PDF(Pubmed)
Abstract：
BT75, a boron-containing retinoid, is a novel retinoic acid receptor (RAR)α agonist synthesized by our group. Previous studies indicated that activation of retinoic acid (RA) signaling may attenuate progression of Alzheimer\'s disease (AD). Presently, we aimed to examine the anti-inflammatory effect of BT75 and explore the possible mechanism using cultured cells and an AD mouse model. Pretreatment with BT75 (1-25 µM) suppressed the release of nitric oxide (NO) and IL-1β in the culture medium of mouse microglial SIM-A9 cells activated by LPS. BMS195614, an RARα antagonist, partially blocked the inhibition of NO production by BT75. Moreover, BT75 attenuated phospho-Akt and phospho-NF-κB p65 expression augmented by LPS. In addition, BT75 elevated arginase 1, IL-10, and CD206, and inhibited inducible nitric oxide synthase (iNOS) and IL-6 formation in LPS-treated SIM-A9 cells, suggesting the promotion of M1-M2 microglial phenotypic polarization. C57BL/6 mice were injected intracerebroventricularly (icv) with streptozotocin (STZ) (3 mg/kg) to provide an AD-like mouse model. BT75 (5 mg/kg) or the vehicle was intraperitoneally (ip) injected to icv-STZ mice once a day for 3 weeks. Immunohistochemical analyses indicated that GFAP-positive cells and rod or amoeboid-like Iba1-positive cells, which increased in the hippocampal fimbria of icv-STZ mice, were reduced by BT75 treatment. Western blot results showed that BT75 decreased levels of neuronal nitric oxide synthase (nNOS), GFAP, and phosphorylated Tau, and increased levels of synaptophysin in the hippocampus of icv-STZ mice. BT75 may attenuate neuroinflammation by affecting the Akt/NF-κB pathway and microglial M1-M2 polarization in LPS-stimulated SIM-A9 cells. BT75 also reduced AD-like pathology including glial activation in the icv-STZ mice. Thus, BT75 may be a promising anti-inflammatory and neuroprotective agent worthy of further AD studies.
摘要：
BT75，一种含硼的类维生素A，是我们小组合成的新型视黄酸受体（RAR）α激动剂。先前的研究表明，视黄酸（RA）信号的激活可能会减弱阿尔茨海默病（AD）的进展。目前,我们旨在研究BT75的抗炎作用，并利用培养细胞和AD小鼠模型探讨可能的机制。用BT75（1-25µM）预处理抑制了LPS激活的小鼠小胶质SIM-A9细胞培养基中一氧化氮（NO）和IL-1β的释放。BMS195614，一种RARα拮抗剂，部分阻断BT75对NO产生的抑制作用。此外，BT75减弱了LPS增强的磷酸-Akt和磷酸-NF-κBp65表达。此外,BT75升高精氨酸酶1，IL-10和CD206，并抑制LPS处理的SIM-A9细胞中诱导型一氧化氮合酶（iNOS）和IL-6的形成，提示M1-M2小胶质细胞表型极化的促进。C57BL/6小鼠脑室内(icv)注射链脲佐菌素(STZ)(3mg/kg)以提供AD样小鼠模型。每天一次向icv-STZ小鼠腹膜内(ip)注射BT75(5mg/kg)或载体,持续3周。免疫组织化学分析表明GFAP阳性细胞和杆状或变形虫样Iba1阳性细胞，在icv-STZ小鼠的海马菌毛中增加，通过BT75治疗减少。Westernblot结果显示BT75降低神经元型一氧化氮合酶(nNOS)水平,GFAP,磷酸化Tau,icv-STZ小鼠海马中突触素水平升高。BT75可能通过影响LPS刺激的SIM-A9细胞中Akt/NF-κB通路和小胶质细胞M1-M2极化来减轻神经炎症。BT75还减少了icv-STZ小鼠中的AD样病理,包括神经胶质激活。因此，BT75可能是一种有前途的抗炎和神经保护剂，值得进一步研究AD。
