Targeting Epilepsy with Photoactivatable Drugs
1 Dept. of Epileptology, University Medical Center, Bonn, Germany
2 Dept. of Pharmacological and Medicinal Chemistry, University of Bonn, Bonn, Germany
3 Dept. of Chemistry and Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, USA
4 Department of Neurosurgery, University Medical Center, Bonn, Germany
5 Dept. of Epileptology, University Medical Center, Bonn, Germany
6 Institute of Experimental Epileptology and Cognition Research, University of Bonn Medical Center, Bonn, Germany
Photo-activatable drugs (PDs) are rapidly emerging as potential precision therapeutics e.g. for varied forms of cancer, vision loss, or pain disorders. Despite their potential, PDs have not been exploited for epilepsy, a common, often debilitating neurological disorder. As 30% of epilepsies are medically refractory, and anti-seizure drugs often cause multi-organ side effects, PDs could break new therapeutic ground. PDs can be applied on demand, and locally activated/inactivated in single/multiple epileptic brain areas in a targeted fashion. This minimizes side effects, and allows the adoption of potent drugs from other fields yet unthinkable in routine epileptology (e.g. general anesthetics). Further, different PDs can be flexibly combined or exchanged, and do not require gene transfer. Here, we use light-switchable ion-channel blockers QAQ and cQAQ, and a newly developed caged propofol (cProp) in mouse or human brain slices. We show that QAQ and cQAQ can be activated/inactivated in a wavelength-dependent fashion (QAQ: 525/387nm; cQAQ: 400/525nm), and reversibly block firing of hippocampal neurons upon electric cell stimulation. Further, cProp profoundly increases the decay time of inhibitory post-synaptic currents and leak current in neurons in a light-dependent way (400nm). Crucially, PDs block neuronal activity also in post-resective brain tissue from patients with refractory epilepsy or neuro-oncological disorders. Our results showcase photopharmacology as a versatile potential approach to control hard-to-treat focal epilepsy. It could potentially obviate the need for resective surgery in many cases, and be used in multi-focal epilepsy using minimally invasive biocompatible light-fiber implants. Importantly, it may be clinically tested in the foreseeable future.