Cannabidiol Effects on Post‐Seizure Neurogenesis

Abstract

Epilepsy is a complex disorder characterized by a propensity to generate repetitive seizures with molecular and cognitive consequences. Many pharmacological treatments for epilepsy target neurotransmitters or ion channels, leaving nearly 30% of patients resistant to current medications. The recent approval of cannabidiol (CBD), a non‐psychotropic component of Cannabis sativa, has demonstrated the ability to lessen seizure severity and curb neuroinflammation in experimentally induced seizures in animal models. While CBD has been shown to effect multiple pathways and targets, its complete mechanism of action is still not understood.Current models of induced seizures mostly utilize treatments before or during epileptic events, though this practice does not normally occur in the clinic. Here we utilize a more translational model where CBD treatment is administered after the first seizure event. An inciting seizure increases the likelihood of secondary seizures due to epileptogenesis, where seizure susceptibility is increased due to molecular and structural changes within the central nervous system (CNS) parenchyma. The epileptogenic process includes changes in axonal sprouting, cell death, neurotransmitter release, and in the hippocampus aberrant granule neural network reorganization and neurogenesis. Microglia, the resident immune cells in the brain, are involved in hippocampal neurogenesis, controlling apoptosis of the newborn neurons and ultimately the numbers of granule cells. The objective of this study is to investigate whether CBD modulates microglial involvement in neurogenesis post seizure.MethodsFollowing seizure induction in 8–10 week old mice, mice are given BrdU for 7 days post seizure to monitor cell proliferation and survival. Newly generated neurons are assessed using NeuN and DCX, to identify differentiated neuroblasts and mature neurons, respectively. BrdU+ cells are used for quantification and assessment of differentiation and survival of new cells in the dentate gyrus. Neural stem cell (NSC) levels in the hippocampus are also compared using SOX2/GFAP co‐staining.ResultsOur data suggest that CBD affects the number of new neurons after seizure. Mechanisms contributing to neurogenesis will be explored.ConclusionsCBD contributes to microglia‐mediated changes in the numbers of granule cells and neurogenesis in a model of epilepsy.Support or Funding InformationThis work was partially supported by an NSF Predoctoral Fellowship and SBMS funds to TRV.