Cited by 157Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchCholinesterase and Neurodegenerative Diseases

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

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Anekonda, Thimmappa S., Quinn, Joseph F., Harris, Christopher, Frahler, Kate, Wadsworth, Teri L., Woltjer, Randall L.·2011·Neurobiology of 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.

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Authors
Anekonda, T. S., Quinn, J. F., Harris, C., Frahler, K., Wadsworth, T. L., & Woltjer, R. L.
Affiliations
Oregon Health & Science University (US)
Corresponding author
Anekonda, Thimmappa S.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2011-01
Volume
41
Issue
1
Pages
62-70
ISSN
0969-9961 (ISSN-L)
OpenAlex
W2051044968
Cited by
155
References
46
Citations by year
2026: 3 · 2025: 10 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 13 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 12 · 2013: 17 · 2012: 9
FWCI
6.93
Type
journal article
Language
en
Open access
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (P30AG008017)
  • Oregon Health and Science University
  • National Institutes of Health
  • National Eye Institute (5R21 EY 018708-02, T32 AT002688-05)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
Alzheimer's disease, isradipine, L-type calcium channels, calcium channel blockers, amyloid-beta, APP C-terminal fragments, intracellular calcium dysregulation, neuroprotection, Cav1.2 calcium channel, amyloid oligomerization, triple transgenic mouse model, drug bioavailability, verapamil, diltiazem, nimodipine
MeSH terms
Alzheimer Disease, Animals, Calcium Channel Blockers, Female, Humans, Mice, Transgenic, Neurons, Isradipine, Calcium Channels, L-Type, Cell Line, Tumor, Mice

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