Hladky Stephen B, Barrand Margery A
Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.
Handb Exp Pharmacol. 2019;253:385-423. doi: 10.1007/164_2017_37.
Mechanisms for elimination of metabolites from ISF include metabolism, blood-brain barrier transport and non-selective, perivascular efflux, this last being assessed by measuring the clearance of markers like inulin. Clearance describes elimination. Clearance of a metabolite generated within the brain is determined as its elimination rate divided by its concentration in interstitial fluid (ISF). However, the more frequently measured parameter is the rate constant for elimination determined as elimination rate divided by amount present, which thus depends on both the elimination processes and the distribution of the metabolite in the brain. The relative importance of the various elimination mechanisms depends on the particular metabolite. Little is known about the effects of sleep on clearance via metabolism or blood-brain barrier transport, but studies with inulin in mice comparing perivascular effluxes during sleep and wakefulness reveal a 4.2-fold increase in clearance. Amongst the important brain metabolites considered, CO is eliminated so rapidly across the blood-brain barrier that clearance is blood flow limited and elimination quickly balances production. Glutamate is removed from ISF primarily by uptake into astrocytes and conversion to glutamine, but also by transport across the blood-brain barrier. Both lactate and amyloid-β are eliminated by metabolism, blood-brain barrier transport and perivascular efflux and both show decreased production, decreased ISF concentration and increased perivascular clearance during sleep. Taken altogether available data indicate that sleep increases perivascular and non-perivascular clearances for amyloid-β which reduces its concentration and may have long-term consequences for the formation of plaques and cerebral arterial deposits.
从脑间质液（ISF）中清除代谢物的机制包括代谢、血脑屏障转运和非选择性的血管周围流出，最后一种机制通过测量菊粉等标志物的清除率来评估。清除率描述的是清除过程。脑内产生的代谢物的清除率定义为其清除速率除以其在间质液（ISF）中的浓度。然而，更常测量的参数是清除速率常数，定义为清除速率除以存在的量，因此它既取决于清除过程，也取决于代谢物在脑内的分布。各种清除机制的相对重要性取决于特定的代谢物。关于睡眠对通过代谢或血脑屏障转运的清除率的影响知之甚少，但对小鼠进行的使用菊粉比较睡眠和清醒期间血管周围流出情况的研究表明，清除率增加了4.2倍。在考虑的重要脑代谢物中，一氧化碳通过血脑屏障的清除速度非常快，以至于清除率受血流限制，清除迅速与生成达到平衡。谷氨酸主要通过被星形胶质细胞摄取并转化为谷氨酰胺而从ISF中清除，但也可通过血脑屏障转运清除。乳酸和β-淀粉样蛋白都通过代谢、血脑屏障转运和血管周围流出而被清除，并且在睡眠期间两者都表现出产量降低、ISF浓度降低和血管周围清除率增加。综合现有数据表明，睡眠会增加β-淀粉样蛋白的血管周围和非血管周围清除率，这会降低其浓度，可能对斑块和脑动脉沉积物的形成产生长期影响。
