A Novel Hybrid of Telmisartan and Borneol Ameliorates Neuroinflammation and White Matter Injury in Ischemic Stroke Through ATF3/CH25H Axis.
A Novel Hybrid of Telmisartan and Borneol Ameliorates Neuroinflammation and White Matter Injury in Ischemic Stroke Through ATF3/CH25H Axis.
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DOI：
10.1007/s12975-022-01121-5
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发表时间：
2022-12
影响因子：
6.9
通讯作者：
Xin Guan;Jianbing Wu;Jiahui Geng;Duorui Ji;Dasha Wei;Y. Ling;Yihua Zhang;Guojun Jiang
中科院分区：
文献类型：
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作者：
Xin Guan;Jianbing Wu;Jiahui Geng;Duorui Ji;Dasha Wei;Y. Ling;Yihua Zhang;Guojun Jiang
脑缺血性卒中导致大量脑白质损伤，小胶质细胞/星形胶质细胞介导的神经炎症进一步加重了脑白质损伤。鉴于替米沙坦的抗神经炎作用和复苏诱导芳香草药增强血脑屏障(BBB)的通透性，设计、合成了13个替米沙坦(或其简化类似物)与复苏诱导芳香剂的杂交物(3a-m)，并进行了生物学评价。其中，最佳化合物3a(替米沙坦和(+)-冰片的酯杂交物)有效地抑制了小胶质细胞/星形胶质细胞介导的神经炎症，并改善了缺血性中风。特别是，3a通过减少异常去磷酸化的神经丝蛋白，上调髓鞘碱性蛋白，减轻少突胶质细胞损伤，显著保护脑缺血后脑白质的完整性。进一步的RNA测序数据显示，3上调转录调控因子ATF3的表达，以减少CH25H的表达，阻止脂滴聚集的小胶质细胞/星形胶质细胞的促炎状态，以限制过度的炎症，最终保护邻近的少突胶质细胞，以防止白质损伤。3Am具有良好的药代动力学行为和改善的脑分布，可能是治疗缺血性中风和其他神经功能障碍合并脑白质损伤的可行药物。
Cerebral ischemic stroke causes substantial white matter injury, which is further aggravated by neuroinflammation mediated by microglia/astrocytes. Given the anti-neuroinflammatory action of telmisartan and the enhancing blood-brain barrier (BBB) permeability potential of resuscitation-inducing aromatic herbs, 13 hybrids (3a-m) of telmisartan (or its simplified analogues) with resuscitation-inducing aromatic agents were designed, synthesized, and biologically evaluated. Among them, the optimal compound3a(the ester hybrid of telmisartan and (+)-borneol) potently inhibited neuroinflammation mediated by microglia/astrocytes and ameliorated ischemic stroke. Particularly,3asignificantly conferred protection for white matter integrity after cerebral ischemic stroke via decreasing abnormally dephosphorylated neurofilament protein, upregulating myelin basic protein, and attenuating oligodendrocyte damage. Further RNA-sequencing data revealed that3aupregulated expression of transcriptional regulator ATF3 to reduce the expression of CH25H, prevented proinflammatory state of lipid-droplet-accumulating microglia/astrocytes to limit excessive inflammation, and eventually protected neighboring oligodendrocytes to prevent white matter injury. Taken with the desirable pharmacokinetics behavior and improved brain distribution,3amay be a feasible therapeutic agent for ischemic stroke and other neurological disorders with white matter injury.