Development of a simple, rapid, and robust intrathecal catheterization method in the rat
Development of a simple, rapid, and robust intrathecal catheterization method in the rat
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DOI：
10.1016/j.jneumeth.2017.02.001
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发表时间：
2017-03-15
影响因子：
3
通讯作者：
Wancewicz, Ed
中科院分区：
文献类型：
--
作者：
Mazur, Curt;Fitzsimmons, Bethany;Wancewicz, Ed
背景：血脑屏障（BBB）是开发大而高电荷分子作为中枢神经系统（CNS）疾病和损伤治疗药物的障碍。反义寡核苷酸 (ASO) 较大（6000-8000 MW）且带高电荷，因此不会穿过 BBB。一种绕过血脑屏障来测试 ASO 和其他非 BBB 渗透分子的方法，因为中枢神经系统治疗是将这些分子直接施用到中枢神经系统组织或脑脊液中。新方法：我们开发了一种快速、简单且稳健的方法，用于大鼠鞘内插管，以测试假定的治疗性反义寡核苷酸。该方法使用 23 号针头、简单构造的 1/2 英寸长 19 号引导插管和 8 厘米长的塑料 PE-10 尺寸导管。与现有方法比较：与小脑延髓池入路不同，该方法使用腰椎入路进行鞘内导管插入，导管完全位于马尾间隙，最大限度地减少脊髓压迫。这种鞘内导管插入方法使用现成的材料和一些易于制造的专用设备。结论：这种方法易于学习，并已向多名内部外科医生、合作者和合同实验室教授。使用这种方法通常可以实现 90% 以上的导管插入成功率，并且在 6 小时内可以放置多达 100 根导管并施用测试物质。该方法允许对数百种 ASO 作为 CNS 适应症的治疗药物进行临床前测试。 (C) 2017 Elsevier B.V. 保留所有权利。
Background: The blood brain barrier (BBB) is an impediment to the development of large and highly charged molecules as therapeutics for diseases and injuries of the central nervous system (CNS). Antisense oligonucleotides (ASOs) are large (6000-8000 MW) and highly charged and therefore do not cross the BBB. A method of circumventing the blood brain barrier to test ASOs, and other non-BBB penetrant molecules, as CNS therapeutics is the direct administration of these molecules to the CNS tissue or cerebral spinal fluid.New method: We developed a rapid, simple and robust method for the intrathecal catheterization of rats to test putatively therapeutic antisense oligonucleotides. This method utilizes 23-gauge needles, simply constructed 1/2 in. long 19-gauge guide cannulas and 8 cm long plastic PE-10 sized catheters.Comparison with existing methods: Unlike the cisterna magna approach, this method uses a lumbar approach for intrathecal catheterization with the catheter residing entirely in the cauda equina space minimizing spinal cord compression. Readily available materials and only a few specialized pieces of equipment, which are easily manufactured, are used for this intrathecal catheterization method.Conclusions: This method is easy to learn and has been taught to multiple in house surgeons, collaborators and contract laboratories. Greater than 90% catheterization success is routinely achieved with this method and as many as 100 catheters can be placed and test substance administered in one 6-h period. This method has allowed the pre-clinical testing of hundreds of ASOs as therapeutics for CNS indications. (C) 2017 Elsevier B.V. All rights reserved.