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

Lovell MA, Abner E, Kryscio R, Xu L, Fister SX, Lynn BC - Oxid Med Cell Longev (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA ; Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536, USA.

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).

No MeSH data available.


Related in: MedlinePlus

Mean ± SEM H4 survival and Aβ1–42 production after treatment with commonly prescribed CCBs. ∗P < 0.05.
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Related In: Results  -  Collection


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fig3: Mean ± SEM H4 survival and Aβ1–42 production after treatment with commonly prescribed CCBs. ∗P < 0.05.

Mentions: Because the regression model suggested that use of CCBs is associated with slowed progression to dementia we wanted to determine if CCB treatment significantly impacts pathogenic processes associated with AD. To determine if CCBs diminish Aβ1–42 formation we treated H4 neuroglioma cultures overexpressing APP with increasing concentrations of the 8 most commonly prescribed CCBs (amlodipine, dilitiazem, felodipine, isradipine, nicardipine, nimodipine, nifedipine, or nisoldipine) and measured Aβ1–42 secretion into culture medium. Cultures were treated with each drug for 16 hours and cell viability was assessed using the reduction of MTT. Figure 3 shows that 1 μM amlodipine, dilitiazem, felodipine, isradipine, nicardipine, and nifedipine led to minimal cell death whereas higher concentrations of nisoldipine (10 μM) were well tolerated by the cultures. Using these optimized concentrations for further studies, we plated H4 cultures in 6-well plates at a density of 2.5 × 105 cells/well and after 24 hours of equilibration exposed the cells to each agent (N = 9 to 18 over three experiments) for 16 h. Following treatment, medium was collected and mixed with 5 μL 1 mM EDTA to inhibit metalloprotease activity and Aβ1–42 levels secreted into culture medium quantified using standard sandwich ELISAs (Invitrogen) as per manufacturer's instructions. Figure 2 shows that of the 8 CCBs tested 1 μM nifedipine, 1 μM nimodipine, and 10 μM nisoldipine led to significantly lower Aβ1–42 generation with nifedipine showing the most pronounced change. It is interesting to note that nifedipine and nisoldipine are unique among CCBs in that both contain an ortho-nitro group whereas the other drugs contain a meta-nitro group.


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

Lovell MA, Abner E, Kryscio R, Xu L, Fister SX, Lynn BC - Oxid Med Cell Longev (2015)

Mean ± SEM H4 survival and Aβ1–42 production after treatment with commonly prescribed CCBs. ∗P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4499419&req=5

fig3: Mean ± SEM H4 survival and Aβ1–42 production after treatment with commonly prescribed CCBs. ∗P < 0.05.
Mentions: Because the regression model suggested that use of CCBs is associated with slowed progression to dementia we wanted to determine if CCB treatment significantly impacts pathogenic processes associated with AD. To determine if CCBs diminish Aβ1–42 formation we treated H4 neuroglioma cultures overexpressing APP with increasing concentrations of the 8 most commonly prescribed CCBs (amlodipine, dilitiazem, felodipine, isradipine, nicardipine, nimodipine, nifedipine, or nisoldipine) and measured Aβ1–42 secretion into culture medium. Cultures were treated with each drug for 16 hours and cell viability was assessed using the reduction of MTT. Figure 3 shows that 1 μM amlodipine, dilitiazem, felodipine, isradipine, nicardipine, and nifedipine led to minimal cell death whereas higher concentrations of nisoldipine (10 μM) were well tolerated by the cultures. Using these optimized concentrations for further studies, we plated H4 cultures in 6-well plates at a density of 2.5 × 105 cells/well and after 24 hours of equilibration exposed the cells to each agent (N = 9 to 18 over three experiments) for 16 h. Following treatment, medium was collected and mixed with 5 μL 1 mM EDTA to inhibit metalloprotease activity and Aβ1–42 levels secreted into culture medium quantified using standard sandwich ELISAs (Invitrogen) as per manufacturer's instructions. Figure 2 shows that of the 8 CCBs tested 1 μM nifedipine, 1 μM nimodipine, and 10 μM nisoldipine led to significantly lower Aβ1–42 generation with nifedipine showing the most pronounced change. It is interesting to note that nifedipine and nisoldipine are unique among CCBs in that both contain an ortho-nitro group whereas the other drugs contain a meta-nitro group.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA ; Sanders-Brown Center on Aging and Alzheimer's Disease Center, University of Kentucky, Lexington, KY 40536, USA.

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).

No MeSH data available.


Related in: MedlinePlus