Oshio Kotaro, Watanabe Hiroyuki, Song Yaunlin, Verkman A S, Manley Geoffrey T
Department of Neurosurgery, University of California, San Francisco, California 94110, USA.
FASEB J. 2005 Jan;19(1):76-8. doi: 10.1096/fj.04-1711fje. Epub 2004 Nov 8.
Aquaporin-1 (AQP1) is a water channel expressed strongly at the ventricular-facing surface of choroid plexus epithelium. We developed novel methods to compare water permeability in isolated choroid plexus of wild-type vs. AQP1 null mice, as well as intracranial pressure (ICP) and cerebrospinal fluid (CSF) production and absorption. Osmotically induced water transport was rapid in choroid plexus from wild-type mice and reduced by fivefold by AQP1 deletion. AQP1 deletion did not affect choroid plexus size or structure. By stereotaxic puncture of the lateral ventricle with a microneedle, ICP was 9.5 +/- 1.4 cm H2O in wild-type mice and 4.2 +/- 0.4 cm H2O in AQP1 null mice. CSF production, an isosmolar fluid secretion process, was measured by a dye dilution method involving fluid collections using a second microneedle introduced into the cisterna magna. CSF production in wild-type mice was (in microl min(-1)) 0.37 +/- 0.04 (control), 0.16 +/- 0.03 (acetazolamide-treated), and 1.14 +/- 0.15 (forskolin-treated), and reduced by approximately 25% in AQP1 null mice. Pressure-dependent CSF outflow, measured from steady-state ICP at different ventricular infusion rates, was not affected by AQP1 deletion. In a model of focal brain injury, AQP1 null mice had remarkably reduced ICP and improved survival compared with wild-type mice. The reduced ICP and CSF production in AQP1 null mice provides direct functional evidence for the involvement of AQP1 in CSF dynamics, suggesting AQP1 inhibition as a novel option for therapy of elevated ICP.
水通道蛋白-1（AQP1）是一种在脉络丛上皮细胞面向脑室的表面强烈表达的水通道。我们开发了新方法来比较野生型和AQP1基因敲除小鼠分离的脉络丛中的水通透性，以及颅内压（ICP）和脑脊液（CSF）的生成与吸收。在野生型小鼠的脉络丛中，渗透诱导的水转运很快，而AQP1基因敲除使其降低了五倍。AQP1基因敲除不影响脉络丛的大小或结构。通过用微针立体定向穿刺侧脑室，野生型小鼠的ICP为9.5±1.4 cm H₂O，AQP1基因敲除小鼠为4.2±0.4 cm H₂O。CSF生成是一个等渗液体分泌过程，通过染料稀释法测量，该方法涉及使用插入大池的另一根微针收集液体。野生型小鼠的CSF生成量（以微升/分钟计）为0.37±0.04（对照）、0.16±0.03（乙酰唑胺处理）和1.14±0.15（福斯可林处理），在AQP1基因敲除小鼠中减少了约25%。从不同脑室输注速率下的稳态ICP测量的压力依赖性CSF流出不受AQP1基因敲除的影响。在局灶性脑损伤模型中，与野生型小鼠相比，AQP1基因敲除小鼠的ICP显著降低且存活率提高。AQP1基因敲除小鼠中ICP和CSF生成的减少为AQP1参与CSF动力学提供了直接的功能证据，表明抑制AQP1是治疗ICP升高的一种新选择。
