Photopharmacological activation of adenosine A1 receptor signaling suppresses seizures in a mouse model for temporal lobe epilepsy

Abstract

Up to 30 % of epilepsy patients suffer from drug-resistant epilepsy (DRE). The search for innovative therapies is therefore important to close the existing treatment gap in these patients. The adenosinergic system possesses potent anticonvulsive effects, mainly through the adenosine A1 receptor (A1R). However, clinical application of A1R agonists is hindered by severe systemic side effects. To achieve local modulation of A1Rs, we employed a photopharmacological approach using a caged version of the A1R agonist N6-cyclopentyladenosine, termed cCPA. We performed the first in vivo study with intracerebroventricularly (ICV) administered cCPA to investigate the potential to photo-uncage and release sufficient amounts of cCPA in the hippocampus by local illumination in order to suppress hippocampal excitability and seizures in mice. We validated the presence of cCPA in the hippocampus after ICV injection and explored its pharmacokinetic profile and in vivo stability. Using hippocampal evoked potential recordings, we showed a reduction in hippocampal neurotransmission after photo-releasing CPA, similar to that obtained with ICV injection of CPA. Furthermore, in the intrahippocampal kainic acid mouse model for DRE, photo-release of CPA in the epileptic hippocampus resulted in a strong suppression of seizures. Finally, we demonstrated that intrahippocampal photo-release of CPA resulted in less impairment of motor performance in the rotarod test compared to ICV administration of CPA. These results provide a proof of concept for photopharmacological A1R modulation as an effective precision treatment for DRE.