Doctor of Philosophy
Elvin T. Price, Pharm.D, Ph.D.
Phillip M. Gerk, Pharm.D., Ph.D.
Joseph L. McClay, Ph.D.
MaryPeace McRae, Pharm.D, Ph.D.
Michael F. Miles, M.D., Ph.D.
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.
© Omar E. Hassan
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Available for download on Sunday, September 24, 2028
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