TGN-020通过激活AQP4/PPAR-γ/mTOR通路,增强星形胶质细胞自噬和减轻炎症,从而改善脊髓损伤后的运动功能障碍。

IF 4.6 2区 医学 Q1 NEUROSCIENCES Experimental Neurology Pub Date : 2024-09-24 DOI:10.1016/j.expneurol.2024.114975
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引用次数: 0

摘要

脊髓损伤(SCI)是一种严重的疾病,通常会导致严重的神经损伤。本研究旨在探索Aquaporin-4(AQP4)在调节SCI后星形胶质细胞自噬和神经炎症中的作用,并评估使用特异性抑制剂TGN-020抑制AQP4的治疗潜力。利用 Western 印迹、CCK8 检测、免疫荧光染色、组织病理学评估和行为分析,我们研究了 TGN-020 对 SCI 诱导的大鼠和星形胶质细胞模型中自噬、神经炎症、星形胶质细胞增殖、神经元损伤和运动功能恢复变化的影响。我们的研究结果表明,TGN-020 能显著提高星形胶质细胞的自噬能力,减少神经炎症,从而通过抑制 AQP4 的表达减轻星形胶质细胞的激活。这些有益作用与过氧化物酶体增殖激活受体-γ/哺乳动物雷帕霉素靶标(PPAR-γ/mTOR)信号通路的激活有关。值得注意的是,引入 PPAR-γ 特异性抑制剂 GW9662 会减弱 TGN-020 对 SCI 诱导的自噬和神经炎症的正向调节作用。总之,我们的体内和体外实验证明,TGN-020 通过下调 AQP4 激活了 PPAR-γ/mTOR 通路,改善了星形胶质细胞的自噬,减轻了神经炎症,并最终促进了运动功能的恢复。
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TGN-020 ameliorates motor dysfunction post-spinal cord injury via enhancing astrocyte autophagy and mitigating inflammation by activating AQP4/PPAR-γ/mTOR pathway
Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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