Jans Alzate-Morales -  Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer's Disease

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      Publication Details (including relevant citation   information):

      Source: Journal of Alzheimers   Disease Volume: 19 Issue:   2 Pages: 573-589 Published:   2010

      Times Cited: 5

      DOI: 10.3233/jad-2010-1262


      We describe the interactions of two benzimidazole derivatives,   astemizole (AST) and lansoprazole (LNS), with anomalous   aggregates of tau protein (neurofibrillary tangles).   Interestingly, these compounds, with important medical   applications in the treatment of allergies and gastrointestinal   disorders respectively, specifically bind to aggregated variants   of tau protein and to paired helical filaments isolated from   brains of Alzheimer's disease (AD) patients. These ligands appear   to be a powerful tool to tag brain-isolated tau-aggregates and   heparin-induced polymers of recombinant tau. The interactions of   AST and LNS with tau aggregates were assessed by classical   radioligand assays, surface plasmon resonance, and bioinformatic   approaches. The affinity of AST and LNS for tau aggregates was   comparatively higher than that for amyloid-β polymers according   to our data. This is relevant since senile plaques are also   abundant but are not pathognomonic in AD patients. Immunochemical   studies on paired helical filaments from brains of AD patients   and surface plasmon resonance studies confirm these findings. The   capacity of these drugs to penetrate the blood-brain barrier was   evaluated: i) in vitro by parallel artificial membrane   permeability assay followed by experimental Log P determinations;   and ii) in vivo by pharmacokinetic studies comparing distribution   profiles in blood and brain of mice using HPLC/UV. Importantly,   our studies indicate that the brain/blood concentration ratios   for these compounds were suitable for their use as PET   radiotracers. Since neurofibrillary tangles are positively   correlated with cognitive impairment, we concluded that LNS and   AST have a great potential in PET neuroimaing for in vivo early   detection of AD and in reducing the formation of neurofibrillary   tangles.

      Address (URL): http://iospress.metapress.com/content/u406855j83km52t0/