Date of Award

Spring 2021

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Lorne Hofseth

Abstract

Panaxynol (PA) is a polyacetylene that was found to be an abundant active ingredient in American ginseng (AG). Pharmacokinetics (PK) studies of PA were conducted to determine how the body reacts to it by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure PA’s concentration. In vitro, PA’s clearance by microsome metabolism is a moderate 48.1 minutes. In vivo, CD-1® mice were treated with PA by intravenous (IV) injection or orally (PO). Concentrations of PA were measured in plasma and tissue using LC-MS/MS. Also, PA has a high bioavailability of 50.4% and a moderate half-life of 5.9 hours. In addition, mice showed no signs of toxicity when treated with 300 mg/kg of PA. Colonic tissue concentrations of PA peaked at 2 hours post-treatment at 121 ng/ml. PA, a hexane fraction of AG (HAG), and AG reduce oxidative stress in macrophages (mϕ) and induced the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and its target genes. In a DSS-induced colitis mouse model, PA’s efficacy was lost in Nrf2-/- mice, indicating that Nrf2 is key to the efficacy of PA in reducing inflammation. Mining for PA’s mechanism of action, mϕ were observed to be particularly vulnerable to the actions of PA. RNA-seq analysis indicated that PA may achieve its pro-apoptotic effects on mϕ through the MAPK signaling pathway. Future studies will delineate PA’s mechanisms of action utilized in its efficacy in treating colitis and extend the studies to human trials to reduce the burden of colitis using natural ingredients.

Rights

© 2021, Hossam Sami Tashkandi

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