Department of Neurological Surgery, University of Wisconsin, Madison, WI, 53792, USA.
Department of Chemical and Biological Engineering, University of Wisconsin, Madison, WI, 53792, USA.
Neurochem Int. 2019 Jul;127:113-124. doi: 10.1016/j.neuint.2019.01.025. Epub 2019 Jan 30.
Metabolic dysfunction impacts stroke incidence and outcome. However, the intricate association between altered metabolic program due to aging, and focal ischemia in brain, circulation, and peripheral organs is not completely elucidated. Here we identified locally and systemically altered metabolites in brain, liver, and plasma as a result of normal aging, ischemic-stroke, and extended time of reperfusion injury. Comprehensive quantitative metabolic profiling was carried out using nuclear magnetic resonance spectroscopy. Aging, but healthy rats showed significant metabolic alterations in the brain, but only a few metabolic changes in the liver and plasma as compared to younger rats. But, ischemic stroke altered metabolites significantly in liver and plasma of older rats during early acute phase. Major metabolic changes were also seen in the brains of younger rats following ischemic stroke during early acute phase of injury. We further report that metabolic changes occur sequentially in a tissue specific manner during extended reperfusion time of late repair phase. First metabolic alterations occurred in brain due to local injury. Next, changes in circulating metabolites in plasma occurred during acute-repair phase transition time. Lastly, the delayed systemic effect was seen in the peripheral organ, liver that exhibited significant and persistent changes in selected metabolites during later reperfusion time. The metabolic pathways involved in energy/glucose, and amino acid metabolism, inflammation, and oxidative stress were mainly altered as a result of aging and ischemia/reperfusion. Biomarker analysis revealed citrate, lysine, and tyrosine as potential age-independent blood metabolic biomarkers of ischemia/reperfusion. Overall, our study elucidates the complex network of metabolic events as a function of normal aging and acute stroke. We further provide evidence for a clear transition from local to systemic metabolic dysfunction due to ischemic injury in a time dependent manner, which may altogether greatly impact the post-stroke outcome.
代谢功能障碍会影响中风的发病率和预后。然而，由于衰老引起的代谢变化与大脑、循环和外周器官局部缺血之间的复杂关系尚未完全阐明。在这里，我们确定了正常衰老、缺血性中风和延长再灌注损伤后大脑、肝脏和血浆中局部和系统改变的代谢物。使用核磁共振光谱法进行了全面的定量代谢谱分析。与年轻大鼠相比，正常衰老的健康大鼠大脑中出现了显著的代谢变化，但肝脏和血浆中的代谢变化很少。然而，缺血性中风在老年大鼠早期急性阶段导致肝脏和血浆中的代谢物发生显著变化。在损伤的早期急性阶段，年轻大鼠的大脑也发生了主要的代谢变化。我们进一步报告，在晚期修复阶段的延长再灌注时间内，代谢变化以组织特异性的方式依次发生。首先，由于局部损伤，大脑中的代谢发生变化。接下来，在急性修复期过渡时间，循环代谢物在血浆中发生变化。最后，在局部损伤后的晚期，在外周器官肝脏中观察到了延迟的系统效应，在该阶段，在选定的代谢物中发生了显著和持续的变化。参与能量/葡萄糖和氨基酸代谢、炎症和氧化应激的代谢途径主要由于衰老和缺血/再灌注而发生改变。生物标志物分析显示，柠檬酸、赖氨酸和酪氨酸是缺血/再灌注时与年龄无关的潜在血液代谢生物标志物。总的来说，我们的研究阐明了正常衰老和急性中风作为一个功能的代谢事件的复杂网络。我们进一步提供了证据，证明由于缺血损伤，代谢功能障碍从局部向系统性的转变是一个依赖时间的过程，这可能会极大地影响中风后的预后。
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