血脑屏障 (BBB) 处细胞外基质的破坏是多发性硬化症 (MS) 中神经炎症的基础。硫酸乙酰肝素 (HS) 蛋白多糖等细胞外基质成分的降解可以通过使用 HS 模拟物处理来防止，因为它们具有抑制乙酰肝素酶的能力。我们的小树枝状聚合物 HS 模拟物的乙酰肝素酶抑制能力已在多种癌症中进行了研究，但其在神经炎症模型中的功效尚未得到评估。本研究探讨了新型 HS 模拟物 Tet-29 在 MS 动物模型中的应用。实验性自身免疫性脑脊髓炎（一种 MS 小鼠模型）在小鼠中诱导神经炎症。此外，使用轮回试验对血脑屏障和脉络丛进行体外建模，并通过流式细胞术对体内和体外免疫细胞的迁移进行定量。我们发现Tet-29显着减少了中枢神经系统中的淋巴细胞积累，从而反过来，实验性自身免疫性脑脊髓炎的疾病严重程度降低。 Tet-29 的疾病缓解作用与修复 BBB 完整性以及抑制 Transwell 模型中激活的淋巴细胞跨 BBB 和脉络丛的迁移有关。相比之下，Tet-29 不会显着损害稳态条件下的体内或体外稳态运输。这些结果共同表明，Tet-29 调节而不是消除中枢神经系统障碍的运输。© 2023。作者（ s）。

Disruption of the extracellular matrix at the blood-brain barrier (BBB) underpins neuroinflammation in multiple sclerosis (MS). The degradation of extracellular matrix components, such as heparan sulfate (HS) proteoglycans, can be prevented by treatment with HS-mimetics through their ability to inhibit the enzyme heparanase. The heparanase-inhibiting ability of our small dendrimer HS-mimetics has been investigated in various cancers but their efficacy in neuroinflammatory models has not been evaluated. This study investigates the use of a novel HS-mimetic, Tet-29, in an animal model of MS.Neuroinflammation was induced in mice by experimental autoimmune encephalomyelitis, a murine model of MS. In addition, the BBB and choroid plexus were modelled in vitro using transmigration assays, and migration of immune cells in vivo and in vitro was quantified by flow cytometry.We found that Tet-29 significantly reduced lymphocyte accumulation in the central nervous system which, in turn, decreased disease severity in experimental autoimmune encephalomyelitis. The disease-modifying effect of Tet-29 was associated with a rescue of BBB integrity, as well as inhibition of activated lymphocyte migration across the BBB and choroid plexus in transwell models. In contrast, Tet-29 did not significantly impair in vivo or in vitro steady state-trafficking under homeostatic conditions.Together these results suggest that Tet-29 modulates, rather than abolishes, trafficking across central nervous system barriers.© 2023. The Author(s).