We have demonstrated previously that activation of either the ETA or ETB receptor can induce acute electrographic seizures following the intrahippocampal infusion of endothelin-1 (ET-1) in immature (P12) rats. We also demonstrated that activation of the ETA receptor is associated with marked focal ischemia, while activation of the ETB receptor is not. Exploring the mechanisms underlying seizures induced by these two ET-1 receptor interactions can potentially provide insight into how focal ischemia in immature animals produces seizures and whether ischemiarelated seizures differ from seizures not associated with ischemia. To explore these seizure mechanisms we used microdialysis to determine biomarkers associated with seizures in P12 rats following the intrahippocampal infusion of two different agents: (1) ET-1, which activates both the ETA and ETB receptors and causes focal ischemia and (2) Ala-ET-1, which selectively activates only the ETB receptor and does not cause ischemia. Our results show that seizures associated with combined ETA and ETB receptor activation (and ischemia) have a different temporal distribution and microdialysis profile from seizures associated with ETB activation alone (and without ischemia). Seizures with combined activation peak within the first hour after infusion and the microdialysis profile is characterized by a significant increase in the ratio of glutamic acid to GABA. By contrast, seizures with activation of only the ETB receptor peak in the second hour after infusion and microdialysis shows a significant increase in the ratio of leukotriene B4 to prostaglandin E2. These findings suggest that ischemia-related seizures in immature animals involve an imbalance of excitation and inhibition, while non-ischemiarelated seizures involve an inflammatory process resulting from an excess of leukotrienes.

译文

:我们之前已经证明,海马内向未成熟(P12)大鼠中注入内皮素1(ET-1)后,ETA或ETB受体的激活均可诱导急性电图发作。我们还证明了ETA受体的激活与局灶性局部缺血有关,而ETB受体的激活却没有。探索由这两种ET-1受体相互作用诱导的癫痫发作的潜在机制可以潜在地洞察未成熟动物的局灶性缺血如何产生癫痫发作,以及与缺血有关的癫痫发作是否不同于与缺血无关的癫痫发作。为了探索这些癫痫发作的机制,我们使用微透析法确定了海马内注射两种不同药物后与P12大鼠癫痫发作相关的生物标志物:(1)ET-1,其激活ETA和ETB受体并引起局灶性缺血;(2)丙氨酸-ET-1,仅选择性激活ETB受体,不会引起局部缺血。我们的研究结果表明,与ETA和ETB受体联合激活(和局部缺血)相关的癫痫发作与单独与ETB激活相关(而非缺血)相关的癫痫发作具有不同的时间分布和微透析特征。输注后第一个小时内癫痫发作合并激活峰,微透析特征为谷氨酸与GABA的比例显着增加。相比之下,在输注和微透析后的第二小时,仅激活ETB受体峰的癫痫发作显示白三烯B4与前列腺素E2的比率显着增加。这些发现表明,未成熟动物中与缺血有关的癫痫发作涉及兴奋和抑制的不平衡,而与非缺血相关的癫痫发作涉及白三烯过多导致的炎症过程。

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