943C Poster - 15. Models of human disease
Saturday April 09, 1:30 PM - 3:30 PM

Authors:
Alec Candib; Brandon Molina; Jessica Mastroianni; Nicholas Lee; Natasha Sam; Eddie Cho; Kyle DeAlva; Andrea Gonzalez; Gina Torabzadeh; Josephine Vu; Joy Phillips; Kim Finley

Affiliation: Department of Biology, San Diego State University, San Diego, CA

Keywords:
a. neural degeneration; f. drug discovery

A wide range of potential therapeutics, including modified diets, cannabis, turmeric, and probiotics, are being examined as treatments for disorders associated with aging and neural stress. In this report, we detail a unified in vivo method to test the safety, efficacy, therapeutic dosage, and potential molecular mechanism of neuroprotective products using adult Drosophila melanogaster as a model system. This includes an integrated three-part platform that examines the impact of individual compounds and biologics on neural aging, TBI responses, and cytotoxic β-amyloid (Aβ). Adult flies were administered different dosages of cannabis-derived cannabinoids (CBD, CBN, THC), select drugs (J147, metformin, donepezil), and active and inactive biologics (LGG, IAB). Aging studies show select dosages of several therapies preserved locomotor behaviors (negative geotaxis response, NGR) and promoted longevity, while other therapies exacerbated age-related NGR decline and reduced longevity. Pre-treatment with several therapies also helped preserve NGR profiles and promote longevity in traumatized fly cohorts. To examine the potential molecular mechanisms of these compounds, changes to the autophagy and inflammation (NF-κB) pathways were investigated in adult tissues. Several compounds impaired basal and fasting-induced autophagic flux, while others increased autophagic flux and reduced protein aggregate formation. Several therapies reduced the expression of downstream NF-κB signaling targets (antimicrobial peptides) after TBI. The impact of CBD, IAB, and Donepezil on longevity, NGR, NF-κB signaling, and autophagy were studied in flies expressing Aβ peptides. Together, these studies showed that these compounds have a significant impact on Drosophila physiology and molecular pathways. Generally, exposure to every compound but THC had similar neuroprotective and longevity-promoting effects, while THC had a limited positive impact only following mTBI. These findings demonstrate the versatility of Drosophila as a drug discovery model system and highlight the need for future studies to clarify the molecular interactions and downstream consequences of natural products on complex biological systems and tissues.