title: The PPAR-γ agonist pioglitazone protects cortical neurons from inflammatory mediators via improvement in peroxisomal function.
abstract: BACKGROUND
  Inflammation 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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Pioglitazone 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.
  
  
  CONCLUSIONS
  Collectively, 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.
authors.affiliation: Multiple Sclerosis and Stem Cell Group, Burden Centre, Institute of Clinical Neurosciences, Frenchay Hospital, University of Bristol, Bristol BS16 1JB, UK. elizabeth.gray@bristol.ac.uk
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gray
authors.forename: Mark
authors.initials: M
authors.lastname: Ginty
authors.forename: Kevin
authors.initials: K
authors.lastname: Kemp
authors.forename: Neil
authors.initials: N
authors.lastname: Scolding
authors.forename: Alastair
authors.initials: A
authors.lastname: Wilkins
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000502:physiology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects* / Q000473:pathology; D000077205:Pioglitazone; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone