentiation, responsiveness to axon derived stimuli such as the nucleotide ADP, which can potentially promote myelination, and preservation/promotion of mitochondrial functions.…”

Inhibitory effect of rosiglitazone on the acid-induced intracellular generation of hydrogen peroxide in cultured feline esophageal epithelial cells

“…Some studies have demonstrated that drugs of the thiazolidinedione class (families of synthetic compounds with anti-diabetic activity) and PPARγ agonists have potent antioxidant and anti-inflammatory effects Ghanim et al 2001). Notably, the PPARγ agonists have been reported to promote oligodendrocyte progenitor cell differentiation and enhance their antioxidant defenses by increasing levels of catalase and copper-zinc superoxide dismutase (Cu/Zn SOD) in a PPARγ-dependent manner (Bernardo et al 2009). Furthermore, rosiglitazone (a thiazolidinedione class member) activates AMPK, which in turn, prevents the hyperactivity of NAD(P)H oxidase induced by high glucose (Ceolotto et al 2007).…”