Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice
| Autor: | Guo-Yuan Yang, Zhenghong Chen, Yijun Cheng, Hanbing Shang, Wanqun Xie, Yu Cai, Bin Chen, Weiguo Zhao |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Brain Infarction
Male 0301 basic medicine Inflammasomes NF-E2-Related Factor 2 Immunology Pharmacology medicine.disease_cause Neuroprotection Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Humans Immunology and Allergy cardiovascular diseases Cells Cultured Cerebral Hemorrhage Mice Inbred ICR GCLM Inflammasome Glutathione Ghrelin Disease Models Animal 030104 developmental biology GCLC chemistry 030220 oncology & carcinogenesis Carboxylic Ester Hydrolases Oxidative stress Signal Transduction medicine.drug |
| Zdroj: | International Immunopharmacology. 79:106180 |
| ISSN: | 1567-5769 |
| Popis: | Ghrelin, a brain-gut peptide, has been proven to exert neuroprotection in different kinds of neurological diseases; however, its role and the potential molecular mechanisms in secondary brain injury (SBI) after intracerebral hemorrhage (ICH) are still unknown. In this study, we investigate whether treatment with ghrelin may attenuate SBI in a murine ICH model, and if so, whether the neuroprotective effects are due to the inhibition of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and promotion of nuclear factor-E2-related factor 2 (Nrf2)/antioxidative response element (ARE) signaling pathway. Stereotactically intrastriatal infusion of autologous blood was performed to mimic ICH. Ghrelin was given intraperitoneally immediately following ICH and again 1 h later. Results showed that ghrelin attenuated neurobehavioral deficits, brain edema, hematoma volume, and perihematomal cell death post-ICH. Ghrelin inhibited the NLRP3 inflammasome activation and subsequently suppressed the neuroinflammatory response as evidenced by reduced microglia activation, neutrophil infiltration, and pro-inflammatory mediators release after ICH. Additionally, ghrelin alleviated ICH-induced oxidative stress according to the chemiluminescence of luminol and lucigenin, malondialdehyde (MDA) content, and total superoxide dismutase (SOD) activity assays. These changes were accompanied by upregulation of Nrf2 expression, Nrf2 nuclear accumulation, and enhanced Nrf2 DNA binding activity, as well as by increased expressions of Nrf2 downstream target antioxidative genes, including NAD(P)H quinine oxidoreductase-1 (NQO1), glutathione cysteine ligase regulatory subunit (GCLC), and glutathione cysteine ligase modulatory subunit (GCLM). Together, our data suggested that ghrelin protected against ICH-induced SBI by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway. |
| Databáze: | OpenAIRE |
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