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

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.

• Authors: Umut Ocak, Pinar Eser Ocak, Lei Huang, Gang Zuo, Jun Yan, Xin Hu, Zhijun Song, John H Zhang
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 54 Issue 4 Pg. 539-547 (10 2020) ISSN: 1540-0514 [Electronic] United States
• PMID: 32028357 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, PAR-2

Topics

• Animals
• Asphyxia (metabolism, physiopathology)
• Blotting, Western
• Heart Arrest (metabolism, physiopathology)
• MAP Kinase Signaling System (physiology)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-2 (genetics, metabolism)