Cannabidiol Protects Against Neurotoxic Reactive Astrocytes‐Induced Neuronal Death in Mouse Model of Epilepsy

ABSTRACT Reactive astrocytes play a critical role in the initiation and progression of epilepsy, but their molecular subtypes and functional characterization are not fully understood. In this study, we report the existence of neurotoxic reactive astrocytes, a recently identified subtype, that contribute to neuronal death in the epileptic brain. In a kainic acid (KA)‐induced mouse model of epilepsy, we show that neurotoxic reactive astrocytes are induced by microglia‐secreted cytokines, including IL‐1α, TNFα, and C1q, and are detectable as early as 7 days post‐KA stimulation. These cells exhibit a distinct molecular signature marked by elevated expression of complement 3 and adenosine 2A receptor. Transcriptomics and metabolomics analyses of human brain tissues from temporal lobe epilepsy (TLE) patients and an epileptic mouse model reveal that neurotoxic reactive astrocytes induce neuronal damage through lipid‐related mechanisms. Moreover, our results demonstrate that the anti‐seizure medication cannabidiol (CBD) and an adenosine 2A receptor antagonist can both suppress the formation of neurotoxic reactive astrocytes, mitigate gliosis, and reduce neuronal loss in a mouse model of epilepsy. Electrophysiological and behavioral studies indicate 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 both the KA‐induced mouse model of epilepsy and TLE patients and can contribute to neuronal loss through releasing toxic lipids. Importantly, cannabidiol emerges as a promising therapeutic drug for targeted intervention against neurotoxic reactive astrocytes in adult epilepsy. image