Akt/Aquaporin-4 Signaling Aggravates Neuropathic Pain by Activating Astrocytes after Spinal Nerve Ligation in Rats
Akt/Aquaporin-4 Signaling Aggravates Neuropathic Pain by Activating Astrocytes after Spinal Nerve Ligation in Rats
复制标题
Akt/Aquaporin-4 信号传导通过激活大鼠脊髓神经结扎后的星形胶质细胞加重神经病理性疼痛
DOI：
10.1016/j.neuroscience.2021.12.015
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发表时间：
2022-02-01
期刊：
影响因子：
3.3
通讯作者：
Liu, Jinbo
中科院分区：
文献类型：
--
作者：
Guo, Shiwu;Song, Zhiwen;Liu, Jinbo
水通道蛋白（AQP）在中枢神经系统（CNS）的水平衡中起着重要的生理作用。水通道蛋白-4（AQP 4）是中枢神经系统中表达的主要水通道蛋白，参与感觉和疼痛传递的过程。Akt信号传导也参与疼痛介导，如神经炎性疼痛和骨癌疼痛。以前，我们发现，AQP 4和p-Akt的表达在大鼠脊髓脊神经结扎（SNL）后改变。在此，我们进一步研究了脊髓背角（SDH）AQP 4和Akt通路在神经病理性疼痛（NP）发病机制中的作用。脊髓AQP 4在SNL后显著上调，主要表达于SDH的星形胶质细胞。用TGN-020抑制AQP 4通过抑制胶质细胞活化和抗神经炎症机制来减弱NP的发展和维持。此外，抑制AQP 4抑制SDH和原代培养物中的星形胶质细胞活化。与AQP 4类似，我们发现SNL后p-Akt也显著升高。用MK 2206抑制Akt抑制体内和体外AQP 4上调和星形胶质细胞活化。此外，用MK 2206阻断Akt可减轻SNL后早期和晚期的NP。这些结果阐明了参与Akt/AQP 4信号通路在NP的发展和维持中的作用的机制。AQP 4可能成为NP治疗的新靶点。(C)2021年，任作者。由Elsevier Ltd代表IBRO出版。
(AQPs) play critical physiological roles in water balance in the central nervous system (CNS). Aquaporin-4 (AQP4), the principal aquaporin expressed in the CNS, has been implicated in the processing of sensory and pain transmission. Akt signaling is also involved in pain mediation, such as neuroinflammatory pain and bone cancer pain. Previously, we found that expression of AQP4 and p-Akt was altered in the rat spinal cord after spinal nerve ligation (SNL). Here, we further investigated the effects of the AQP4 and Akt pathways in the spinal dorsal horn (SDH) on the pathogenesis of neuropathic pain (NP). Spinal AQP4 was significantly upregulated after SNL and was primarily expressed in astrocytes in the SDH. Inhibition of AQP4 with TGN-020 attenuated the development and maintenance of NP by inhibiting glial activation and anti-neuroinflammatory mechanisms. Moreover, inhibition of AQP4 suppressed astrocyte activation both in the SDH and in primary cultures. Similar to AQP4, we found that p-Akt was also significantly elevated after SNL. Inhibition of Akt with MK2206 suppressed AQP4 upregulation and astrocyte activation both in vivo and in vitro. Furthermore, Akt blockade with MK2206 alleviated NP in the early and late phases after SNL. These results elucidate the mechanisms involved in the roles of Akt/AQP4 signaling in the development and maintenance of NP. AQP4 is likely to be a novel therapeutic target for NP management. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of IBRO.