title: Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.
abstract: Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.
authors.affiliation: The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, USA. cbachmeier@rfdn.org
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008568:Memory / Q000187:drug effects; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D057900:Transcytosis / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D004095:Dihydropyridines; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C038806:1,4-dihydropyridine