Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacology

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Nasser H. Zawia

Abstract

Dementia is an umbrella term describing several diseases which cause cognitive impairment, confusion, difficulty completing tasks and social withdrawal. Alzheimer’s disease (AD) is the most common form of dementia, and the incidence is rapidly increasing as the ‘baby boomers’ age. Currently, there is one disease-modifying treatment approved for AD patients, however, its ability to decrease or reverse cognitive decline has yet to be confirmed.

The etiology of AD is unknown, however, there are two forms of AD associated with onset age. Early-onset AD (EOAD) is considered genetic and accounts for less than 5% of AD cases worldwide. Typically, EOAD is associated with genetic mutations to presenilin 1 (PSEN), presenilin 2 (PSEN2), amyloid precursor protein (APP) or beta-secretase 1 (BACE-1). Late-onset AD (LOAD) accounts for over 95% of AD cases and is sporadic. The LOAD-associated environmental risk factors include exposure to heavy metals, a high-fat diet, lack of exercise, obesity and metabolic syndrome. The strongest genetic risk factor for LOAD is apolipoprotein E4 (APOE4) which is expressed in over 50% of AD patients.

Interestingly, epidemiological studies have shown a decreased incidence of AD in individuals who reported long-term use of non-steroidal anti-inflammatory drugs (NSAIDS). NSAIDS have since been widely researched for their potential neuroprotective effects. However, there has been mounting controversy concerning the long-term use of NSAIDS due to the increased risk of adverse cardiovascular events, liver toxicity, and gastrointestinal ulcers. Fenamate NSAIDS have been overlooked in many studies although many fenamates have shown non-canonical neuroprotective effects.

Tolfenamic acid (TA) is a fenamate NSAID that has been extensively researched and proven to intervene with AD pathology and decrease cognitive impairment in human transgenic mice. However, the mechanism by which TA modifies AD-related biomarkers is unknown. This dissertation explores the relevant literature on fenamates and their ability to impact neurological pathways. Following a survey of the literature, this dissertation determines the ability of Tolfenamic acid and its analogs to decrease AD-related biomarkers, using a mechanistic perspective. Finally, we examined the pathways affected by TA and its analogs using an unbiased approach to understand the upstream effects and downstream mediation of treatment with these potential therapeutics.

Herein, we found two potentially effective TA analogs which decreased AD-related biomarkers. We, also, provided insights into key pathways of interest in fenamate NSAID research. In the future, drug repurposing should gain more attention as a method to deliver therapeutics to patients burdened by neurodegenerative diseases as it accelerates the timeline from bench to bedside which is exceedingly necessary in the war against neurodegenerative disease.

Available for download on Thursday, January 05, 2023

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