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

Shengpeng Liu; Shuixiang Deng; Yan Ding; Jerry J Flores; Xiaoli Zhang; Xiaojing Jia; Xiao Hu; Jun Peng; Gang Zuo; John H Zhang; Ye Gong; Jiping Tang

doi:10.1016/j.expneurol.2022.114276

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

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

Authors

Shengpeng Liu¹, Shuixiang Deng², Yan Ding³, Jerry J Flores³, Xiaoli Zhang⁴, Xiaojing Jia⁴, Xiao Hu³, Jun Peng³, Gang Zuo³, John H Zhang⁵, Ye Gong⁶, Jiping Tang⁷

Affiliations

¹ 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.
² 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.
³ Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
⁴ 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 Pediatrics, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology, Guangdong, China.
⁵ Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
⁶ Department of Critical Care Medicine, HuaShan Hospital, Fudan University, Shanghai 200040, China; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: gong_ye@fudan.edu.cn.
⁷ Department of Physiology and Pharmacology, Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. Electronic address: jtang@llu.edu.

PMID: 36402169
DOI: 10.1016/j.expneurol.2022.114276

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.

Keywords: GMH; IL-17A; Neurobehavior; Neuroinflammation; Secukinumab.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Cerebral Hemorrhage / metabolism
NF-kappa B*
Neuroinflammatory Diseases*
Rats
Rats, Sprague-Dawley

Substances

NF-kappa B
secukinumab