Focal activation of adenosine A1 receptor signaling in the hippocampus by means of photopharmacology: a possible tool for epileptic seizure suppression

01 November 2020 → Ongoing
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Neurological and neuromuscular diseases
Photopharmacology adenosine epilepsy
Project description

Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy, often with a seizure focus in the hippocampus (HC). To treat this disorder, innovative therapies are needed. Adenosine is an endogenous nucleoside known to have potent seizure-suppressive effects in the brain. These effects are mediated by the activation of inhibitory adenosine A1 receptors (A1Rs). The HC is a structure with high A1R expression, making A1R modulation possibly an effective treatment for TLE. However, A1Rs are expressed ubiquitously and local modulation is desired to avoid side effects. Photopharmacology is a promising technique which provides precise spatiotemporal control over the activity of a drug with the use of light. Photopharmacology could be very well suited for the treatment of focal epilepsies such as TLE, where modulation of neuronal excitability is only needed where and when seizures arise. A photocaged (inactivated) A1R agonist will be tested in vivo with the aim of suppressing seizures by locally uncaging (activating) this agonist in the HC of epileptic animals. First, a proof of concept for local A1R activation with the new photopharmacological compound will be provided and the possibility of systemic administration will be explored. Then, seizure-suppressive effects of A1R activation will be evaluated in a mouse model for TLE.