Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

• Published in: CNS neuroscience & therapeutics Vol. 25; no. 10; pp. 1151 - 1161
• Main Authors: Liu, Sheng‐Peng, Huang, Lei, Flores, Jerry, Ding, Yan, Li, Peng, Peng, Jun, Zuo, Gang, Zhang, John H., Lu, Jun, Tang, Ji‐Ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2019; John Wiley and Sons Inc
• Subjects: Administration, Intranasal; Animals; Animals, Newborn; Antibodies, Monoclonal, Humanized - administration & dosage; Astrocytes - drug effects; Astrocytes - metabolism; Brain injury; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Collagen; Collagenase; Cortex; CRISPR; Disease Models, Animal; Female; Glial fibrillary acidic protein; Gliosis; Gliosis - drug therapy; Gliosis - metabolism; Hemorrhage; IL‐17A; Immunohistochemistry; Male; Monoclonal antibodies; neurobehavior; Neurological diseases; Original; Pregnancy; Proliferating cell nuclear antigen; Rats; Rats, Sprague-Dawley; reactive astrogliosis; Receptors, Interleukin-17 - metabolism; secukinumab; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; SIRT1 protein; Sirtuin 1 - metabolism; United States > US; neurobehavior; reactive astrogliosis; IL-17A; secukinumab
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13144

Aims Reactive astrogliosis plays a critical role in neurological deficits after germinal matrix hemorrhage (GMH). It has been reported that interleukin‐17A and IL‐17A receptor IL‐17RA/(C/EBPβ)/SIRT1 signaling pathway enhances reactive astrogliosis after brain injuries. We evaluated the effects of secukinumab on reactive astrogliosis in a rat pup model of GMH. Methods A total of 146 Sprague Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of collagenase. Secukinumab was administered intranasally 1 hour post‐GMH. C/EBPβ CRISPR or SIRT1 antagonist EX527 was administrated intracerebroventricularly (icv) 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, histology, and immunohistochemistry were used to assess treatment regiments in the short term and long term. Results The endogenous IL‐17A, IL‐17RA, C/EBPβ, and GFAP and proliferation marker CyclinD1 were increased, while SIRT1 expression was decreased after GMH. Secukinumab treatment improved neurological deficits, reduced ventriculomegaly, and increased cortical thickness. Additionally, treatment increased SIRT1 expression and lowered proliferation proteins PCNA and CyclinD1 as well as GFAP expression. C/EBPβ CRISPR activation plasmid and EX527 reversed the antireactive astrogliosis effects of secukinumab. Conclusion Secukinumab attenuated reactive astrogliosis and reduced neurological deficits after GMH, partly by regulating IL‐17RA/(C/EBPβ)/SIRT1 pathways. Secukinumab may provide a promising therapeutic strategy for GMH patients.