Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex
| Autor: | Didier Scavarda, Sergey Shityakov, Rashid Giniatullin, Mathieu Milh, Andrew D. Miller, Alexandre Pons-Bennaceur, Marat Minlebaev, Thi-Thien Bui, Mike Wright, Nail Burnashev, Natalia Lozovaya, Timur Tsintsadze, Vera Tsintsadze, Raisa Giniatullina |
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| Rok vydání: | 2017 |
| Předmět: |
Male
Adenosine Potassium Channels Cognitive Neuroscience medicine.medical_treatment Population Mice Transgenic Neocortex 050105 experimental psychology Tuberous Sclerosis Complex 1 Protein Membrane Potentials 03 medical and health sciences Cellular and Molecular Neuroscience Epilepsy Mice 0302 clinical medicine In vivo Seizures medicine Animals Humans 0501 psychology and cognitive sciences education Neurons education.field_of_study Chemistry Receptor Adenosine A1 05 social sciences medicine.disease Potassium channel Cortex (botany) medicine.anatomical_structure Anticonvulsant Anticonvulsants Female TSC1 Neuroscience 030217 neurology & neurosurgery Dinucleoside Phosphates medicine.drug Signal Transduction |
| Zdroj: | Cerebral cortex (New York, N.Y. : 1991). 29(9) |
| ISSN: | 1460-2199 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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