司库奇尤单抗通过 GMH 大鼠模型中的 PKCβ/ERK/NF-κB 通路减轻神经炎症和神经行为缺陷。

Secukinumab attenuates neuroinflammation and neurobehavior defect via PKCβ/ERK/NF-κB pathway in a rat model of GMH.

机构信息

Department of Pediatrics, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, China; Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Department of Pediatrics, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Guangdong, China.

Department of Critical Care Medicine, HuaShan Hospital, Fudan University, Shanghai 200040, China; Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.

出版信息

Exp Neurol. 2023 Feb;360:114276. doi: 10.1016/j.expneurol.2022.114276. Epub 2022 Nov 17.

DOI:10.1016/j.expneurol.2022.114276

PMID:36402169

Abstract

AIMS

Germinal matrix hemorrhage (GMH) is a disastrous clinical event for newborns. Neuroinflammation plays an important role in the development of neurological deficits after GMH. The purpose of this study is to investigate the anti-inflammatory role of secukinumab after GMH and its underlying mechanisms involving PKCβ/ERK/NF-κB signaling pathway.

METHODS

A total of 154 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. Secukinumab was administered intranasally post-GMH. PKCβ activator PMA and p-ERK activator Ceramide C6 were administered intracerebroventricularly at 24 h prior to GMH induction, respectively. Neurobehavioral tests, western blot and immunohistochemistry were used to evaluate the efficacy of Secukinumab in both short-term and long-term studies.

RESULTS

Endogenous IL-17A, IL-17RA, PKCβ and p-ERK were increased after GMH. Secukinumab treatment improved short- and long-term neurological outcomes, reduced the synthesis of MPO and Iba-1 in the perihematoma area, and inhibited the synthesis of proinflammatory factors, such as NF-κB, IL-1β, TNF-α and IL-6. Additionally, PMA and ceramide C6 abolished the beneficial effects of Secukinumab.

CONCLUSION

Secukinumab treatment suppressed neuroinflammation and attenuated neurological deficits after GMH, which was mediated through the downregulation of the PKCβ/ERK/NF-κB pathway. Secukinumab treatment may provide a promising therapeutic strategy for GMH patients.

摘要

目的

脑室内出血（GMH）是新生儿的灾难性临床事件。神经炎症在 GMH 后神经功能缺损的发展中起重要作用。本研究旨在探讨 GMH 后司库奇尤单抗的抗炎作用及其涉及蛋白激酶 Cβ/细胞外信号调节激酶/核因子-κB 信号通路的潜在机制。

方法

共使用 154 只 P7 龄 Sprague-Dawley 大鼠幼仔。GMH 通过脑实质内注射细菌胶原酶诱导。GMH 后经鼻内给予司库奇尤单抗。PKCβ 激活剂 PMA 和 p-ERK 激活剂神经酰胺 C6 分别在 GMH 诱导前 24 小时经侧脑室给药。神经行为学测试、western blot 和免疫组织化学用于评估 Secukinumab 在短期和长期研究中的疗效。

结果

GMH 后内源性 IL-17A、IL-17RA、PKCβ 和 p-ERK 增加。司库奇尤单抗治疗改善了短期和长期神经功能结局，减少了血肿周围区 MPO 和 Iba-1 的合成，并抑制了促炎因子如 NF-κB、IL-1β、TNF-α和 IL-6 的合成。此外，PMA 和神经酰胺 C6 消除了司库奇尤单抗的有益作用。