Using cannabidiol and trazodone to treat protein misfolding neurodegenerative disease in C. elegans

Abstract

Alzheimer's disease is one of the most common neurodegenerative disorders and is typically characterized by the accumulation of the misfolded proteins Amyloid-Beta (Aβ1-42) and/or hyperphosphorylation of Tau (p-Tau). Despite the lack of a cure for the disease, it is well known that targeting signaling pathways involved in reactive oxygen species (ROS) or the unfolded protein response (UPR) mitigates the toxic effects of misfolded proteins, including behavioral deficits, glial inflammation, and neuronal toxicity. Laboratory animals, which have long been used to study this disease, have been genetically modified to express the two aforementioned proteins and express similar deleterious effects. However, despite the individual targeting of these pathways—although neuroprotective for some time—the laboratory model still succumbs to the disease. In this work, we hypothesized that drug-stacking Cannabidiol and Trazadone, which respectively target ROS production and UPR, would improve the neuronal function and extend the lifespan of neurodegenerative nematode models. To test this hypothesis, we utilized specific strains of C. elegans that have been genetically modified to contain the two common misfolded proteins found to aggregate in the brains of patients with Alzheimer's, Aβ1-42 and p-Tau. The AD-modeled nematodes were designed to parallel the middle- and late-stage in humans, starting at the point where signs of the disease first begin to become apparent. This research used Cannabidiol and Trazodone to inhibit ROS and UPR, respectively. Our experiments revealed that neurodegenerative C. elegans motility and lifespan significantly improved with both combination and isolated treatments of CBD and TRA. Our data also suggest that genetically susceptible neurodegenerative C. elegans can benefit from both full-life and late-stage rescue utilizing CBD and TRA. We predict these results may help guide future experimentation that incorporates the use of both CBD and TRA in higher organisms, including rodent models of neurodegeneration and aged canines with cognitive decline.