The adenosine kinase hypothesis of epileptogenesis

摘要: Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given large percentage pharmacoresistant chronic epilepsies, novel approaches needed to understand modify pathogenetic mechanisms. Although different types brain injury (e.g. status epilepticus, traumatic injury, stroke) can trigger epileptogenesis, astrogliosis appears be a homotypic response hallmark epilepsy. Indeed, recent findings indicate that might astrocyte dysfunction. This review focuses on inhibitory neuromodulator endogenous anticonvulsant adenosine, which is regulated by astrocytes its key metabolic enzyme adenosine kinase (ADK). Recent support “ADK hypothesis epileptogenesis”: (i) Mouse models epileptogenesis suggest sequence events leading from initial downregulation ADK elevation ambient as an acute protective response, changes in astrocytic receptor expression, proliferation hypertrophy (i.e. astrogliosis), consequential overexpression ADK, reduced – finally spontaneous focal seizure activity restricted regions astrogliotic ADK. (ii) Transgenic mice overexpressing display increased sensitivity seizures. (iii) Inhibition prevents seizures mouse model (iv) Intrahippocampal implants stem cells engineered lack prevent Thus, emerges both diagnostic marker predict, well prime therapeutic target prevent,