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Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation

  • 0Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Circulation +

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February 18, 2009

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February 18, 2009

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Summary

This summary is machine-generated.

Thiazolidinediones protect against brain injury by activating peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This activation increases 14-3-3epsilon, which reduces neuronal apoptosis and cerebral infarction.

Area Of Science

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background

  • Thiazolidinediones are known to protect against ischemia-reperfusion injury.
  • Their protective effects are linked to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation.
  • The precise mechanism by which PPAR-gamma activation confers protection remains unclear.

Purpose Of The Study

  • To investigate the role of PPAR-gamma activation in protecting against cerebral infarction.
  • To elucidate the molecular mechanisms underlying the protective effects of PPAR-gamma in neuronal cells.
  • To evaluate the therapeutic potential of targeting the PPAR-gamma pathway.

Main Methods

  • Utilized a rat model of cerebral infarction and N2-A neuroblastoma cells.
  • Administered rosiglitazone or employed PPAR-gamma overexpression.
  • Investigated the effects of PPAR-gamma small interfering RNA and dominant-negative mutants.
  • Performed proteomic analysis, promoter analysis, and chromatin immunoprecipitation.
  • Assessed the impact of 14-3-3epsilon modulation on cellular damage and apoptosis.

Main Results

  • Rosiglitazone and PPAR-gamma overexpression significantly reduced infarct volume in rats.
  • The protective effects were dependent on PPAR-gamma activation, as shown by abrogation with small interfering RNA and dominant-negative mutants.
  • Proteomic analysis revealed upregulation of brain 14-3-3epsilon, which was PPAR-gamma-dependent.
  • PPAR-gamma directly bound to the 14-3-3epsilon promoter, increasing its transcription.
  • Overexpression of 14-3-3epsilon mimicked the protective effects, while its inhibition abrogated them.
  • Elevated 14-3-3epsilon protected mitochondrial membrane potential and enhanced the sequestration of phosphorylated Bad.

Conclusions

  • Ligand-activated PPAR-gamma confers resistance to neuronal apoptosis and cerebral infarction.
  • This protection is mediated by the transcriptional upregulation of 14-3-3epsilon.
  • 14-3-3epsilon suppresses apoptosis by enhancing the sequestration of phosphorylated Bad, thereby protecting neuronal cells.

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