Tarenflurbil Protection from Cytotoxicity is Associated with an Upregulation of Neurotrophins

Abstract

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-β 42 (Aβ₄₂)-lowering agent, the concentrations of drug that achieved an IC50 for Aβ₄₂-lowering activity are approximately two orders of magnitude higher than the concentrations found in the brain (i.e., 1–5 μM). 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 μM) protect both cultured human neuroblastoma cell lines and primary neurons from cytotoxicity associated with exposure to Aβ₄₂ or H₂O₂. 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 Aβ₄₂ and H₂O₂ cytotoxicity. These findings suggest that up-regulation of neurotrophins might represent an underlying mechanism contributing to the beneficial effects seen with tarenflurbil in AD.