ATP release during seizures - A critical evaluation of the evidence
ATP release during seizures - A critical evaluation of the evidence
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DOI：
10.1016/j.brainresbull.2018.12.021
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发表时间：
2019-09-01
影响因子：
3.8
通讯作者：
Engel, Tobias
中科院分区：
文献类型：
--
作者：
Beamer, Edward;Conte, Giorgia;Engel, Tobias
三磷酸腺苷(ATP)作为一种细胞外信号分子的功能始于20世纪70年代。作为细胞内能量的主要分子储存体，三磷酸腺苷普遍存在于体内，其细胞外半衰期短，难以直接测量。胞外三磷酸腺苷的浓度取决于细胞释放速率和酶降解速率。体外研究的一些发现表明，在海马片中神经元活动和癫痫样事件的高水平期间，细胞外ATP浓度增加。药理学研究表明，拮抗ATP敏感的嘌呤能受体可以抑制癫痫发作的严重程度，阻断癫痫的发生。然而，直接测量大脑中的细胞外ATP浓度存在一些特殊的挑战，特别是ATP的快速水解性和细胞内和细胞外区域之间的巨大梯度。两项使用微透析的研究发现，在实验诱导的癫痫持续状态期间，大鼠海马区细胞外ATP没有变化。其中一项研究表明，只有在外膜ATPase抑制剂存在的情况下，ATP才有可测量的增加，而另一项研究表明，只有在较晚的自发性癫痫发作期间才会增加。目前的证据喜忧参半，似乎高度依赖于所使用的模型和检测方法。更灵敏的、空间分辨率更高的检测方法，引起更少的组织破坏，将是必要的，以提供证据支持或反对癫痫诱导的细胞外ATP升高的假说。在这里，我们描述了癫痫发作期间ATP释放的当前假说及其在癫痫发生中的作用，描述了涉及的技术挑战，并对现有证据进行了批判性检查。
That adenosine 5' triphosphate (ATP) functions as an extracellular signaling molecule has been established since the 1970s. Ubiquitous throughout the body as the principal molecular store of intracellular energy, ATP has a short extracellular half-life and is difficult to measure directly. Extracellular ATP concentrations are dependent both on the rate of cellular release and of enzymatic degradation. Some findings from in vitro studies suggest that extracellular ATP concentrations increase during high levels of neuronal activity and seizure-like events in hippocampal slices. Pharmacological studies suggest that antagonism of ATP-sensitive purinergic receptors can suppress the severity of seizures and block epileptogenesis. Directly measuring extracellular ATP concentrations in the brain, however, has a number of specific challenges, notably, the rapid hydrolysis of ATP and huge gradient between intracellular and extracellular compartments. Two studies using microdialysis found no change in extracellular ATP in the hippocampus of rats during experimentally-induced status epilepticus. One of which demonstrated that ATP increased measurably, only in the presence of ectoATPase inhibitors, with the other study demonstrating increases only during later spontaneous seizures. Current evidence is mixed and seems highly dependent on the model used and method of detection. More sensitive methods of detection with higher spatial resolution, which induce less tissue disruption will be necessary to provide evidence for or against the hypothesis of seizure-induced elevations in extracellular ATP. Here we describe the current hypothesis for ATP release during seizures and its role in epileptogenesis, describe the technical challenges involved and critically examine the current evidence.