Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier

Increasing evidence suggests that the soluble form of the beta-amyloid peptide (A beta) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate A beta production in whole cells and reduce brain A beta burden in a mouse model of Alzheimer's disease. As A beta clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of A beta in the brain, we examined the effect of DHP treatment on A beta brain clearance. Treatment with certain DHP compounds significantly increased A beta(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 A beta(1-42) BBB transcytosis. In an in vivo paradigm of A beta clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous A beta(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central A beta(1-42) insult. Thus, in addition to the effect of certain DHP compounds on A beta production, we demonstrate that certain DHP compounds also facilitate the clearance of A beta across the BBB. This dual mechanism of action may be particularly effective in attenuating A beta brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease. (C) 2011 Elsevier B.V. All rights reserved.