Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects
Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects
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DOI：
10.1016/j.neuropharm.2010.04.014
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发表时间：
2010-09-01
影响因子：
4.7
通讯作者：
Franklin, Robin J. M.
中科院分区：
文献类型：
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作者：
Buckley, Clare E.;Marguerie, Anita;Franklin, Robin J. M.
自身免疫性脱髓鞘疾病多发性硬化症（MS）的治疗需要限制和修复损伤的疗法。虽然存在几种免疫调节治疗以限制损伤，但目前没有促进髓鞘再生过程的治疗。因此，需要一种快速筛选潜在的促髓鞘再生化合物的方法。在药物再分析筛选中使用斑马鱼幼虫允许快速体内筛选，并且在过去已成功地用作鉴定现有药物的新适应症的有效方法。利用斑马鱼幼体开发了一种新的筛选潜在的前髓鞘形成化合物的平台。2%的化合物筛选从重新配置库改变少突胶质细胞谱系细胞的招募和/或增殖，作为衡量背迁移的脊髓寡2（+）细胞的数量。选择性筛选确定了三种化合物，改变髓鞘形成的水平，整个幼虫髓鞘碱性蛋白（MBP）的转录水平; src家族激酶抑制剂PP 2，生物胺和噻吨。除了许多以前未识别的化合物外，已鉴定的化合物包括那些以前已知对髓鞘和/或少突胶质细胞谱系有影响的化合物，如PPAR激动剂、类固醇激素和src家族激酶抑制剂。除了提供进一步评估潜在有益化合物的方法外，该筛选还突出了25个靶点，这些靶点能够改变体内少突胶质细胞谱系细胞募集或增殖和/或mbp转录水平，并且值得进一步研究其对髓鞘再生的潜在影响。(C)2010爱思唯尔有限公司版权所有。
Treatment of the autoimmune demyelinating disease multiple sclerosis (MS) requires therapies that both limit and repair damage. While several immunomodulatory treatments exist to limit damage there are currently no treatments that promote the regenerative process of remyelination. A rapid way of screening potential pro-remyelination compounds is therefore required. The use of larval zebrafish in a drug reprofiling screen allows rapid in vivo screening and has been used successfully in the past as an efficient way of identifying new indications for existing drugs. A novel screening platform for potential pro-myelination compounds was developed using zebrafish larvae. Two percent of compounds screened from reprofiling libraries altered oligodendrocyte lineage cell recruitment and/or proliferation, as measured by the numbers of dorsally migrated spinal cord olig2(+) cells. Selective screening identified three compounds that altered levels of myelination, as measured by whole larvae myelin basic protein (mbp) transcript levels; the src family kinase inhibitor PP2, a biogenic amine and a thioxanthene. As well as many previously unrecognised compounds, identified compounds included those with previously known effects on myelin and/or the oligodendrocyte lineage, such as a PPAR agonist, steroid hormones and src family kinase inhibitors. As well as providing methods for further assessment of potentially beneficial compounds, this screen has highlighted 25 targets that are able to alter oligodendrocyte lineage cell recruitment or proliferation and/or mbp transcript levels in vivo and are worthy of further investigation for their potential effects on remyelination. (C) 2010 Elsevier Ltd. All rights reserved.