Abstract
Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/-), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/- mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.
Highlights
About 1% of the world’s population is affected by epileptic episodes during their lifetime, which makes epilepsy the second most frequent neurological disorder (Schmidt and Schachter 2014)
We have recently shown that Spontaneous excitatory postsynaptic currents (sEPSCs) recorded in neocortical excitatory neurons in brain slices from heterozygous Tsc1+/− mice, appear as repetitive, highly synchronized epileptiform bursts initiated in layer 4 spiny stellate cells (SSCs) (Lozovaya et al 2014)
In current clamp whole-cell recordings the spontaneous spiking activity observed in SSCs of Tsc1+/− mice was totally abolished by the administration of AppCH2ppA (Fig. 1C)
Summary
About 1% of the world’s population is affected by epileptic episodes during their lifetime, which makes epilepsy the second most frequent neurological disorder (Schmidt and Schachter 2014). A large body of evidence shows that adenosine is an excellent candidate to block seizures in a variety of epileptic mouse models (Dunwiddie and Masino 2001; Huber et al 2001; Boison 2005; Borea et al 2016) including the temporal lobe epilepsy model (Hargus et al 2012), the hyperthermia induced model (Leon-Navarro et al 2015), and in the human surgical epileptic patient brain tissue (Angelatou et al 1993) This anticonvulsant effect was shown primarily mediated by adenosine A1 receptor (A1R) activation (Gouder et al 2003; Borea et al 2016). The proconvulsant properties of A2A subtype adenosine receptors (A2ARs; as demonstrated in the pentylenetetrazol-induced kindled seizures model), have to be taken into account and have been suggested to limit utilization of adenosine as an antiepileptic drug (El Yacoubi et al 2008, 2009)
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