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
- MeSH
- akupunktura * MeSH
- beta-endorfin fyziologie metabolismus MeSH
- bolest * rehabilitace MeSH
- cholecystokinin fyziologie metabolismus MeSH
- elektroakupunktura MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- nervový systém MeSH
- opioidní peptidy MeSH
- receptor adenosinový A1 fyziologie MeSH
- transkutánní elektrická neurostimulace MeSH
- Check Tag
- lidé MeSH
The aim of the present study was to investigate the relaxatory function of adenosine receptor subtypes in rat urinary bladder, and if it is altered in the state of inflammation. The in vitro responses to the P1 receptor agonist adenosine were investigated in the presence of the general P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 1*10(-4)M). Experiments were performed on preparations from normal (healthy) rats and rats with cyclophosphamide (CYP; 100mg kg(-1) i. p.)-induced cystitis. The specific P1A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 1*10(-5)M) decreased the adenosine relaxatory response in normal bladders (-60%), but not in preparations from CYP pre-treated rats. Immunohistochemical findings support the hypothesis that the expression of P1A(1) receptors in the rat urinary bladder is decreased during cystitis. The adenosine-evoked relaxation was not affected by the specific P1A(2A) antagonist SCH 58261 (3*10(-7)M), neither in normal nor in CYP pre-treated rats. The relaxation to adenosine was, however, significantly increased by the specific P1A(3) antagonist MRS 1523 (1*10(-5)M) in preparations from both normal and CYP pre-treated rats, suggesting P1A(3) to be mediating bladder contraction. Thus, in the rat urinary bladder the relaxation to adenosine is mainly due to the P1A(1) receptor, while the P1A(3) receptor seems to be responsible for contractile responses. The DPCPX-resistant part of the relaxation is possibly due to the P1A(2B) receptor, the fourth subtype of the adenosine receptor family.
- MeSH
- adenosin farmakologie fyziologie MeSH
- agonisté purinergního receptoru P1 farmakologie MeSH
- antagonisté purinergního receptoru P1 farmakologie MeSH
- cystitida metabolismus patofyziologie MeSH
- hladké svalstvo účinky léků metabolismus patofyziologie MeSH
- krysa rodu rattus MeSH
- léková rezistence účinky léků fyziologie MeSH
- mediátory zánětu fyziologie MeSH
- močový měchýř účinky léků metabolismus fyziologie MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- purinergní receptory P2 - antagonisté farmakologie MeSH
- receptor adenosinový A1 fyziologie MeSH
- svalová kontrakce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- agonisté adenosinového receptoru A1 MeSH
- agonisté adenosinového receptoru A2 MeSH
- agonisté adenosinového receptoru A3 MeSH
- finanční podpora výzkumu jako téma MeSH
- fluorouracil analogy a deriváty aplikace a dávkování MeSH
- hematopoéza fyziologie MeSH
- myši MeSH
- receptor adenosinový A1 fyziologie MeSH
- receptor adenosinový A2A fyziologie MeSH
- receptor adenosinový A3 fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH