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Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex
A. Pons-Bennaceur, V. Tsintsadze, TT. Bui, T. Tsintsadze, M. Minlebaev, M. Milh, D. Scavarda, R. Giniatullin, R. Giniatullina, S. Shityakov, M. Wright, AD. Miller, N. Lozovaya, N. Burnashev,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
PubMed
30295710
DOI
10.1093/cercor/bhy257
Knihovny.cz E-resources
- MeSH
- Adenosine physiology MeSH
- Anticonvulsants administration & dosage MeSH
- Dinucleoside Phosphates administration & dosage MeSH
- Potassium Channels physiology MeSH
- Tuberous Sclerosis Complex 1 Protein genetics MeSH
- Humans MeSH
- Membrane Potentials drug effects MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Neocortex drug effects physiopathology MeSH
- Neurons drug effects physiology MeSH
- Receptor, Adenosine A1 physiology MeSH
- Signal Transduction drug effects MeSH
- Seizures physiopathology prevention & control MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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