A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons

John Dill, Ankur R. Patel, Xiao Li Yang, Robert Bachoo, Craig M. Powell, Shuxin Li

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Ibuprofen is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-β42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-β42 formation by direct inhibition of the γ-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. Ibuprofen activates PPARγ in neuronlike PC12 and B104 cells. Activation of PPARγwith traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARγ blocks RhoA suppression of PPARγ agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARγinhibition. These findings support that PPARγplays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)963-972
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number3
DOIs
StatePublished - Jan 20 2010

Fingerprint

Ibuprofen
Neurons
Peroxisome Proliferator-Activated Receptors
PC12 Cells
Neurites
Amyloid
Inhibition (Psychology)
Growth
Growth Inhibitors
Amyloid Precursor Protein Secretases
Spinal Cord Diseases
Prostaglandin-Endoperoxide Synthases
Spinal Cord Injuries
Small Interfering RNA
Rodentia
Spinal Cord
Alzheimer Disease
Anti-Inflammatory Agents
Transcription Factors
Inflammation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. / Dill, John; Patel, Ankur R.; Yang, Xiao Li; Bachoo, Robert; Powell, Craig M.; Li, Shuxin.

In: Journal of Neuroscience, Vol. 30, No. 3, 20.01.2010, p. 963-972.

Research output: Contribution to journalArticle

Dill, John ; Patel, Ankur R. ; Yang, Xiao Li ; Bachoo, Robert ; Powell, Craig M. ; Li, Shuxin. / A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 3. pp. 963-972.
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