Vick, Zaria Denise, authorMoreno, Julie, advisorLegare, Marie, advisorBouma, Jerry, committee memberTjalkens, Ronald, committee member2022-01-072022-01-072021https://hdl.handle.net/10217/234212Metronidazole is a broad-spectrum antibiotic approved for clinical therapeutic use in veterinary and human medicine. Although the literature has reported neurotoxic unintended side effects with the use of this drug, these incidences occur in less than 1% of human cases making this instance rare. The mechanism of this neurotoxicity has not been fully elucidated, nor the susceptible population identified. We explore in this work that these susceptible populations are humans and animals with concurrent localized and/or systemic inflammation. Some proposed mechanisms are axonal swelling with increased water content due to toxic injury, vascular spasm with mild reversible localized ischemia, modulation of the gamma-aminobutyric acid (GABA) receptors within cerebellar and vestibular systems, RNA binding with inhibition of protein synthesis, and axonal degeneration. While these mechanisms offer some insights into the neurotoxicity, we propose a novel connection between cholesterol inhibition and the reductive activation of metronidazole resulting in poor glial myelination that explicates low dose neurotoxic clinical outcomes in vulnerable humans and animals with the use of this drug. In order to investigate this, we have implemented physiologically based pharmacokinetic computational models of a human, equine, murine, and rabbit with metronidazole exposure. Furthermore, in combination with computational techniques, we assess cellular and molecular analyses to address this neurotoxicity in a primary murine glial cell model. Additionally, we use liquid chromatography and mass spectrometry work in order to address the reductive activation of metronidazole. We then ask if inflamed glia are more susceptible to metronidazole-dependent neurotoxic outcomes. With these data, we offer insight into this elusive mechanism and will aid human and veterinary literature in a way that improves the quality of life of affected patients and better predicts populations vulnerable to this neurotoxicity.born digitalmasters thesesengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.neurotoxicitymetronidazoleText