Dataset Information

Impaired autophagic flux is associated with the severity of trauma and the role of A_2AR in brain cells after traumatic brain injury.

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 A_2A receptor (A_2AR) knockout (KO) mice subjected to moderate TBI. Thus, A_2AR 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, A_2AR may be a target for alleviating the impairment in autophagic flux after TBI.

SUBMITTER: Zeng XJ

PROVIDER: S-EPMC5833790 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Impaired autophagic flux is associated with the severity of trauma and the role of A<sub>2A</sub>R in brain cells after traumatic brain injury.

Zeng Xu-Jia XJ Li Ping P Ning Ya-Lei YL Zhao Yan Y Peng Yan Y Yang Nan N Zhao Zi-Ai ZA Chen Jiang-Fan JF Zhou Yuan-Guo YG

Cell death & disease 20180214 2

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 ...[more]

PMID: 29449536

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Project description:Beta-amyloid (A?) burden and impaired neuronal autophagy contribute to secondary brain injury after traumatic brain injury (TBI). 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) treatment has been reported to reduce A? aggregation and rescue behavioral deficits in Alzheimer's disease-like mice. Here, we investigated neuroprotective effects of EPPS in a mouse model of TBI. Mice subjected to controlled cortical impact (CCI) were treated with EPPS (120?mg/kg, orally) immediately after CCI and thereafter once daily for 3 or 7?days. We found that EPPS treatment profoundly reduced the accumulation of beta-amyloid precursor protein (?-APP) and A? over a widespread area detected in the pericontusional cortex, external capsule (EC), and hippocampal CA1 and CA3 at 3?days after TBI, accompanied by significant reduction in the TBI-induced diffuse axonal injury identified by increased immunoreactivity of SMI-32 (an indicator for axonal damage). We also found that EPPS treatment ameliorated the TBI-induced synaptic damage (as reflected by enhanced postsynaptic density 95, PSD-95), and impairment of autophagy flux in the neurons as reflected by reduced autophagy markers (LC3-II/LC3-I ratio and p62/SQSTM1) and increased lysosomal enzyme cathepsin D (CTSD) in neurons detected in the cortex and hippocampal CA1. As a result, EPPS treatment significantly reduced the TBI-induced early neuronal apoptosis (assessed by active caspase-3), and eventually prevented cortical tissue loss and hippocampal neuronal loss at 28?days after TBI. Additionally, we found that inhibition of autophagic flux with chloroquine by decreasing autophagosome-lysosome fusion significantly reversed the decreased expressions of neuronal p62/SQSTM1 and apoptosis by EPPS treatment. These data suggest that the neuroprotection by EPPS is, at least in part, related to improved autophagy flux. Finally, we found that EPPS treatment significantly improved the cortex-dependent motor and hippocampal-dependent cognitive deficits associated with TBI. Taken together, these findings support the further investigation of EPPS as a treatment for TBI.

Project description:Heterogeneity of injury severity among children with traumatic brain injury (TBI) classified by the Glasgow Coma Scale (GCS) makes comparisons across research cohorts, enrollment in clinical trials, and clinical predictions of outcomes difficult. The present study uses latent class analysis (LCA) to distinguish severity subgroups from a prospective cohort of 433 children 2.5-15 years of age with TBI who were recruited from two level 1 pediatric trauma centers. Indicator variables available within 48 h post-injury including emergency department (ED) GCS, hospital motor GCS, Abbreviated Injury Score (AIS), Rotterdam Score, hypotension in the ED, and pre-hospital loss of consciousness, intubation, seizures, and sedation were evaluated to define subgroups. To understand whether latent class subgroups were predictive of clinically meaningful outcomes, the Pediatric Injury Functional Outcome Scale (PIFOS) at 6 and 12 months, and the Behavior Rating Inventory of Executive Function at 12 months, were compared across subgroups. Then, outcomes were examined by GCS (primary) and AIS (secondary) classification alone to assess whether LCA provided improved outcome prediction. LCA identified four distinct increasing severity subgroups (1-4). Unlike GCS classification, mean outcome differences on PIFOS at 6 months showed decreasing function across classes. PIFOS differences relative to the lowest latent class (LC1) were: LC2 2.27 (0.83, 3.72), LC3 3.99 (1.88, 6.10), and LC4 11.2 (7.04, 15.4). Differences in 12 month outcomes were seen between the most and least severely injured groups. Differences in outcomes in relation to AIS were restricted to the most and less severely injured at both time points. This study distinguished four latent classes that are clinically meaningful, distinguished a more homogenous severe injury group, and separated children by 6-month functional outcomes better than GCS alone. Systematic reporting of these variables would allow comparisons across research cohorts, potentially improve clinical predictions, and increase sensitivity to treatment effects in clinical trials.

Project description:Self-awareness is commonly impaired after traumatic brain injury. This is an important clinical issue as awareness affects long-term outcome and limits attempts at rehabilitation. It can be investigated by studying how patients respond to their errors and monitor their performance on tasks. As awareness is thought to be an emergent property of network activity, we tested the hypothesis that impaired self-awareness is associated with abnormal brain network function. We investigated a group of subjects with traumatic brain injury (n = 63) split into low and high performance-monitoring groups based on their ability to recognize and correct their own errors. Brain network function was assessed using resting-state and event-related functional magnetic resonance imaging. This allowed us to investigate baseline network function, as well as the evoked response of networks to specific events including errors. The low performance-monitoring group underestimated their disability and showed broad attentional deficits. Neural activity within what has been termed the fronto-parietal control network was abnormal in patients with impaired self-awareness. The dorsal anterior cingulate cortex is a key part of this network that is involved in performance-monitoring. This region showed reduced functional connectivity to the rest of the fronto-parietal control network at 'rest'. In addition, the anterior insulae, which are normally tightly linked to the dorsal anterior cingulate cortex, showed increased activity following errors in the impaired group. Interestingly, the traumatic brain injury patient group with normal performance-monitoring showed abnormally high activation of the right middle frontal gyrus, putamen and caudate in response to errors. The impairment of self-awareness was not explained either by the location of focal brain injury, or the amount of traumatic axonal injury as demonstrated by diffusion tensor imaging. The results suggest that impairments of self-awareness after traumatic brain injury result from breakdown of functional interactions between nodes within the fronto-parietal control network.

Dataset Information

Impaired autophagic flux is associated with the severity of trauma and the role of A_2AR in brain cells after traumatic brain injury.

Publications

Impaired autophagic flux is associated with the severity of trauma and the role of A<sub>2A</sub>R in brain cells after traumatic brain injury.

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Dataset Information

Impaired autophagic flux is associated with the severity of trauma and the role of A2AR in brain cells after traumatic brain injury.

Publications

Impaired autophagic flux is associated with the severity of trauma and the role of A<sub>2A</sub>R in brain cells after traumatic brain injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Impaired autophagic flux is associated with the severity of trauma and the role of A_2AR in brain cells after traumatic brain injury.