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RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: Dependent on AMPK pathway.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2018 May 05; Vol. 499 (2), pp. 112-119. Date of Electronic Publication: 2018 Feb 19. - Publication Year :
- 2018
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Abstract
- Traumatic brain injury (TBI) is a leading cause of disability and mortality in young adults worldwide. The pathophysiology is not fully understood. Programmed necrosis (necroptosis) is a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Receptor-interacting protein 3 (RIP3) plays an important role in programmed necrosis. However, the effect of RIP3-related pathway in TBI is little to be known. We attempted to explore the significance of RIP3 in regulating TBI in vivo. Significantly, TBI induced over-expression of RIP3 in the hippocampus of mice, as well as RIP1 and phosphorylated mixed lineage kinase domain-like protein (MLKL). Mice after TBI exhibited cognitive dysfunction and activation of glia cells, which were significantly attenuated by RIP3-knockout (KO). Moreover, inflammation and oxidative stress in hippocampus were markedly induced by TBI in wild type (WT) mice. Of note, the reduction of pro-inflammatory cytokines and oxidants was observed in RIP3-deficient mice, which was linked to the blockage of NLR pyrin domain containing 3 (NLRP3)/apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase-1 and kelch-like ECH-associated protein 1 (Keap 1) pathways. Further, TBI induced hippocampus apoptosis, evidenced by the increase of cleaved Caspase-8/-3 and poly (ADP)-ribose polymerase (PARP) in WT mice, whereas being decreased by RIP3-knockout. In addition, RIP3 knockout led to phosphorylation of AMP-activated protein kinase α (AMPKα) in hippocampus of mice after TBI. And of note, the in vitro findings indicated that RIP3-ablation attenuated oxidative stress, inflammation and apoptosis in astrocytes, which was dependent on AMPKα activation. Together, suppressing RIP3 might be served as a therapeutic target against brain injury through inhibiting inflammation, oxidative stress and apoptosis.<br /> (Copyright © 2018. Published by Elsevier Inc.)
- Subjects :
- Animals
Astrocytes enzymology
Astrocytes pathology
Brain Injuries, Traumatic pathology
Brain Injuries, Traumatic physiopathology
Cognition
Constriction, Pathologic
Gene Deletion
Hippocampus pathology
Mice, Inbred C57BL
Mice, Knockout
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Adenylate Kinase metabolism
Apoptosis
Brain Injuries, Traumatic enzymology
Brain Injuries, Traumatic prevention & control
Inflammation pathology
Oxidative Stress
Receptor-Interacting Protein Serine-Threonine Kinases deficiency
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 499
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 29470982
- Full Text :
- https://doi.org/10.1016/j.bbrc.2018.02.150