L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease.

Abstract

There is strong evidence that intracellular calcium dysregulation plays an important pathological role in Alzheimer's disease, and specifically that beta amyloid may induce increases in intracellular calcium and lead to neuronal cell dysfunction and death. Here we investigated the feasibility of modifying Alzheimer's pathology with the L-type voltage-gated calcium channel blockers verapamil, diltiazem, isradipine and nimodipine. All four compounds protected MC65 neuroblastoma cells from amyloid beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity. Isradipine was the most potent blocker, preventing APP CTF neurotoxicity at nanomolar concentrations. Intracellular beta amyloid expression was associated with increased expression of Cav 1.2 calcium channels and increased intracellular calcium influx from the extracellular space. Despite the cytoprotection afforded by calcium channel blockers, amyloid beta oligomer formation was not suppressed. The mechanism of cell death in MC65 cells is appeared to be caspase-3 independent. With the goal of determining if there is sufficient experimental support to move forward with animal trials of isradipine, we determined its bioavailability in the triple transgenic mouse model of AD. Subcutaneous implantation of carrier-bound isradipine (3 μg/g/day) for 60 days resulted in nanomolar concentrations in both the plasma and brain. Taken together, our in vitro results support the theory that calcium blockers exert protective effects downstream of the effects of beta amyloid. Isradipine's neuroprotective effect at concentrations that are clinically relevant and achievable in vitro and in vivo suggests that this particular calcium blocking agent may have therapeutic value in the treatment of Alzheimer's disease.

• Authors: Thimmappa S Anekonda, Joseph F Quinn, Christopher Harris, Kate Frahler, Teri L Wadsworth, Randall L Woltjer
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 41 Issue 1 Pg. 62-70 (Jan 2011) ISSN: 1095-953X [Electronic] United States
• PMID: 20816785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Calcium Channels, L-Type
• Isradipine

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Animals
• Calcium Channel Blockers (blood, pharmacology, therapeutic use)
• Calcium Channels, L-Type (metabolism, physiology)
• Cell Line, Tumor
• Female
• Humans
• Isradipine (blood, pharmacology, therapeutic use)
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism)