The PPAR-gamma agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function

Abstract

BackgroundInflammation is known to play a pivotal role in mediating neuronal damage and axonal injury in a variety of neurodegenerative disorders. Among the range of inflammatory mediators, nitric oxide and hydrogen peroxide are potent neurotoxic agents. Recent evidence has suggested that oligodendrocyte peroxisomes may play an important role in protecting neurons from inflammatory damage.MethodsTo assess the influence of peroxisomal activation on nitric oxide mediated neurotoxicity, we investigated the effects of the peroxisomal proliferator activated receptor (PPAR) gamma agonist, pioglitazone in primary cortical neurons that were either exposed to a nitric oxide donor or co-cultured with activated microglia.ResultsPioglitazone protected neurons and axons against both nitric-oxide donor-induced and microglia-derived nitric oxide-induced toxicity. Moreover, cortical neurons treated with this compound showed a significant increase in the protein and gene expression of PPAR-gamma, which was associated with a concomitant increase in the enzymatic activity of catalase. In addition, the protection of neurons and axons against hydrogen peroxide-induced toxicity afforded by pioglitazone appeared to be dependent on catalase.ConclusionsCollectively, these observations provide evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both NO and hydrogen peroxide-mediated neuronal and axonal damage suggesting a new therapeutic approach to protect against neurodegenerative changes associated with neuroinflammation.

Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis

“…Additionally, Gray et al (2012) provides evidence that modulation of PPAR-gamma activity and peroxisomal function by pioglitazone attenuates both nitric oxide (NO) and hydrogen peroxide [40], confirming the antioxidant effect of PPARɤagonist and reducing the effect of PPARɤ agonists on ceruloplasmin levels as shown in the present results.…”

Protective Effect of PPARγAgonists on Cerebellar Tissues Oxidative Damage in Hypothyroid Rats

“…First, it has been well documented that activation of PPAR γ has beneficial effects on expression of antioxidant enzymes including SOD, GPx 3 , and CAT [58, 63]. An increased level of the antioxidant enzymes activities including CAT and SOD by PPAR γ agonists has also been reported [64].…”

Effect of NDP-α-MSH on PPAR-γ and –β Expression and Anti-Inflammatory Cytokine Release in Rat Astrocytes and Microglia

“…In the past few years, accumulating evidence has implicated PPARs in the regulation of inflammatory processes in the CNS [49]. Also, activation of PPAR-γ has been found to protect cortical neurons against NO and hydrogen peroxide-dependent toxicity [50] and PPAR-γ agonists were found to inhibit the release of pro-inflammatory cytokines by microglial cells and astrocytes [51]. Thus, it is possible that PPAR-γ could be taking part in the anti-inflammatory effects of NDP-α-MSH in the CNS.…”