Graduation Date
5-2018
Document Type
Master's Thesis
Degree Name
Master of Science
Department or Program
Biological Sciences
Department or Program Chair
Meredith Protas, PhD
First Reader
Pankah Kapahi, PhD
Second Reader
Kiowa Bower, PhD
Abstract
Diabetes mellitus is a metabolic disease characterized by hyperglycemia that affects 30 million children and adults in the United States alone. Patients suffering from diabetes have high concentrations of reactive α-dicarbonyls (α-DCs) like, methylglyoxal (MGO). The abundance of α-DCs form advanced glycation end products (AGEs); in turn, the accumulation of AGEs has been linked to secondary complications. Secondary complications include diabetic neuropathy, nephropathy and cardiomyopathy. A recently discovered TRPA-1-Nrf-2 pathway is a conserved mechanism in vertebrates and invertebrates that detoxifies α-DCs; however, regulators that activate the detoxification mechanism are currently unknown. Several supplement grade compounds were screened for TRPA-1-Nrf2 induced activity in Caenorhabditis elegans. The drug screen revealed several candidates that decreased methylglyoxal levels using the TRPA-1-Nrf-2 pathway. Regulatory mechanisms that trigger this detoxification pathway open up avenues for therapeutic studies. Candidates were utilized to determine their therapeutic efficacy in mammalian in vitro studies, in the background of methylglyoxal stress. In this work, we pursue combinational therapy to identify a more effective approach at mitigating neurotoxicity. We show that a five-compound combination ameliorates methylglyoxal stress in multiple dopaminergic cell lines: N27, PC12 and SH-SY5Y. Results indicate that combinational therapy counteracts methylglyoxal stress more effectively than compounds used in isolation. Data suggests that the five-compound mixture can be used as a potential supplement to treat diabetic complications in patients suffering from long term diabetes.