Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination
Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination
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DOI：
10.1002/glia.24363
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发表时间：
2023-03-21
期刊：
影响因子：
6.2
通讯作者：
Barnett，Susan C.
中科院分区：
文献类型：
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作者：
Lindsay，Susan L.;McCanney，George A.;Barnett，Susan C.
迫切需要靶向中枢神经系统（CNS）疾病的多细胞病理学的疗法。修饰的非抗凝肝素模拟硫酸乙酰肝素聚糖家族，是已知的多种细胞过程的调节剂。体外研究表明，低硫酸化修饰肝素模拟物（LS-mHep）可驱动CNS脱髓鞘后的修复。在此，我们测试了LS-mHep 7（一种体外先导化合物）在实验性自身免疫性脑脊髓炎（EAE）和铜腙诱导的脱髓鞘中的作用。在EAE中，LS-mHep 7治疗导致更快的恢复和快速减少的炎症，伴随着动物体重的恢复。LS-mHep 7处理对cuprizone模型中胼胝体内的髓鞘再生或OLIG 2阳性少突胶质细胞数量没有影响。进一步的体外研究证实，LS-mHep 7可能通过隔离炎性细胞因子（如在免疫介导的炎症发作期间上调的CCL 5）来介导其在EAE模型中的促修复作用。这些数据支持这种下一代改性肝素作为主动免疫系统参与的CNS疾病的治疗的未来临床转化。
There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS‐mHeps) drive repair after CNS demyelination. Herein, we test LS‐mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone‐induced demyelination. In EAE, LS‐mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS‐mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS‐mHep7 likely mediates its pro‐repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune‐mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.