PPAR-gamma agonist Azelaoyl PAF increases frataxin protein and mRNA expression: new implications for the Friedreich's ataxia therapy

Cerebellum. 2009 Jun;8(2):98-103. doi: 10.1007/s12311-008-0087-z. Epub 2008 Dec 23.

Abstract

Friedreich's ataxia is a neurodegenerative disease due to frataxin deficiency, and thus, drugs increasing the frataxin amount are excellent candidates for therapy. By screening Gene Expression Omnibus profiles, we identified records showing a frataxin response to the peroxisome proliferator-activated receptors gamma (PPAR-gamma) agonist rosiglitazone. We decided to investigate the effect of the PPAR-gamma agonist Azelaoyl PAF on the frataxin protein and mRNA expression profile. We treated human neuroblastoma cells SKNBE and primary fibroblasts from skin biopsies from Friedreich's ataxia (FRDA) patients and healthy controls with the PPAR-gamma agonist Azelaoyl PAF. We show in this paper for the first time that Azelaoyl PAF significantly increases the intracellular frataxin levels by twofold in the neuroblastoma cell line SKNBE and fibroblasts from FRDA patients and that Azelaoyl PAF increases frataxin protein through a transcriptional mechanism. PPAR-gamma agonist Azelaoyl PAF increases both messenger RNA and protein levels of frataxin. We hypothesize that PPAR-gamma agonists could play a role in the treatment of FRDA, and our results offer the logical bases to further investigate the usefulness of this group of agents for the treatment of the FRDA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cells, Cultured
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Cerebellum / physiopathology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Frataxin
  • Friedreich Ataxia / drug therapy*
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Iron-Binding Proteins / drug effects*
  • Iron-Binding Proteins / genetics
  • Iron-Binding Proteins / metabolism*
  • PPAR gamma / agonists*
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacology
  • Phosphorylcholine / therapeutic use
  • RNA, Messenger / drug effects
  • Rosiglitazone
  • Thiazolidinediones / pharmacology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • 1-0-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocoline
  • Hypoglycemic Agents
  • Iron-Binding Proteins
  • PPAR gamma
  • RNA, Messenger
  • Thiazolidinediones
  • Rosiglitazone
  • Phosphorylcholine