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.
- MeSH
- adenosin fyziologie MeSH
- antikonvulziva aplikace a dávkování MeSH
- dinukleosidfosfáty aplikace a dávkování MeSH
- draslíkové kanály fyziologie MeSH
- hamartin genetika MeSH
- lidé MeSH
- membránové potenciály účinky léků MeSH
- myši transgenní MeSH
- myši MeSH
- neokortex účinky léků patofyziologie MeSH
- neurony účinky léků fyziologie MeSH
- receptor adenosinový A1 fyziologie MeSH
- signální transdukce účinky léků MeSH
- záchvaty patofyziologie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
