title: Nimodipine selectively stimulates beta-amyloid 1-42 secretion by a mechanism independent of calcium influx blockage.
abstract: Several lines of evidence indicate that perturbed cellular Ca2+ homeostasis may play a prominent role in synaptic dysfunction and neuronal death in Alzheimer's disease (AD), suggesting a potential benefit of drugs capable to stabilize Ca2+ homeostasis. We here investigated the effects of a panel of L-type Ca2+ channel antagonists on the secretion of the amyloid beta-peptide (Abeta), which abnormally accumulates in the senile plaques of the brain of AD patients. We found that, in primary and immortalized neuronal cells in culture, nimodipine robustly stimulated secretion (up to about four-fold at 30 microM) of the highly amyloidogenic 42-residue isoform of Abeta (Abeta42), while leaving largely unaffected total Abeta secretion. An analogous effect was also observed in vivo, as the administration of a single dose of nimodipine (10 mg/kg i.p.) induced a significant rise of Abeta42 levels in plasma of Tg2576 mice. The effect of nimodipine was independent of blockage of L-type Ca2+ channels and capacitative calcium entry. Accordingly, nimodipine effect was largely Ca2+-independent, as neither depletion nor rise of extracellular Ca2+ abolished it. Hence, by showing that the effect of nimodipine on Abeta42 production is distinct from its ability to block Ca2+-influx pathways, we provide evidence for a previously uncharacterized effect of this long known molecule also used in clinical practice.
authors.affiliation: Research and Innovation (R&I) Company, Padova, Italy. facchinetti@researchinnovation.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Fasolato
authors.forename: Elda
authors.initials: E
authors.lastname: Del Giudice
authors.forename: Andrea
authors.initials: A
authors.lastname: Burgo
authors.forename: Sara
authors.initials: S
authors.lastname: Furegato
authors.forename: Mariella
authors.initials: M
authors.lastname: Fusco
authors.forename: Elisa
authors.initials: E
authors.lastname: Basso
authors.forename: Roberta
authors.initials: R
authors.lastname: Seraglia
authors.forename: Antonello
authors.initials: A
authors.lastname: D'Arrigo
authors.forename: Alberta
authors.initials: A
authors.lastname: Leon
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D014162:Transfection / Q000379:methods
chemical_list: C105562:2,6-dimethyl-3,5-diethoxycarbonyl-4-carboxyl-1,4-dihydropyridine; D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D009553:Nimodipine; D003997:Dicarbethoxydihydrocollidine; D002118:Calcium