PPAR-γ Ameliorates Neuronal Apoptosis and Ischemic Brain Injury via Suppressing NF-κB-Driven p22phox Transcription

Mol Neurobiol. 2016 Aug;53(6):3626-3645. doi: 10.1007/s12035-015-9294-z. Epub 2015 Jun 25.


Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor, protects neurons against ischemic stroke insult by reducing oxidative stress. NADPH oxidase (NOX) activation, a major driving force in ROS generation in the setting of reoxygenation/reperfusion, constitutes an important pathogenetic mechanism of ischemic brain damage. In the present study, both transient in vitro oxygen-glucose deprivation and in vivo middle cerebral artery (MCA) occlusion-reperfusion experimental paradigms of ischemic neuronal death were used to investigate the interaction between PPAR-γ and NOX. With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15-deoxy-∆(12,14)-PGJ2 (15d-PGJ2), via selectively attenuating p22phox expression, inhibited NOX activation and the subsequent ROS generation and neuronal death in a PPAR-γ-dependent manner. Secondly, results of promoter analyses and subcellular localization studies further revealed that PPAR-γ, via inhibiting hypoxia-induced NF-κB nuclear translocation, indirectly suppressed NF-κB-driven p22phox transcription. Noteworthily, postischemic p22phox siRNA treatment not only reduced infarct volumes but also improved functional outcome. In summary, we report a novel transrepression mechanism involving PPAR-γ downregulation of p22phox expression to suppress the subsequent NOX activation, ischemic neuronal death, and brain infarct. Identification of a PPAR-γ → NF-κB → p22phox neuroprotective signaling cascade opens a new avenue for protecting the brain against ischemic insult.

Keywords: Gene regulation; NADPH oxidase; NF-κB; Nox2.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Base Sequence
  • Brain Ischemia / complications
  • Brain Ischemia / drug therapy
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cerebral Cortex / pathology
  • Cerebral Infarction / complications
  • Cerebral Infarction / drug therapy
  • Cerebral Infarction / pathology
  • Cytochrome b Group / metabolism*
  • Cytosol / metabolism
  • Down-Regulation / drug effects
  • Glucose / deficiency
  • Male
  • Mice
  • NADPH Oxidases / metabolism*
  • NF-kappa B / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Oxidation-Reduction
  • Oxygen
  • PPAR gamma / metabolism*
  • Promoter Regions, Genetic / genetics
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Prostaglandin D2 / therapeutic use
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • RNA, Small Interfering / metabolism
  • Rats, Long-Evans
  • Reactive Oxygen Species / metabolism
  • Transcription, Genetic* / drug effects


  • 15-deoxyprostaglandin J2
  • Cytochrome b Group
  • NF-kappa B
  • PPAR gamma
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Cyba protein, mouse
  • Glucose
  • Prostaglandin D2
  • Oxygen