title: 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.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA. anekondt@ohsu.edu
authors.forename: Thimmappa S
authors.initials: TS
authors.lastname: Anekonda
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Christopher
authors.initials: C
authors.lastname: Harris
authors.forename: Kate
authors.initials: K
authors.lastname: Frahler
authors.forename: Teri L
authors.initials: TL
authors.lastname: Wadsworth
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D017275:Isradipine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017275:Isradipine
references.citation: Neuron. 2005 Mar 3;45(5):639-42
references.pmid: 15748837
references.citation: J Alzheimers Dis. 2008 Jun;14(2):225-34
references.pmid: 18560133
references.citation: Neuron. 2005 Mar 3;45(5):675-88
references.pmid: 15748844
references.citation: Toxicol Appl Pharmacol. 2009 Oct 15;240(2):189-97
references.pmid: 19631677
references.citation: Neurobiol Aging. 2007 Feb;28(2):213-25
references.pmid: 16448723
references.citation: Biophys J. 2009 May 20;96(10):4200-11
references.pmid: 19450490
references.citation: Neurobiol Aging. 2011 May;32(5):821-33
references.pmid: 19540623
references.citation: J Neural Transm Suppl. 1995;46:439-53
references.pmid: 8821080
references.citation: Cell. 2005 Feb 25;120(4):545-55
references.pmid: 15734686
references.citation: Mol Pharmacol. 2009 Feb;75(2):407-14
references.pmid: 19029287
references.citation: Brain Res Mol Brain Res. 1994 Oct;26(1-2):207-17
references.pmid: 7854049
references.citation: Neurobiol Aging. 2006 Feb;27(2):218-27
references.pmid: 16399208
references.citation: Nat Rev Neurol. 2010 Apr;6(4):188-9
references.pmid: 20379202
references.citation: Neurobiol Dis. 2007 Feb;25(2):427-37
references.pmid: 17141508
references.citation: Neurobiol Dis. 2009 May;34(2):230-44
references.pmid: 19385055
references.citation: J Mol Neurosci. 2002 Aug-Oct;19(1-2):57-61
references.pmid: 12212794
references.citation: Am J Pathol. 2010 Feb;176(2):870-80
references.pmid: 20042680
references.citation: Cochrane Database Syst Rev. 2001;(1):CD000147
references.pmid: 11279679
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):567-71
references.pmid: 8380642
references.citation: Brain Res. 2007 Jan 26;1130(1):223-34
references.pmid: 17157826
references.citation: J Neuroinflammation. 2009 Jan 05;6:1
references.pmid: 19123954
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jan 1;877(1-2):59-64
references.pmid: 19041284
references.citation: Biol Psychiatry. 1990 May 15;27(10):1133-42
references.pmid: 2187540
references.citation: Lancet. 1998 Oct 24;352(9137):1347-51
references.pmid: 9802273
references.citation: Neurobiol Aging. 1999 Nov-Dec;20(6):597-603
references.pmid: 10674425
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: Mol Chem Neuropathol. 1996 Oct-Dec;29(2-3):153-68
references.pmid: 8971693
references.citation: Ann Intern Med. 2004 Apr 20;140(8):627-38
references.pmid: 15096334
references.citation: FASEB J. 2005 Jan;19(1):150-2
references.pmid: 15494446
references.citation: FASEB J. 2005 Nov;19(13):1923-5
references.pmid: 16129700
references.citation: Ann N Y Acad Sci. 2000;924:17-25
references.pmid: 11193794
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Neural Transm (Vienna). 2006 Dec;113(12):1837-45
references.pmid: 16752047
references.citation: J Neurochem. 2005 May;93(4):1047-56
references.pmid: 15857408
references.citation: Trends Neurosci. 2008 Sep;31(9):454-63
references.pmid: 18675468
references.citation: J Neurochem. 2006 Jul;98(1):57-67
references.pmid: 16805796
references.citation: J Neurosci Methods. 2004 Oct 30;139(2):195-201
references.pmid: 15488232
references.citation: Clin Cancer Res. 2005 May 1;11(9):3155-62
references.pmid: 15867207
references.citation: Neuron. 2009 Jun 25;62(6):788-801
references.pmid: 19555648
references.citation: Nature. 2007 Jun 28;447(7148):1081-6
references.pmid: 17558391
references.citation: Ann N Y Acad Sci. 1993 Sep 24;695:165-8
references.pmid: 8239277
references.citation: Neurobiol Aging. 2009 Jan;30(1):81-92
references.pmid: 17590240
references.citation: Cell Biol Int Rep. 1987 May;11(5):367-71
references.pmid: 2440589
references.citation: BMC Res Notes. 2008 Dec 01;1:122
references.pmid: 19046449