Tarenflurbil Protection from Cytotoxicity is Associated with an Upregulation of Neurotrophins.
 

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11-11-08 08:32 AM
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Tarenflurbil Protection from Cytotoxicity is Associated with an Upregulation of Neurotrophins.
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Tarenflurbil Protection from Cytotoxicity is Associated with an Upregulation of Neurotrophins.

J Alzheimers Dis. 2008 Nov;15(3):397-407

Authors: Zhao X, Rebeck GW, Hoe HS, Andrews PM

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 muM). 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 muM) 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.

PMID: 18997293 [PubMed - in process]