Affiliations: [a] Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, USA | [b] Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
Correspondence:
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Corresponding author: Peter Andrews, Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Washington, DC 20007, USA. Tel.: +1 202 687 1228; Fax: +1 202 687 1823; E-mail: [email protected].
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.
