https://journals.sagepub.com/doi/pdf/10.1177/0963689717714102

Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors

Introduction: Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encourag...

An update on diagnostic and prognostic biomarkers for traumatic brain injury.

Aims Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. Methods After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. Results TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. Conclusion This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13069

Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice.

Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term “effective half-life” (t½) in order to describe the “fall” rate in serum Material and methods: Through searches on EMBASE, Medline and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. Results: Following screening (10,389 papers), n=122 papers were included. The proteins S100B (n=66) and NSE (n=27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t½ of about 24 hours, even if very early sampling in these patients reveals rapid decreases (1-2 hours) though possibly of non-cerebral origin. In contrast, the t½ for NSE is comparably longer, ranging from 48-72 hours in severe TBI cases. The protein GFAP (n=18) appears to have t½ of about 24-48 hours in severe TBI. The protein UCH-L1 (n=9) present a t½ around 7 hours in mild TBI, and about 10 hours in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n=2) only increased in the few studies available, suggesting a serum availability >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. Conclusion: Serial sampling of brain specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.

/pdf/serial-sampling-of-serum-protein-biomarkers-for-monitoring-2w4ak2v448.pdf

Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review.

Autophagy is an evolutionarily ancient mechanism that ensures the lysosomal degradation of old, supernumerary or ectopic cytoplasmic entities. Most eukaryotic cells, including neurons, rely on proficient autophagic responses for the maintenance of homeostasis in response to stress. Accordingly, autophagy mediates neuroprotective effects following some forms of acute brain damage, including methamphetamine intoxication, spinal cord injury and subarachnoid haemorrhage. In some other circumstances, however, the autophagic machinery precipitates a peculiar form of cell death (known as autosis) that contributes to the aetiology of other types of acute brain damage, such as neonatal asphyxia. Here, we dissect the context-specific impact of autophagy on non-infectious acute brain injury, emphasizing the possible therapeutic application of pharmacological activators and inhibitors of this catabolic process for neuroprotection.

Autophagy in acute brain injury

Glial fibrillary acidic protein (GFAP) may serve as a serum marker of traumatic brain injury (TBI) that can be used to monitor biochemical changes in patients and gauge the response to treatment. However, the temporal profile of serum GFAP in the acute period of brain injury and the associated utility for outcome prediction has not been elucidated. We conducted a prospective longitudinal cohort study of consecutive severe TBI patients in a local tertiary neurotrauma center in Shanghai, China, between March 2011 and September 2014. All patients were monitored and managed with a standardized protocol with inclusion of hypothermia and other intensive care treatments. Serum specimens were collected on admission and then daily for the first 5 days. GFAP levels were measured using enzyme-linked immunosorbent assay techniques. Patient outcome was assessed at 6 months post injury with the Glasgow Outcome Scale and further grouped into death versus survival and unfavorable versus favorable. A total of 67 patients were enrolled in the study. The mean time from injury to admission was 2.6 hours, and the median admission Glasgow Coma Scale score was 6. Compared with healthy subjects, patients with severe TBI had increased GFAP levels on admission and over the subsequent 5 days post injury. Serum GFAP levels showed a gradual reduction from admission to day 3, and then rebounded on day 4 when hypothermia was discontinued with slow rewarming. GFAP levels were significantly higher in patients who died or had an unfavorable outcome across all time points than in those who were alive or had a favorable outcome. Results of receiver operating characteristic curve analysis indicated that serum GFAP at each time point could predict neurological outcome at 6 months. The areas under the curve for GFAP on admission were 0.761 for death and 0.823 for unfavorable outcome, which were higher than those for clinical variables such as age, Glasgow Coma Scale score, and pupil reactions. Serum GFAP levels on admission and during the first 5 days of injury were increased in patients with severe TBI and were predictive of neurological outcome at 6 months.

/pdf/glial-fibrillary-acidic-protein-as-a-biomarker-in-severe-43prgs32sb.pdf

Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study

Here, we evaluated changes in autophagy after post-traumatic brain injury (TBI) followed by moderate hypothermia in rats. Adult male Sprague-Dawley rats were randomly divided into four groups: sham injury with normothermia group (37°C); sham injury with hypothermia group (32°C); TBI with normothermia group (TNG; 37°C); and TBI with hypothermia group (THG; 32°C). Injury was induced by a fluid percussion TBI device. Moderate hypothermia (32°C) was achieved by partial immersion in a water bath (0°C) under general anesthesia for 4 h. All rats were killed at 24 h after fluid percussion TBI. The ipsilateral hippocampus in all rats was analyzed with hematoxylin and eosin staining; terminal deoxynucleoitidyl transferase-mediated nick end labeling staining was used to determine cell death in ipsilateral hippocampus. Immunohistochemistry and western blotting of microtubule-associated protein light chain 3 (LC3), Beclin-1, as well as transmission electron microscopy performed to assess changes in autophagy....

Yichao Jin

Papers

Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: a prospective cohort study

Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury

Attenuation of Cell Death in Injured Cortex After Post-Traumatic Brain Injury Moderate Hypothermia: Possible Involvement of Autophagy Pathway

Autophagy Inhibitor 3-MA Weakens Neuroprotective Effects of Posttraumatic Brain Injury Moderate Hypothermia

Role of Microglia Autophagy in Microglia Activation After Traumatic Brain Injury