Abstracts

Rationale: While cannabidiol (CBD) and cannabidiol oil (CBO) show anecdotal efficacy in reducing seizure frequency, little is known about the potential adverse side-effects of CBD and CBO on child physiology, brain development, adult disease, and/or offspring. Therefore, the goal of this project is to compare the relative morphological, behavioral, reproductive and multigenerational phenotypes that result after a developmental exposure to CBD, CBO and Δ9-tetrahydrocannabinol (THC). Additionally, there is a critical need for new, non-scheduled drugs for treatment of pediatric epilepsy.Methods: Our comparative approach allows us to determine the unique effects of CBD, CBO and THC and provides insight into the molecular pathways of both toxic and therapeutic action. We measure mortality at 24 and 96 hour post fertilization (hpf), touch response suppression, yolk sac and pericardial edemas, axis mutations, fin deformities, and gene expression of 15 mRNAs critical in morpho-/neurogensis. We will also leverage our experience with the zebrafish model and the University of Mississippi’s extensive natural product and chemical libraries in our high-throughput screen for epilepsy drug discovery.Results: Preliminary LC50 data for WIN 55,212-2 (synthetic cannabinoid) was 1.2 mg/L ± 0.19 (0.0022 mM). Developmental toxicities included decreased touch response (IC50 = 0.5 µM) and increased pericardial edemas. After assessing toxicity for various cannabinoids and structural analogues, positive leads with anti-epileptic activity will be pipelined: A) back into zebrafish toxicity assays; and B) submitted to the in vitro and in vivo cores of our NIH-Center for Biomedical Research Excellence Natural Product Neuroscience.Conclusions: Ultimately, using this high-throughput developmental model, we hope to identify a relatively non-toxic cannabinoid with anti-seizure activity. Our comparative approach is highly relevant due to the known adverse effects THC exposure on humans including brain development deficits and social disorders, while the developmental toxicity of CBD, CBO and other analogues is unknown. Supported by Grant Number P20GM104932 from the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH).