DOI
https://doi.org/10.25772/T2P9-R069
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Elvin T. Price, Pharm.D, Ph.D.
Second Advisor
Phillip M. Gerk, Pharm.D., Ph.D.
Third Advisor
Joseph L. McClay, Ph.D.
Fourth Advisor
MaryPeace McRae, Pharm.D, Ph.D.
Fifth Advisor
Michael F. Miles, M.D., Ph.D.
Abstract
Alcohol Use Disorder (AUD) is a pressing health concern with limited therapeutic options. Chronic EtOH misuse or acute withdrawal is associated with innate immune activation and reduced glutamate reuptake transporters. Preclinical studies have explored several nuclear receptor (NR) ligands to have a benefit in modulating animal drinking behavior. Fenofibrate, a PPARα ligand, appears to modulate several pathways: reducing inflammation and restoring glutamate reuptake transport protein levels.
To further the translation effort, we employed two approaches:
(1) Identification of Novel Druggable Targets: We examined a set of 20 NR genes previously shown to be modulated by fenofibrate in our lab. Their associations with AUD phenotypes were investigated using GWAS summary statistics. To further refine our findings, we employed an in vitro model using normal fetal human astrocytes to assess biological plausibility. The outcome of these analyses led to the identification of candidate genes associated with Drinks-per-week that were modifiable by fenofibrate.
(2) Exploration of Fenofibrate's Mechanism of Action: Our inquiry into the interplay among glutamate reuptake transporters, EtOH, and inflammation began with characterizing the inflammatory cytokine release by normal human astrocytes (NHA) in response to acute EtOH. Time-dependent release of TNFα was also evaluated. We found that acute EtOH did not modulate glutamate reuptake transporter mRNA expression. However, IL-1β and TNF-α differentially influenced these transporters. Interestingly, fenofibrate and its active metabolite, fenofibric acid, attenuated some of the cytokine release activated by TNF-α in NHA. Furthermore, our co-treatment exploratory study indicated that fenofibrate and its metabolite may reduce the suppression of glutamate reuptake transporters instigated by TNF-α. In conclusion, fenofibrate holds potential for mitigating the TNF-α mediated suppression of glutamate reuptake transporters in NHA and may offer a novel avenue for the treatment of AUD, particularly in the context of acute EtOH withdrawal.
Rights
© Omar E. Hassan
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-26-2023
Included in
Genomics Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Molecular and Cellular Neuroscience Commons, Pharmacy and Pharmaceutical Sciences Commons, Translational Medical Research Commons