Adenosine dysfunction in epilepsy.
Adenosine dysfunction in epilepsy.
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DOI：
10.1002/glia.22285
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发表时间：
2012-08
期刊：
影响因子：
6.2
通讯作者：
Boison, Detlev
中科院分区：
文献类型：
--
作者：
Boison, Detlev
脑的内源性抗惊厥剂和神经保护剂腺苷的细胞外水平在很大程度上取决于基于星形胶质细胞的腺苷循环，包括ATP释放、ATP快速降解为腺苷、以及通过平衡核苷转运蛋白和腺苷激酶（ADK）磷酸化的腺苷的代谢再摄取。因此，ADK表达和活性的变化迅速转化为细胞外腺苷的变化，细胞外腺苷通过激活突触前和突触后腺苷A1受体发挥其有效的抗惊厥和神经保护作用。ADK的增加增加神经元兴奋性，而ADK的减少使大脑对癫痫发作和损伤具有抵抗力。重要的是，ADK被发现过表达，并与星形胶质细胞增生和自发性癫痫发作的啮齿类动物模型，以及从海马硬化和颞叶癫痫患者切除的人类标本。一些证据表明，星形胶质细胞ADK的过度表达和腺苷缺乏是癫痫脑的病理标志。因此，腺苷增强疗法构成了用于癫痫发作预防的有力方法，其在对常规抗癫痫药物具有抗性的癫痫模型中是有效的。癫痫发生的腺苷激酶假说表明，癫痫中腺苷功能障碍经历了一个双相反应：任何类型的损伤都可能触发腺苷的急性激增，这可能通过腺苷受体依赖性和非依赖性机制促进星形胶质细胞增生的发展。星形胶质细胞增生反过来与ADK过度表达相关，ADK过度表达足以触发自发性复发性电描记癫痫发作。因此，ADK成为预测和预防癫痫的一个有前途的靶点。
Extracellular levels of the brain’s endogenous anticonvulsant and neuroprotectant adenosine largely depend on an astrocyte-based adenosine cycle, comprised of ATP release, rapid degradation of ATP into adenosine, and metabolic reuptake of adenosine through equilibrative nucleoside transporters and phosphorylation by adenosine kinase (ADK). Changes in ADK expression and activity therefore rapidly translate into changes of extracellular adenosine, which exerts its potent anticonvulsive and neuroprotective effects by activation of pre- and postsynaptic adenosine A1 receptors. Increases in ADK increase neuronal excitability, whereas decreases in ADK render the brain resistant to seizures and injury. Importantly, ADK was found to be overexpressed and associated with astrogliosis and spontaneous seizures in rodent models of epilepsy, as well as in human specimen resected from patients with hippocampal sclerosis and temporal lobe epilepsy. Several lines of evidence indicate that overexpression of astroglial ADK and adenosine deficiency are pathological hallmarks of the epileptic brain. Consequently, adenosine augmentation therapies constitute a powerful approach for seizure prevention, which is effective in models of epilepsy that are resistant to conventional antiepileptic drugs. The adenosine kinase hypothesis of epileptogenesis suggests that adenosine dysfunction in epilepsy undergoes a biphasic response: An acute surge of adenosine that can be triggered by any type of injury might contribute to the development of astrogliosis via adenosine receptor –dependent and –independent mechanisms. Astrogliosis in turn is associated with overexpression of ADK, which was shown to be sufficient to trigger spontaneous recurrent electrographic seizures. Thus, ADK emerges as a promising target for the prediction and prevention of epilepsy.
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影响因子：
12.4
作者：
Boison, D.;Chen, J-F;Fredholm, B. B.
通讯作者：
Fredholm, B. B.
影响因子：
11.2
作者：
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通讯作者：
SPENCER, DD
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38.1
作者：
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影响因子：
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作者：
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通讯作者：
Abbracchio, MP
DOI：
10.1016/j.bbrc.2009.07.106
发表时间：
2009-10-09
影响因子：
3.1
作者：
Cui, Xianying Amy;Singh, Bhag;Gupta, Radhey S.
通讯作者：
Gupta, Radhey S.