Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building 3.82, 150 Stamford St, London, SE1 9NH, UK.
Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA.
Acta Neuropathol. 2018 Mar;135(3):387-407. doi: 10.1007/s00401-018-1812-4. Epub 2018 Feb 10.
Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K, Ca, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.
脑液受到严格调控，为神经元功能提供稳定的环境，例如低 K、Ca 和蛋白质，以优化信号传递并最大程度减少神经毒性。同时，神经元和星形胶质细胞废物必须迅速清除。脑组织的细胞间质液（ISF）和脑脊髓液（CSF）浸润中枢神经系统对于这种体内平衡至关重要，并且清除大脑废物的“胶质淋巴”或“神经胶质淋巴”系统的概念在过去 5 年中得到了发展。这与 CSF 沿着穿透性动脉的外部的批量（对流）流动、星形胶质细胞介导的脑内液体和溶质的对流运输有关，涉及水通道蛋白-4（AQP4）水通道，最后将液体输送到小静脉，沿小静脉周围空间清除。然而，最近的证据倾向于对“神经胶质淋巴”假说进行重要修正，特别是关于胶质的作用和 ECS 内溶质转移的问题。这篇综述讨论了一些质疑 AQP4 在 ISF 流动中的作用以及缺乏其运输溶质能力的证据的研究；总结了强烈支持小和大分子扩散而无需 ISF 流动的脑细胞外空间（ECS）属性；讨论了关于液压传导率和可能阻碍液体运动的细胞外基质的性质的工作；并重新考虑了血管周围空间（PVS）在 CSF-ISF 交换和引流中的作用。我们还考虑了 CSF-ISF 交换的程度和可能性，神经病理学对液体引流的影响，以及为什么使用 CSF 作为大脑成分或药物输送的代理测量值是有问题的。我们提出，新的工作和关键的历史研究都支持了一个血管周围液体系统的概念，即 CSF 通过 PVS 对流或沿较大口径的动脉/小动脉扩散进入大脑，扩散主要调节与 CNS 微血管相关的神经血管单元的 CSF/ISF 交换，最后，CSF/ISF/废物产物的混合物通常沿小静脉/静脉的 PVS 以及其他途径清除；这样的系统可能构成或不构成真正的“循环”，但至少表明需要重新全面评估先前提出的“神经胶质淋巴”概念，以支持一个更好地考虑基本脑血管生理学和液体运输考虑因素的新系统。
