A photoswitchable cannabinoid for precision treatment of refractory hippocampal discharges in a mouse epilepsy model

Abstract Temporal lobe epilepsy (TLE) has an unmet need for precision treatments targeting the seizure focus while avoiding effects on other body parts to minimise side effects. Photopharmacology could enable precision treatment by combining systemic administration of a photoswitchable drug with implantation of an optic fibre in the epileptic focus to induce light-dependent drug conversion from an inactive to an active configuration that interacts with its target receptor to suppress seizures. The photoswitchable Δ9-tetrahydrocannabinol (Δ9-THC) derivative, azo-THC-3, transitions from an inactive trans to an active cis configuration upon UV irradiation. We demonstrate that local or systemic administration of azo-THC-3 and local UV irradiation in the hippocampus supresses difficult-to-treat seizures in the intrahippocampal kainic acid mouse model of TLE. Furthermore, our findings illustrate that the photoswitch strategy avoids hypolocomotion, a common side effect of systemic Δ9-THC administration. As such, we provide the first demonstration of seizure suppression with the systemic administration of a photoswitchable compound and its local photoactivation in the seizure focus. Competing Interest Statement The authors have declared no competing interest.