Drews Henning Johannes, Klein Roman, Lourhmati Ali, Buadze Marine, Schaeffeler Elke, Lang Thomas, Seferyan Torgom, Hanson Leah R, Frey Ii William H, de Vries Tom C G M, Thijssen-van Loosdregt Inge A E W, Gleiter Christoph H, Schwab Matthias, Danielyan Lusine
Department of Clinical Pharmacology, University Hospital of Tuebingen, 72076 Tuebingen, Germany.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
Pharmaceuticals (Basel). 2021 Feb 20;14(2):166. doi: 10.3390/ph14020166.
Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer's disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further investigation, which may lead to new strategies for AD treatment.
血管紧张素受体阻滞剂（ARBs）已在阿尔茨海默病（AD）模型中展现出多种神经保护益处。然而，它们对记忆缺陷、胆碱能活性、神经发生和β淀粉样蛋白（Aβ）清除的有益作用显示出显著的研究间差异。给药途径不仅会影响ARBs的递送，还会影响其靶向性和治疗效果。我们之前关于经鼻给予氯沙坦在AD的APP/PS1模型中的有益作用的研究结果促使我们在此通过采用氯沙坦的全身给药来探索给药途径的影响。与我们之前经鼻给予氯沙坦的结果一致，重复腹腔注射（10 mg/kg）导致Aβ斑块和可溶性Aβ42以及炎性细胞因子（IL-2、IL-6和TNFα）显著减少。Aβ的减少可归因于其被中性内肽酶促进降解以及β-分泌酶1（BACE1）生成减少。氯沙坦在体内和体外均增加了神经发生，并改善了从成年转基因AD小鼠分离的星形胶质细胞的迁移特性。总之，这些数据与我们之前的结果共同表明氯沙坦的治疗特性与给药途径无关。氯沙坦对受Aβ影响的星形胶质细胞的细胞运动性的改善值得进一步研究，这可能会带来AD治疗的新策略。
