Nimodipine selectively stimulates beta-amyloid 1-42 secretion by a mechanism independent of calcium influx blockage.
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.
Facchinetti
Fabrizio
F
Research and Innovation (R&I) Company, Padova, Italy. facchinetti@researchinnovation.com
Fasolato
Cristina
C
Del Giudice
Elda
E
Burgo
Andrea
A
Furegato
Sara
S
Fusco
Mariella
M
Basso
Elisa
E
Seraglia
Roberta
R
D'Arrigo
Antonello
A
Leon
Alberta
A
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
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