Umut Ocak1,2,3, Pinar Eser Ocak1,4, Lei Huang1,5, Gang Zuo1,6, Jun Yan1,7, Xin Hu1,8, Zhijun Song1,9, John H Zhang1,5,10,11. 1. Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California. 2. Department of Emergency Medicine, Bursa Yuksek Ihtisas Training and Research Hospital, University of Health Sciences, Bursa, Turkey. 3. Department of Emergency Medicine, Bursa City Hospital, Bursa, Turkey. 4. Department of Neurosurgery, Uludag University School of Medicine, Bursa, Turkey. 5. Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, California. 6. Department of Neurosurgery, The Affiliated Taicang Hospital, Soochow University, Taicang Suzhou, Jiangsu, China. 7. Department of Neurosurgery, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China. 8. Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China. 9. Department of Neurosurgery, Xingtai Third Hospital, Xingtai, Hebei, China. 10. Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California. 11. Department of Neurology, Loma Linda University School of Medicine, Loma Linda, California.
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.
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.
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