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

Share

COinS