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