Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production

Abstract

Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate of progression to dementia. Significantly, use of CCBs ameliorated the negative effects of the presence of APOE-4 alleles on cognitive decline. To determine if CCBs could minimize amyloid beta peptide (Aβ 1–42) production, H4 neuroglioma cultures transfected to overexpress APP were treated with various CCBs and Aβ 1–42 levels and levels of proteins involved in Aβ production were quantified. Results show that treatment with nifedipine led to a significant decrease in levels of Aβ 1–42, with no significant decrease in cell viability. Collectively, these data suggest that use of CCBs significantly diminishes the rate of progression to dementia and may minimize formation of Aβ 1–42.

A Novel Small Molecule Modulator of Amyloid Pathology

“…In our previous studies we showed that nifedipine, a dihydropyridine calcium channel blocker, significantly decreased Aβ 1–42 production in an in vitro model [37]. In the course of those studies, we observed that nifedipine solutions became more effective after exposure to ambient light in the laboratory.…”

“…In recent studies we demonstrated that AD subjects taking calcium channel blocker anti-hypertensives showed a slowed progression to dementia and that nifedipine in particular was effective in the decrease of Aβ production through decreases in PS-1 [37]. During the course of our studies of nifedipine, we identified a functionalized naphthyridine byproduct of the parent compound that appeared to have comparable efficacy on the inhibition of Aβ production in in vitro models.…”

Calcium-Channel Blockers and Dementia Risk in Older Adults – National Health Insurance Service – Senior Cohort (2002–2013) –

“…16 In vitro studies show that blockade of calcium channels in neurons has a protective effect on "neurodegeneration" caused by β-amyloid. 10, 22 Nevertheless, it is not yet clear how to choose different types of CCBs for maximizing the neuroprotective benefits because of controversy surrounding the effects of CCB on cognitive function and reports that DHP CCBs would be more effective than non-DHP CCBs. Additionally, previous research has found that specific drugs, such as nitrendipine and nivaldipine, which can penetrate the blood-brain barrier, are more likely to affect cognitive function and improve "β-amyloid clearance".…”

Hypertension and Dementia: A comprehensive review from the HOPE Asia Network

“…In that study, a calcium channel blocker (CCB) was used and had a protective effect against dementia, especially Alzheimer's . Another similar study in Kentucky showed that CCBs could reduce dementia progression and minimize amyloid beta peptide formation without changes to cell viability . And in a study conducted on the predominantly male population of the Veterans Healthcare System in the United States, angiotensin receptor blockers achieved a significant reduction in the incidence and progression of AD and dementia compared to other cardiovascular drugs, including angiotensin converting enzyme inhibitors …”

“…81 Both calcium channel blockers (CCBs) and angiotensin receptor blockers (ARBs) are suggested to have a more pronounced protective effect than other anti-hypertensives. [82][83][84] In addition, the Syst-Eur trial also showed that anti-hypertensive medications can reduce stroke morbidity and mortality, and respondents may not be affected by dementia until at least 60 years of age. In that study, a calcium channel blocker (CCB) was used and had a protective effect against dementia, especially Alzheimer's.…”