期刊
PROGRESS IN NEUROBIOLOGY
卷 84, 期 3, 页码 249-262出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pneurobio.2007.12.002
关键词
adenosine; adenosine kinase; adenosine receptors; hippocampus; astrogliosis; status epilepticus; epileptogenesis; seizures; cell transplantation; transgenic mice
资金
- NINDS NIH HHS [R21 NS057475-01A2, R21 NS057538, R01 NS058780-01A1, R01 NS061844, R21 NS057538-01A2, R01 NS047622-01, R01 NS058780, R21 NS057475, R01 NS047622] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS058780, R01NS061844, R21NS057475, R01NS047622, R21NS057538] Funding Source: NIH RePORTER
Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the ADK hypothesis of epileptogenesis: (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and - finally - to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis. (c) 2007 Elsevier Ltd. All rights reserved.
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