Tarenflurbil protection from cytotoxicity is associated with an upregulation of neurotrophins.
Both epidemiological and clinical trial data have demonstrated the value of some non-steroidal anti-inflammatory drugs (NSAIDs) and NSAID derivatives for lowering the incidence, slowing the progression, and reducing the symptomatic severity of Alzheimer's disease (AD). Tarenflurbil (R-flurbiprofen, MPC-7869, Myriad Pharmaceuticals) is an attractive compound because its usage is not associated with the adverse side effects of NSAIDs. Although tarenflurbil has been reported to be a selective amyloid-beta 42 (Abeta_{42})-lowering agent, the concentrations of drug that achieved an IC50 for Abeta_{42}-lowering activity are approximately two orders of magnitude higher than the concentrations found in the brain (i.e., 1-5 microM). Therefore, the mechanism by which this compound accomplishes behavioral/physiological effects requires further study. The present investigation reports that clinically relevant concentrations of tarenflurbil (i.e., 1-5 microM) protect both cultured human neuroblastoma cell lines and primary neurons from cytotoxicity associated with exposure to Abeta_{42} or H_{2}O_{2}. In concert with this protection, there is an upregulation of neurotrophins [i.e., nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)]. Furthermore, blocking exogenous NGF or BDNF by binding it to antibody prevents tarenflurbil from protecting human neuronal cells from Abeta_{42} and H_{2}O_{2} cytotoxicity. These findings suggest that up-regulation of neurotrophins might represent an underlying mechanism contributing to the beneficial effects seen with tarenflurbil in AD.
Zhao
Xu
X
Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Rebeck
G William
GW
Hoe
Hyang-Sook
HS
Andrews
Peter M
PM
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005480:Flurbiprofen / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D007052:Ibuprofen / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D016877:Oxidants / Q000633:toxicity; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D016877:Oxidants; D005480:Flurbiprofen; D012313:RNA; D006861:Hydrogen Peroxide; D007052:Ibuprofen