AdipoRon 通过 SNI 小鼠中的 AdipoR1/AMPK 通路与小神经胶质细胞相互作用以产生抗伤害感受作用。
AdipoRon Engages Microglia to Antinociception through the AdipoR1/AMPK Pathway in SNI Mice.
机构信息
Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282 Guangdong, China.
Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence; Key Laboratory of Mental Health of the Ministry of Education; Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, 510515 Guangdong, China.
出版信息
Mediators Inflamm. 2023 Apr 10;2023:7661791. doi: 10.1155/2023/7661791. eCollection 2023.
BACKGROUND
Microglia-associated neuroinflammation plays a crucial role in the initiation and development of neuropathic pain (NeuP). AdipoRon is an analog of adiponectin that exerts an anti-inflammatory effect in various diseases through the adiponectin receptor 1 (AdipoR1) signaling mechanism. Adenosine monophosphate-activated protein kinase (AMPK) is a downstream target of AdipoR1, and the AdipoR1/AMPK pathway is involved in the regulation of inflammation. This study is aimed at investigating whether AdipoRon could alleviate NeuP by inhibiting the expression of microglia-derived tumor necrosis factor-alpha (TNF-) through the AdipoR1/AMPK pathway.
METHODS
In vivo, the NeuP model was established in mice through the spared nerve injury. The von Frey test was used to detect the effect of AdipoRon on the mechanical paw withdrawal threshold. Western Blot was performed to detect the effects of AdipoRon on the expression of TNF-, AdipoR1, AMPK, and p-AMPK. Immunofluorescence was performed to observe the effects of AdipoRon on spinal microglia. In vitro, lipopolysaccharide (LPS) was used to induce inflammatory responses in BV2 cells. The effect of AdipoRon on cell proliferation was detected by CCK-8. qPCR was used to examine the effects of AdipoRon on the expression of TNF- and polarization markers. And the effect of AdipoRon on the AdipoR1/AMPK pathway was confirmed by Western Blot.
RESULTS
Intraperitoneal injection of AdipoRon alleviated mechanical nociception in SNI mice, and the application of AdipoRon reduced the expression of TNF- and the number of microglia in the ipsilateral spinal cord. Additionally, AdipoRon decreased the protein level of AdipoR1 and increased the protein level of p-AMPK in the ipsilateral spinal cord. In vitro, AdipoRon inhibited BV2 cell proliferation and reversed LPS-induced TNF- expression and polarization imbalance. Furthermore, AdipoRon reversed the LPS-induced increase in AdipoR1 expression and decrease in p-AMPK expression in BV2 cells.
CONCLUSIONS
AdipoRon may alleviate NeuP by reducing microglia-derived TNF- through the AdipoR1/AMPK pathway.
背景
小胶质细胞相关的神经炎症在神经病理性疼痛（NeuP）的发生和发展中起着关键作用。AdipoRon 是脂联素的类似物，通过脂联素受体 1（AdipoR1）信号机制在多种疾病中发挥抗炎作用。腺苷单磷酸激活蛋白激酶（AMPK）是 AdipoR1 的下游靶点，AdipoR1/AMPK 途径参与炎症的调节。本研究旨在探讨 AdipoRon 是否通过抑制小胶质细胞衍生的肿瘤坏死因子-α（TNF-）的表达来缓解 NeuP，其机制与 AdipoR1/AMPK 途径有关。
方法
在体内，通过 spared 神经损伤建立小鼠 NeuP 模型。von Frey 测试用于检测 AdipoRon 对机械性足底退缩阈值的影响。Western Blot 用于检测 AdipoRon 对 TNF-、AdipoR1、AMPK 和 p-AMPK 表达的影响。免疫荧光观察 AdipoRon 对脊髓小胶质细胞的影响。在体外，脂多糖（LPS）诱导 BV2 细胞炎症反应。CCK-8 检测 AdipoRon 对细胞增殖的影响。qPCR 检测 AdipoRon 对 TNF-表达和极化标记物的影响。Western Blot 检测 AdipoRon 对 AdipoR1/AMPK 途径的影响。
结果
腹腔注射 AdipoRon 可缓解 SNI 小鼠的机械性痛觉过敏，应用 AdipoRon 可减少同侧脊髓 TNF-的表达和小胶质细胞的数量。此外，AdipoRon 降低了同侧脊髓 AdipoR1 的蛋白水平，增加了 p-AMPK 的蛋白水平。在体外，AdipoRon 抑制 BV2 细胞增殖，并逆转 LPS 诱导的 TNF-表达和极化失衡。此外，AdipoRon 逆转了 LPS 诱导的 BV2 细胞中 AdipoR1 表达增加和 p-AMPK 表达减少。
结论
AdipoRon 可能通过 AdipoR1/AMPK 途径减少小胶质细胞衍生的 TNF-，从而缓解 NeuP。
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