星形胶质细胞在神经炎症中起着关键作用。激活的星形胶质细胞表现出至少两种表型，A1型（神经毒性）和A型（神经保护）。A1型表型是与衰老和神经退行性疾病相关的主要反应型星形胶质细胞表型。替米沙坦是一种有前景的神经保护剂，它也是一种抗高血压药物。本研究旨在探究替米沙坦对反应型星形胶质细胞表型的影响。将星形胶质细胞培养在由脂多糖刺激的小胶质细胞培养液中，可以激活星形胶质细胞。这种培养液诱导了早期且短暂的A2型星形胶质细胞转变（在24小时内），以及迟发型且持续的A1型转变（持续时间从24小时开始，持续至7天），伴随着促炎性细胞因子（白介素-1β、肿瘤坏死因子α和白介素-6）的产生及核转录因子κB（NF-κB）/p65的磷酸化增加。替米沙坦处理促进A2型转变，抑制A1型转变。替米沙坦降低了p65蛋白总量和磷酸化水平。洛沙坦，一种特异性血管紧张素Ⅱ型1受体（AT1R）拮抗剂，不影响反应型星形胶质细胞的状态。此外，血管紧张素Ⅱ的AT1R激活也不诱导促炎性细胞因子和A1/A2标记物的表达，表明AT1R信号通路不参与星形胶质细胞介导的炎症反应。过氧化物酶体增殖物激活受体γ（PPARγ）拮抗剂逆转了替米沙坦的作用。此外，蛋白酶体抑制剂MG132逆转了替米沙坦诱导的p65下调。这些结果表明，替米沙坦通过p65降解抑制了活化小胶质细胞诱导的神经毒性A1型星形胶质细胞转化。我们的发现有助于阐明替米沙坦在脑疾病中的抗炎作用。版权所有 © 2023 作者。由 Elsevier B.V. 发表，保留所有权利。

Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.