DOI
https://doi.org/10.25772/CMQ2-4A23
Defense Date
2020
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmaceutical Sciences
First Advisor
Elvin T. Price
Second Advisor
Joseph L. McClay
Third Advisor
Lana Sargent
Abstract
Studies reveal that 10-27% of older adults chronically use anticholinergic medications. Increased cumulative anticholinergic burden scores are associated with increased risks of dementia. The mechanisms by which anticholinergic drugs negatively impact cognition remain elusive. However, researchers speculate that the drug’s impairment of cholinergic neurons promotes neuroinflammation.
We hypothesize that drugs with anticholinergic properties will induce inflammation in the brain. MCP1 and IL 6 are chemokines that contribute to neuroinflammation. We investigated the influence of diphenhydramine (Benadryl) on the production of MCP1 and IL-6 in Normal Human Astrocytes and Paroxetine on the production of MCP1 in Normal Human Astrocytes and Normal Human Brain Microvascular Endothelial Cells.
Normal Human Astrocytes were cultured (seeded at 5,000 cells/cm2) and treated with a clinically relevant concentration (equivalent to clinically observed Cmax for the respective drugs) of diphenhydramine (66ng/ml) and Paroxetine (1.67*10-4mM). RNA was isolated and converted into cDNA, and then gene expression was measured via RT-PCR. MCP1 and IL-6 protein production were measured from cell culture supernatants by ELISA. One-way ANOVA compared MCP-1 and IL-6 protein concentrations with Tukey correction for multiple corrections. The gene expression was reported with relative significance (p= 0.05) using Student’s t-test.
Drugs with anticholinergic properties are considered to be pro-inflammatory. However, our data from normal human astrocytes treated suggest that diphenhydramine possesses anti-inflammatory properties. This preliminary finding suggests the possibility of pathological mechanisms of anticholinergic medications with dementia that may not be associated with inflammation.
Our data from Paroxetine in normal human brain microvascular endothelial cells suggest that Paroxetine possesses pro-inflammatory properties. Our preliminary findings indicate the possibility of a pathological pro-inflammatory mechanism associated with Paroxetine. Further evaluation of anticholinergic drugs in the human brain is warranted.
Rights
© Syeda Rehma Hashimi
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-7-2020