Investigating the Involvement of GPR55 Signaling in the Antiepileptic Effects of Cannabidiol (P5.244)

Abstract

Objective: Investigate whether the alteration of GPR55-mediated signaling contributes to the anticonvulsant effect of cannabidiol (CBD). Background: CBD is a nonpsychoactive phytocannabinoid that exerts anticonvulsant and antiepileptic effects independently of the endocannabinoid system. Its underlying therapeutic mechanism remains unknown. CBD is an antagonist of G protein-coupled receptor 55 (GPR55), which is modulated by phyto- and endo-cannabinoids as well as L-α-lysophosphatidylinositol (LPI), its endogenous ligand. GPR55 has been associated with cancer, obesity, diabetes as well as inflammatory and neuropathic pain. GPR55 appears to be a promising target for the treatment of epileptic disorders. Because the therapeutic target for CBD in epilepsy has not yet been defined, it is important to investigate whether the alteration of GPR55-mediated signaling may contribute to its anticonvulsant effect. In rat acute hippocampal slices, LPI increases synaptic release probability at CA3-CA1 synapses, facilitating excitatory synaptic transmission. LPI is produced by phospholipase A2, the activity of which is increased during epileptic seizures (Yegin et al, 2002). CBD abolishes GPR55-mediated elevation of presynaptic Ca2+ (Sylantyev et al, 2013), thus decreasing excitation of CA1 pyramidal cell — a mechanism that may contribute to its anticonvulsant properties. Methods: Whole cell patch-clamp recordings of hippocampal CA1 pyramidal cells and interneurons were made in acute brain slices of healthy and epileptic rats (reduced intensity status epilepticus-induced model of spontaneous recurrent seizures [RISE-SRS]). Changes in LPI-mediated effects on frequency and waveform of miniature postsynaptic currents were examined in the presence and absence of CBD (10 µM). Results: We report that GPR55 function is altered in epileptic rat tissue. Importantly, our results indicate that CBD effects on GPR55-mediated signaling are consistent with its anticonvulsant properties. Conclusions: We describe for the first time a pathophysiologic alteration of GPR55 receptor function due to epilepsy, and report phytocannabinoid effects upon dysfunctional GPR55 signaling consistent with reported anticonvulsant effects.

Disclosure: Dr. Bazelot has received personal compensation for activities with GW Pharmaceuticals as an employee. Dr. Whalley has received research support from GW Pharmaceuticals.