Merck & Co., Inc., Neuroscience, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA.
J Neurosci Methods. 2012 Mar 30;205(1):36-44. doi: 10.1016/j.jneumeth.2011.12.010. Epub 2011 Dec 29.
Cerebrospinal fluid (CSF) provides a window into central nervous system (CNS) physiology and pathophysiology in human neurodegenerative conditions such as Alzheimer's disease. Changes in CSF bioanalytes also provide a direct readout of target engagement in the CNS following pharmacological interventions in clinical trials. Given the importance of tracking CNS bioanalytes in drug discovery, we have developed a novel cisterna magna cannulated rat model for repeated CSF sampling and used it to assess an amyloid beta (Aβ) lowering agent. The surgically implanted cisterna magna cannula was patent over a period of 1-2 weeks and enabled repeated sampling of CSF (volume of ∼30-50μL/sample) from each rat. CSF Aβ40 levels showed good intra-animal variability across time points and inter-animal variability within a time point. Peripheral treatment with a gamma-secretase inhibitor (GSI) led to a rapid and robust decline in CSF Aβ40 levels that returned to baseline over 24-96h after dosing. Terminal brain, CSF and plasma Aβ levels measured at 24h after dosing demonstrated robust Aβ lowering and showed excellent correlation across these compartments. These results are the first pharmacological validation of the repeated CSF sampling rat model for Aβ lowering agents. This model can have broad applicability in pharmacological evaluation for diverse CNS targets.
脑脊液（CSF）为人类神经退行性疾病（如阿尔茨海默病）的中枢神经系统（CNS）生理学和病理生理学提供了一个窗口。CSF 生物分析物的变化也为临床试验中药物干预后 CNS 中的靶标结合提供了直接的读出。鉴于在药物发现中跟踪 CNS 生物分析物的重要性，我们开发了一种新的枕骨大孔套管大鼠模型，用于重复 CSF 采样，并将其用于评估淀粉样蛋白β（Aβ）降低剂。在手术植入的枕骨大孔套管在 1-2 周的时间内保持通畅，并能够从每只大鼠中重复采集 CSF（每次采样体积约为 30-50μL）。CSF Aβ40 水平在不同时间点表现出良好的个体内变异性，在同一时间点内也表现出个体间变异性。外周给予γ-分泌酶抑制剂（GSI）可迅速而显著降低 CSF Aβ40 水平，在给药后 24-96 小时恢复基线水平。给药后 24 小时测量的终脑、CSF 和血浆 Aβ 水平显示出强大的 Aβ降低作用，并在这些隔室之间表现出极好的相关性。这些结果是针对 Aβ 降低剂的重复 CSF 采样大鼠模型的首次药理学验证。该模型在针对各种 CNS 靶标的药理学评估中具有广泛的适用性。
