PT  - JOURNAL ARTICLE
AU  - John Dill
AU  - Ankur R. Patel
AU  - Xiao-Li Yang
AU  - Robert Bachoo
AU  - Craig M. Powell
AU  - Shuxin Li
TI  - A Molecular Mechanism for Ibuprofen-Mediated RhoA Inhibition in Neurons
AID  - 10.1523/JNEUROSCI.5045-09.2010
DP  - 2010 Jan 20
TA  - The Journal of Neuroscience
PG  - 963--972
VI  - 30
IP  - 3
4099  - http://www.jneurosci.org/content/30/3/963.short
4100  - http://www.jneurosci.org/content/30/3/963.full
SO  - J. Neurosci.2010 Jan 20; 30
AB  - 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 neuron-like PC12 and B104 cells. Activation of PPARγ with 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 PPARγ inhibition. These findings support that PPARγ plays 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.