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Impaired autophagic flux is associated with the severity of trauma and the role of A2AR in brain cells after traumatic brain injury
- Source :
- Cell Death and Disease, Vol 9, Iss 2, Pp 1-16 (2018), Cell Death & Disease
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
Abstract
- Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy. Furthermore, the level of the autophagic substrate sequestosome 1 (SQSTM1) was decreased in the ipsilateral cortex. This result, together with the results observed in tandem mRFP-GFP-LC3 adeno-associated virus (AAV)-infected mice, indicates that autophagosome clearance was also increased after mild TBI. Conversely, following moderate and severe TBI, there was no change in the initiation of autophagy, and autophagosome accumulation was observed. Next, we used chloroquine (CQ) to artificially impair autophagic flux in the injured cortex of the mild TBI model and found that the severity of trauma was obviously exacerbated. In addition, autophagic flux and trauma severity were significantly improved in adenosine A2A receptor (A2AR) knockout (KO) mice subjected to moderate TBI. Thus, A2AR may be involved in regulating the impairment of autophagic flux in response to brain injury. Our findings suggest that whether autophagy is increased after TBI is associated with whether autophagic flux is impaired, and the impairment of autophagic flux exacerbates the severity of trauma. Furthermore, A2AR may be a target for alleviating the impairment in autophagic flux after TBI.
- Subjects :
- 0301 basic medicine
Autophagosome
Cancer Research
Adenosine A2A receptor
Autophagy-Related Protein 5
Mice
0302 clinical medicine
Brain Injuries, Traumatic
Sequestosome-1 Protein
Cerebral Cortex
Mice, Knockout
Neurons
education.field_of_study
Trauma Severity Indices
Triazines
lcsh:Cytology
Chloroquine
Adenosine A2 Receptor Antagonists
Neuroprotective Agents
medicine.anatomical_structure
Cerebral cortex
Beclin-1
Female
Microtubule-Associated Proteins
Autophagy-Related Protein 12
Signal Transduction
medicine.medical_specialty
Receptor, Adenosine A2A
Traumatic brain injury
Immunology
ATG5
Article
ATG12
03 medical and health sciences
Cellular and Molecular Neuroscience
Sequestosome 1
Internal medicine
Autophagy
medicine
Animals
Humans
lcsh:QH573-671
education
business.industry
Autophagosomes
Cell Biology
Triazoles
medicine.disease
nervous system diseases
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Endocrinology
Gene Expression Regulation
nervous system
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Volume :
- 9
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease
- Accession number :
- edsair.doi.dedup.....5c705e978ff4e0730a81d455c11a8cbd