Journal
NEUROBIOLOGY OF DISEASE
Volume 41, Issue 1, Pages 62-70Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2010.08.020
Keywords
Amyloid precursor protein; Beta amyloid oligomers; Calcium channel blocker; Neurotoxicity
Categories
Funding
- NIH/NEI [5R21 EY 018708-02]
- NIH [T32 AT002688-05, P30AG008017]
- Department of Veterans Affairs
- OHSU
- National Center for Complementary & Integrative Health [T32AT002688] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [R21EY018708] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG008017] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 mu g/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. (C) 2010 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available