Year of Award

2021

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Neuroscience

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Philippe Diaz

Committee Co-chair

Kasper Hansen

Commitee Members

Philippe Diaz, Kasper Hansen, Richard Bridges, Mark Grimes, Yoonhee Jang

Keywords

all-trans retinoic acid, Traumatic Brain Injury, Parkinson's Disease, RAMBA, CYP26A1, CYP26B1

Subject Categories

Medicinal and Pharmaceutical Chemistry | Nervous System Diseases | Pharmaceutics and Drug Design

Abstract

Neurodegenerative diseases (NDs) take a wide spectrum of pathologies and have a tendency to present themselves later in life. Neurodegenerative diseases affect 6 million Americans annually with ~1 million currently living with Parkinson’s disease (PD). One of the greatest contributors to the pathogenesis of neurodegenerative diseases is the occurrence of a traumatic brain injury (TBI) during life.

All-trans-retinoic acid (atRA) is the active metabolite of Vitamin A. The retinoic acid pathway is known to be activated following TBI and is reduced in PD patients. Previous studies found a decrease in inflammation and behavioral deficits following administration of Vitamin A or atRA post TBI. Retinoic acid receptor stimulation has been found to protect dopaminergic neurons of the substantia nigra. Studies have shown that endogenous atRA within brain tissue supports neuronal protection, axonal growth, inflammatory modulation, and glial differentiation. Retinoic acid metabolism blocking agents (RAMBAs) are emerging as new therapeutic interventions with the goal of increasing endogenous atRA brain concentration, for the treatment of TBI and PD.

Our hypothesis was that instead of directly activating retinoic acid receptors, inhibition of the metabolism of atRA produced after central nervous system injury will have a neuroprotective effect and reduce the development of neurodegenerative diseases or cognitive impairments induced by TBI. This research sourced a newly synthesized RAMBA, DX308, for the purpose of confirming its action as a CYP26A1/B1 inhibitor. The aim of this project was to determine DX308 binding mode, and to characterize the effect of DX308 on atRA signaling in vitro. Modeling DX308-CYP26A1/B1 ligand-protein interaction was performed in order to support competitive binding of DX308. Glial- and neuroblastoma cell culture experiments were the preliminary investigation into DX308 as a functional RAMBA within the central nervous system.

DX308 was shown to have a binding mode similar with tazarotenic acid, and atRA. Treatment of SNB19 and SHSY5Y cells with atRA dose dependently modulated retinoid-responsive genes. DX308 potentiated the effects of a nanomolar concentration of atRA in SNB19 however, this effect was not confirmed in SHSY5Y. Follow up experiments involving SHSY5Y atRA/TPA dopaminergic differentiation displayed an altered dopamine receptor expression compared to SHSY5Y control cells.

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