An Investigation on the Lipidomic Profile of a Mouse Model of Dravet Syndrome and the Molecular Action of Cannabinoids

Abstract

Epilepsy is a chronic neurological disorder marked by recurrent seizures, cognitive and motor impairments, and increased mortality. Around 30% of patients are drug-resistant, making it vital to better understand its mechanisms and develop new treatments. Dravet syndrome, a severe developmental and epileptic encephalopathy beginning in infancy, involves persistent seizures, cognitive and behavioural disabilities, sleep problems, and strong resistance to treatment. About 80% of cases are linked to mutations in the SCN1A gene, but much about its underlying biology remains unclear. Evidence suggests lipid dysregulation may contribute to Dravet syndrome, as lipids regulate neuronal activity and are involved in neuroinflammation and the endocannabinoid system. The effectiveness of cholesterol modulators such as soticlestat, the ketogenic diet, and cannabinoids supports this link. However, more research is needed to understand how lipids influence drug-resistant epilepsy and how lipid-like compounds such as cannabinoids act therapeutically.

This thesis investigated the lipid neurochemistry of Dravet syndrome and the pharmacology of cannabinoids. Lipidomic analysis of cortical and hippocampal tissue in Scn1a+/- mouse models revealed lipid profile changes associated with seizure susceptibility. Hexosylceramides emerged as key molecules, showing region- and strain-specific alterations, particularly upregulation in the hippocampus of seizure-prone mice, suggesting disrupted lipid pathways may contribute to seizure vulnerability.

Two cannabinoids, CBC and CBCA, were then examined for their interactions with ABC transporters that regulate brain drug access. Results showed CBCA is an ABCB1 substrate while CBC is not, and neither compound inhibited ABCB1 or ABCG2 activity. Molecular docking confirmed CBCA binding sites on ABCB1, offering insights into cannabinoid pharmacology and their potential as next-generation anti-seizure agents.