Inhibition of PAR-2 Attenuates Neuroinflammation and Improves Short-Term Neurocognitive Functions Via ERK1/2 Signaling Following Asphyxia-Induced Cardiac Arrest in Rats. Issue 4 (October 2020)

• Record Type: Journal Article
• Authors: Ocak, Umut; Ocak, Pinar Eser; Huang, Lei; Zuo, Gang; Yan, Jun; Hu, Xin; Song, Zhijun; Zhang, John H.
• Is Part Of: Shock. Volume 54:Issue 4(2020)
• Publication Date: 2020-10
• Subjects: Cardiac arrest -- global cerebral ischemia -- neurocognitive -- neuroinflammation -- protease activated receptor 2 -- Abbreviations -- ACA -- Asphyxial CA -- CA -- Cardiac arrest -- FJC -- Fluoro-Jade C -- GCI -- Global cerebral ischemia -- GFAP -- Glial fibrillary acidic protein -- I/R -- Ischemia/reperfusion -- Iba-1 -- Calcium-binding adaptor molecule 1 -- MAPK -- Mitogen-activated protein kinases -- NDS -- Neurological deficit score -- NFkB -- Nuclear factor kappa-B -- PAR-2 -- Protease activated receptor-2 -- PBS -- Phosphate buffered saline -- ROSC -- return of spontaneous circulation; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000001516
• Languages: English
• ISSNs: 1073-2322

Abstract

ABSTRACT: Objective: Global cerebral ischemia-induced neuroinflammation causes neurofunctional impairment following cardiac arrest. Previous studies have demonstrated that the activation of protease-activated receptor-2 (PAR-2) contributes to neuroinflammation. In the present study, we aimed to determine the potential treatment effect of PAR-2 inhibition against neuroinflammation in the setting of asphyxial CA (ACA) in rats. Methods: A total of 116 adult, male Sprague-Dawley rats were randomly divided into Sham (n = 18) and ACA (n = 98) groups. Time course, short-term outcome, and mechanism studies were conducted. All drugs were delivered intranasally. The effect of PAR-2 inhibitor FSLLRY-NH2 on neurocognitive functions was assessed by neurologic deficit score, number of seizures, and T-maze test, while hippocampal neuronal degeneration was evaluated by Fluoro-Jade C staining after ACA. Western blotting was performed for the mechanism study at 24 h following ACA. Selective PAR-2 agonist (AC55541) and ERK1/2 inhibitor (PD98059) were used for intervention. Results: Inhibition of PAR-2 decreased neuroinflammation, reduced the number of degenerating hippocampal neurons and improved neurocognitive functions following ACA. PAR-2 activator alone exerted opposite effects to PAR-2 inhibitor. PAR-2 mediated the augmented brain levels of proinflammatory cytokines by promoting the phosphorylation of ERK1/2. Conclusions: PAR-2 inhibition diminished neuroinflammation and thereby reduced hippocampal neuronal degeneration and neurocognitive impairment following ACA. This effect was at least partly mediated via the PAR-2/ERK1/2 signaling.