The effect of A1R agonist on epileptiform activity in organotypic slices

Epilepsy is a common neurological disorder but resistance to pharmacotherapy makes it necessary the development of novel antiepileptic drugs (AEDs). An A1 adenosine receptor (A1R) agonist, MRS5474, possesses anticonvulsant activity in an animal model (Tosh et al.,2012-J.Med.Chem., 55,8075), without the cardiac side effects common to other A1R agonists, leading us to hypothesise that it could operate through a mechanism different from classical A1R agonists. We thus tested this hypothesis in an ex vivo model of epileptogenesis in rhinal cortex -hippocampus organotypic slices (Magalhaes et al., 2018-J.Neuroinflam.15:203). MRS5474 (250nM) was incubated during 1h with slices under depolarizing ([K + ] o =8.5mM) or non-depolarizing ([K + ] o =3mM) conditions. Interestingly, MRS5474 decreased by 6615% (n=4, P<0.05) the number of bursts from slices under high K + but not under normal K + . Event frequency, amplitude and burst duration were not affected. The canonical A1R agonist, N 6 -cyclopentyladenosine (30nM, n=4) prevented burst-like activity (number of bursts decreased to zero, spike amplitude markedly reduced) even under non-depolarizing conditions. Our results showing that MRS5474 prevents spontaneous neuronal firing only under depolarizing conditions, suggest that it may predominantly influence spontaneous synchronous firing of stressed neurons, sparing non-injured ones. This renders this compound with presumably less side effects than other A1R agonists and currently available AEDs.