Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats
Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats
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DOI：
10.1177/0271678x20925164
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发表时间：
2020-06-14
影响因子：
6.3
通讯作者：
Raval, Ami P.
中科院分区：
文献类型：
--
作者：
Diaz, Francisca;Raval, Ami P.
吸烟衍生的尼古丁(N)和口服避孕药(OC)协同加剧了女性的缺血性脑损伤，其潜在机制仍不清楚。我们发表的研究表明，由于细胞色素c氧化酶活性的缺陷，OC通过改变线粒体功能而加剧了N的毒性。在这里，我们研究了暴露于N+/-OC的青春期雌性SD大鼠大脑的整体代谢谱。大鼠随机暴露于生理盐水或N+/-OC 16-21天，然后随机分配到两个队列中。其中一组接受大脑中动脉短暂性闭塞，30天后进行组织病理学检查。从第二个队列中，收集了皮质组织，以获得无偏见的全球代谢组学概况。途径浓缩分析显示，与生理盐水相比，N+/-OC暴露组的葡萄糖、葡萄糖6-磷酸和果糖-6-磷酸显著降低，丙酮酸显著增加(p<；0.05)，这表明糖酵解途径发生了变化，这一点得到了糖酵解酶的Western印迹分析的证实。与生理盐水对照组相比，单纯N组或N+OC组的脑梗塞体积显著增加。由于葡萄糖代谢对大脑生理至关重要，糖酵解改变会恶化神经功能，从而加剧缺血性脑损伤。
Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate ischemic brain damage in the females and underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial function owing to a defect in the activity of cytochrome c oxidase. Here, we investigated the global metabolomic profile of brains of adolescent female Sprague-Dawley rats exposed to N +/- OC. Rats were randomly exposed to saline or N + /-OC for 16-21 days followed by random allocation into two cohorts. One cohort underwent transient middle cerebral artery occlusion and histopathology was performed 30 days later. From the second cohort, cortical tissues were collected for an unbiased global metabolomic profile. Pathway enrichment analysis showed significant decrease in glucose, glucose 6-phosphate and fructose-6-phosphate, along with a significant increase in pyruvate in the N + /-OC exposed groups when compared to saline (p < 0.05), suggesting alterations in the glycolytic pathway which were confirmed by Western blot analyses of glycolytic enzymes. Infarct volume quantification showed a significant increase following N alone or N + OC as compared to saline control. Because glucose metabolism is critical for brain physiology, altered glycolysis deteriorates neural function, thus exacerbating ischemic brain damage.