The effects and mechanisms of action of TC-G 1008, GPR39 agonist, in animal models of seizures and epilepsy

Extracellular/intracellular zinc ions are implicated in processes underlying seizures/epileptogenesis. The G-protein coupled receptor 39 (GPR39) was suggested as a target for extracellular zinc. Activation of GPR39 was proposed as a novel strategy for treating seizures but there was a paucity of data on the relationship between the function of this receptor and epileptogenesis. Furthermore, TC-G 1008, GPR39 agonist, has been increasingly used to study the function of GPR39 but it has not been validated in the GPR39 knockout setting. We found that the concentration of TC-G 1008 attained in the brain tissue following its i.p. administration in mice was sufficient to occupy GPR39. TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold test, but it increased the seizure threshold in the 6-Hz induced seizure threshold test. The compound increased the mean duration of EEG discharges in response to pentylenetetrazole (PTZ) in zebrafish larvae and facilitated the development of epileptogenesis in a chronic, PTZ-induced kindling model of epilepsy in mice. Using GPR39 knockout mouse line, generated by the CRISPR-Cas-9 method, we demonstrated that GPR39 is target for TC-G 1008 regarding PTZ-induced epileptogenesis. However, a concomitant analysis of the downstream effects on cyclic-AMP-response element binding protein in GPR39 knockout mice suggested that TC-G 1008 also acts via other targets. Conclusion and implications: Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy. They also suggest that investigations need to consider whether TC-G 1008 is indeed a selective agonist of the GPR39 receptor.