Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Eur J Med Chem. 2022 Dec 5;243:114732. doi: 10.1016/j.ejmech.2022.114732. Epub 2022 Sep 2.
The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities. B9 has promising pharmacokinetic profiles, and significantly ameliorates the symptom and reduces demyelination in EAE mice. Moreover, the inflammation microenvironment is remodeled after B9 administration, with promoted M2-type macrophages and inhibited M1 polarization in the CNS and periphery, and suppressed the proinflammatory Th1 and Th17 cells responses. Therefore, the new macrophage M2 polarization modulator B9 could present a candidate for fulfilling the therapeutic strategies of MS.
M2 极化巨噬细胞的调节已被描述为一种有益的方法，可促进多发性硬化症 (MS) 的髓鞘修复和炎症微环境重塑。然而，M2 极化涉及复杂的机制，调节剂仍然有限。作为一种蛋白激酶 B (Akt) 抑制剂，我们之前的研究发现化合物 2 具有促进 M2 极化活性的作用，在此我们报告了一种新的调节剂 B9 的鉴定，它具有高 M2 标志物 Arg1 上调活性、抑制 M1 极化和消除 Akt1 抑制活性。B9 具有有前景的药代动力学特征，可显著改善 EAE 小鼠的症状并减少脱髓鞘。此外，B9 给药后炎症微环境得到重塑，中枢神经系统和外周血中促进 M2 型巨噬细胞和抑制 M1 极化，并抑制促炎 Th1 和 Th17 细胞反应。因此，新型巨噬细胞 M2 极化调节剂 B9 可能成为满足 MS 治疗策略的候选药物。
