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-beta42
peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the
gamma-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 gamma (
PPARgamma) is essential for coupling
ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons.
Ibuprofen activates
PPARgamma in neuron-like PC12 and B104 cells. Activation of
PPARgamma 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
PPARgamma blocks RhoA suppression of
PPARgamma agonists in PC12 cells. Moreover, the effect of
ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective
PPARgamma inhibition. These findings support that
PPARgamma 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.