Cannabidiol protects against neurotoxic reactive astrocytes-induced neuronal death in mouse models of epilepsy

Abstract

Reactive astrocytes play a critical role in the pathology of various neurological disorders, often resulting in neuronal damage and death. Accumulating evidences demonstrate that reactive astrocyte is an important component of glia scar of epileptic human brain, but the molecular subtyping and functional characterization of reactive astrocytes in the initiation and progression of epilepsy is not fully understood. In this study, we report the existence of neurotoxic reactive astrocytes, a novel defined reactive astrocyte subtype, that are pro-epileptic in the epileptic brain. In a kainic acid-induced mouse model of epilepsy, these neurotoxic reactive astrocytes are induced by microglia-secreted cytokines IL-1α, TNFα, and C1q and formed in the mouse brain as early as seven days post kainic acid stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses using brain tissues from patients with temporal lobe epilepsy and epileptic mice reveal that neurotoxic reactive astrocytes contribute to neuronal loss through lipid-related mechanisms. Moreover, our study demonstrated that the anti-epileptic drug cannabidiol and an adenosine 2A receptor antagonist can suppress the formation of neurotoxic reactive astrocytes. These compounds also exhibit pronounced effects in inhibiting gliosis and neuronal loss in mouse models of epilepsy. Electrophysiological and behavioral studies provide compelling evidences that cannabidiol attenuates seizure symptoms and enhances memory capabilities in epileptic mice. Our findings suggest that neurotoxic reactive astrocytes are formed at an early stage in the epileptic mouse brain and can lead to neuronal death through releasing toxic lipids. Importantly, cannabidiol and adenosine 2A receptor antagonist emerge as promising therapeutic candidates for epilepsy treatment. Our study provides valuable insights into the mechanism of action of cannabidiol in epilepsy and opens avenues for targeted interventions against neurotoxic reactive astrocytes in neurological disorders.