Date of Award
Doctor of Philosophy in Interdisciplinary Neuroscience
Navindra P. Seeram
Alzheimer’s and Parkinson’s disease (AD and PD, respectively) are the two most common neurodegenerative diseases. Currently, no interventions have been successful in stopping the progression of these diseases. Here, we utilize two independent strategies: the use of natural products and repurposed pharmaceuticals to target neuroinflammation in models of neurodegeneration.
Natural products have been used for their medicinal properties for centuries in traditional eastern medicine practices. Mucuna pruriens (Mucuna) is a well-known natural source of levodopa, typically prescribed in Ayurveda for PD. A novel levodopa reduced seed extract exhibited protective effects against oxidative stress and PD specific toxic agents, both in vitro and in vivo. Further phytochemical investigation of our extract led to the isolation and identification of seven newly reported compounds. Isolates failed to protect against toxin inducers of PD in cellular models. These data support that our novel levodopa reduced seed extract, but not isolated compounds, protect against toxin-induced models of PD.
The Mediterranean diet, which is primarily composed of polyphenols, has gained considerable interest in the management of age-related diseases. Therefore, common polyphenols classes, isoflavones, and lignans with their gut-derived microbial metabolites were evaluated. Polyphenol microbial metabolites generally showed greater blood-brain barrier permeability and protection against oxidative stress, as compared to their parent compounds. Moreover, polyphenol microbial metabolites may heavily contribute to the beneficial effects of polyphenol enriched diets in disease prevention.
Repurposing pharmaceuticals is an approach that allows for expedited drug discovery to fast track pharmaceuticals to a new targeted patient population. Here, we analyze direct thrombin inhibitor, dabigatran etexilate (Pradaxa®), against neuroinflammation in AD and PD models. In a Drosophila melanogaster transgenic model of PD, dabigatran treatment improved locomotor ability and reduced neuroinflammatory markers in males. Further, in a tau-based animal model of AD short-term treatment with dabigatran modulates expression of proteins related to antioxidants, mitogen-activated protein kinases, tau, thrombin, and oxidative stress. Taken together, these data indicate short-term treatment with a direct thrombin inhibitor modulates protein expression in the brains of aged Tg4510 mice. These findings support our hypothesis that targeting thrombin, a key mediator of neuroinflammation and neurotoxicity may be effective in reducing neuroinflammation in neurodegenerative diseases.
Our results indicate two common drug discovery methods, namely, investigation of natural products and repurposing pharmaceuticals, may provide insights for targeting neuroinflammation in neurodegenerative diseases. Further research should focus on moving these therapeutics through the drug discovery pipeline to the patient population.
Johnson, Shelby L., "INVESTIGATING NAT PRODUCTS & PHARMACEUTICALS TARGETING INFLAMMATION IN NEURODEGENERATIVE DISEASES" (2020). Open Access Dissertations. Paper 1132.