A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.
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.
Dill
John
J
Department of Neurology and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
Patel
Ankur R
AR
Yang
Xiao-Li
XL
Bachoo
Robert
R
Powell
Craig M
CM
Li
Shuxin
S
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001577:Benzophenones / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009288:Naproxen / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D016716:PC12 Cells; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001577:Benzophenones; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D014404:Tubulin; D014443:Tyrosine; D009288:Naproxen; D020742:rhoA GTP-Binding Protein; D007052:Ibuprofen; C120099:GW 1929