Anti-CD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury.

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people.

Change in Nfkb/Nrf2/Bax Levels by High Monomeric Polyphenols Berries Extract (HMPBE) in Acute and Chronic Secondary Brain Damage.

BACKGROUND/AIMS: High Monomeric Polyphenols Berries Extract (HMPBE) is a formula highly rich in polyphenols clinically proven to enhance learning and memory. It is currently used to enhances cognitive performance including accuracy, working memory and concentration. METHODS: Here, we investigated for the first time the beneficial effects of HMPBE in a mouse model of acute and chronic traumatic brain injury (TBI). RESULTS: HMPBE, at the dose of 15 mg/kg was able to reduce histological alteration as well as inflammation and lipid peroxidation. HMPBE ameliorate TBI by improving Nrf-2 pathway, reducing Nf-kb nuclear translocation and apoptosis, and ameliorating behavioral alteration such as anxiety and depression. Moreover, in the chronic model of TBI, HMPBE administration restored the decline of Tyrosine Hydroxylase (TH) and dopamine transporter (DAT) and the accumulation of a-synuclein into the midbrain region. This finding correlates the beneficial effect of HMPBE administration with the onset of parkinsonism related to traumatic brain damage. CONCLUSION: The data may open a window for developing new support strategies to limit the neuroinflammation event of acute and chronic TBI.

Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway.

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.

Daidzein ameliorates experimental traumatic brain injury-induced neurological symptoms by suppressing oxidative stress and apoptosis.

Traumatic brain injury (TBI) causes deficits in neurological function, induces pathological changes, and increases oxidative stress. The current investigation aimed to determine Daidzein's neuroprotective potential in experimental TBI. Initially, the HT-22 cell line exposed to H2O2 underwent in vitro examination, and the results showed that Daidzein had a neuroprotective effect evident from enhanced cell viability and decreased NO generation. Using three different Daidzein doses-1 mg/kg, 5 mg/kg, and 10 mg/kg-in the in vivo experiment, the potential of Daidzein was evaluated against TBI. The neurological severity score (NSS), kondziela's screen test, and elevated plus maze showed improvements after treatment with Daidzein manifested by decreased score, enhanced motor coordination, and anti-anxiety effects. Additionally, Daidzein improved mechanical allodynia and restored the breakdown of the blood-brain barrier. The FTIR spectral analysis showed restoration of the biochemical compositional changes. Furthermore, H & E and Toluidine blue staining revealed an improvement in the histopathological alterations. The RT-qPCR revealed an increase in mRNA expression level of Nrf2, HO-1, and Bcl-2 and the downregulation of Keap-1, Bax and Cleaved caspase-3 expressions. Thus, exhibiting its antioxidant and antiapoptotic potential. The RT-qPCR also manifested a decrease in mRNA expression of GFAP and Iba-1. Further immunohistochemistry results indicated Daidzein's antioxidant and antiapoptotic properties by upregulating Nrf2 and downregulating cleaved caspase-3. Daidzein also lowered the apoptosis index and improved neuronal survival evidenced by flow cytometric analysis. In addition to this, Daidzein notably increased the antioxidant enzyme levels and decreased the oxidative stress markers. The current study's findings point to the neuroprotective potential of the phytoestrogen Daidzein as it lessened neurological abnormalities, decreased oxidative stress, and lowered proapoptotic protein expression.

Deferoxamine alleviates ferroptosis in seawater immersion combined with traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with its severity potentially exacerbated by seawater immersion. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been implicated in TBI pathogenesis. However, the specific occurrence and underlying mechanisms of ferroptosis in the context of TBI compounded by seawater immersion remain unclear. Subsequently, we investigated the effects of seawater immersion on ferroptosis after the application of deferoxamine (DFO), an iron chelator and ferroptosis inhibitor, to explore its potential therapeutic value. We conducted RNA sequencing, protein expression analysis, oxidative stress assessment, histopathological examination, and behavioral testing to comprehensively evaluate the impact of DFO on ferroptosis and neurological outcomes. Our results demonstrated that seawater immersion significantly exacerbated ferroptosis in TBI. DFO treatment, however, attenuated ferroptosis, alleviated oxidative stress, reduced brain tissue damage, improved neuronal survival, and promoted motor function recovery. Despite these benefits, DFO exhibited limited effects on anxiety, novel object recognition, and spatial learning and memory. These findings suggest that ferroptosis represents a novel pathological mechanism in TBI under seawater immersion, and that DFO is a promising neuroprotective agent capable of modulating ferroptosis and enhancing neurological function. This study offers new insights into the complex injury conditions associated with TBI and seawater immersion, highlighting the potential of targeting ferroptosis for therapeutic intervention.

Loss of microglial Arid1a exacerbates microglial scar formation via elevated CCL5 after traumatic brain injury.

Traumatic brain injury (TBI) is an acquired insult to the brain caused by an external mechanical force, potentially resulting in temporary or permanent impairment. Microglia, the resident immune cells of the central nervous system, are activated in response to TBI, participating in tissue repair process. However, the underlying epigenetic mechanisms in microglia during TBI remain poorly understood. ARID1A (AT-Rich Interaction Domain 1 A), a pivotal subunit of the multi-protein SWI/SNF chromatin remodeling complex, has received little attention in microglia, especially in the context of brain injury. In this study, we generated a Arid1a cKO mouse line to investigate the potential roles of ARID1A in microglia in response to TBI. We found that glial scar formation was exacerbated due to increased microglial migration and a heightened inflammatory response in Arid1a cKO mice following TBI. Mechanistically, loss of ARID1A led to an up-regulation of the chemokine CCL5 in microglia upon the injury, while the CCL5-neutralizing antibody reduced migration and inflammatory response of LPS-stimulated Arid1a cKO microglia. Importantly, administration of auraptene (AUR), an inhibitor of CCL5, repressed the microglial migration and inflammatory response, as well as the glial scar formation after TBI. These findings suggest that ARID1A is critical for microglial response to injury and that AUR has a therapeutic potential for the treatment of TBI.

The Emerging Landscape of the Cerebellum after a Pediatric Traumatic Brain Injury: From Diaschisis to Sociality.

There is an expanding interest in the cerebellum in the context of focal and diffuse traumatic injuries to the cerebral cortex. In the adult brain, preclinical studies have revealed acute as well as progressive loss of Purkinje cells in the cerebellum coincident with microglial activation. This pathogenesis, remote to the site of the primary injury, is termed "diaschisis." Here we consider traumatic injuries to the developing brain, where the cerebellum likewise undergoes neurodegeneration. As injury is superimposed on a young brain, long-term adverse consequences may reflect diaschisis that is compounded by disruption of brain development.

Age at Injury as a Modifier of Preclinical TBI Behavioral, Neuropathological, and Inflammatory Outcomes.

Traumatic brain injury (TBI) is a leading cause of injury-related death and disability. In high-income countries, TBI is most prevalent among the older population (≥65 years), commonly caused by falls. Though age at injury is associated with increased risk of mortality and poor outcome, the underlying mechanisms are unclear. Studies in animal models may yield insights into the intersection of TBI with age. Here we review recent studies in animal models where TBI induced in aged animals is associated with exacerbated behavioral deficits (e.g., mortality, thigmotaxis, and cognitive deficits), neuropathology (microgliosis and astrogliosis), neuroinflammation (e.g., cytokines and iNOS), microglial alterations (e.g., more cellular vesicles and adopting a damage-associated microglia gene signature), and cell signaling and pathway changes (e.g., complement, phagocytosis, autophagy, trophic factor signaling). As relatively few preclinical studies focus on aged animals, more research is needed to fully understand the pathophysiology of TBI in the aged population. Particularly, we recommend that (1) more aged animals should be used, (2) closed-head TBI models should be considered, and (3) animal models of comorbidity or polytrauma should be considered.

The Immune Response in Two Models of Traumatic Injury of the Immature Brain.

Traumatic brain injury (TBI) can cause major disability and increases the risk of neurodegeneration. Post-TBI, there is infiltration of peripheral myeloid and lymphoid cells; there is limited information on the peripheral immune response post-TBI in the immature brain-where injury may interfere with neurodevelopment. We carried out two injury types in juvenile mice: invasive TBI with a controlled cortical impact (CCI) and repetitive mild TBI (rmTBI) using weight drop injury and analysed the response at 5- and 35-days post-injury. In the two models, we detected the brain infiltration of immune cells (e.g., neutrophils, monocytes, dendritic cells, CD4+ T cells, and NK cells). There were increases in macrophages, neutrophils, and dendritic cells in the spleen, increases in dendritic cells in blood, and increases in CD8+ T cells and B cells in lymph nodes. These results indicate a complex peripheral immune response post-TBI in the immature brain, with differences between an invasive injury and a repetitive mild injury.

The Relationship between History of Traumatic Brain Injury and Longitudinal Changes in Cortical Thickness among Patients with Alzheimer's Disease.

BACKGROUND: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer's disease (AD). METHODS: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness. RESULTS: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI. CONCLUSION: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions.

Comparison of Cerebral Saturation and Brain Net Water Uptake After Moderate Traumatic Brain Injury.

The aim was to study the relationship between net water uptake (NWU) and cerebral oxygenation in patients with posttraumatic ischaemia (PTI) foci after moderate traumatic brain injury (moTBI). MATERIALS AND METHODS: Perfusion computed tomography (PCT) was performed for 72 patients with PTI foci after moTBI in 2013-2022. The mean age of the patients was 32.7 ± 12.5 years (from 18 to 65 years), 25 women and 47 men. Cerebral tissue oxygen saturation (SctO2) was evaluated using Fore-Sight 2030 (CAS Medical Systems Inc., USA) in the region of the frontal lobe pole (FLP). NWU was calculated from non-contrast CT. Data are shown as a median [interquartile range]. P < 0.05 was considered statistically significant. RESULTS: SctO2 in FLP varied within the range from 61% to 88%. It was 62% [55.4;72.1] over the lesion frontal lobe with PTI and 64% [58.5;73.7] over the opposite FLP side. The average NWU in the FLP cortex on the PTI side was 4.98% [2.21;7.39]. In the case when there were no focal injuries in the frontal lobes, SctO2 was significantly correlated with higher NWU (R = -0.780, p < 0.00001). CONCLUSIONS: The cerebral oxygen tissue saturation correlates with net water uptake in patients with PTI after moTBI (p < 0.005).

Monoacylglycerol Lipase Inhibition Using ABX-1431 Attenuates Cerebral Ischaemia Early After Traumatic Brain Injury.

An early event in the pathology of traumatic brain injury (TBI) is a reduction in cerebral blood flow (CBF), which exacerbates secondary injury development and inhibits brain recovery. The endogenous cannabinoid system signalling (eCBs) might be critical in TBI recovery due to modulating synaptic activity and exerting neuroprotective and anti-inflammatory effects. In the brain, eCBs predominantly occur at cannabinoid receptor type 1 via the eCB 2-arachidonoylglycerol (2-AG). The aim of this work was to test the efficacy of potentiating 2-AG signalling by monoacylglycerol lipase (MAGL) inhibition using ABX-1431 immediately following TBI. Laser speckle contrast imaging (LSCI) was used to create a high-resolution map of regional cerebral blood flow (CBF) over the pericontusion cortical surface. In-vivo two-photon laser scanning microscopy (2PLSM) was used to monitor cerebral microcirculation (i.v. fluorescein isothiocyanate dextran, FITC) and mitochondrial respiration and brain tissue oxygen supply (nicotinamide adenine dinucleotide autofluorescence, NADH) during 4 hours after CHI. After baseline imaging, male C57BL/6 J mice (10-12 weeks, >28 g) were subjected to a modified moderate Shohami weight-drop closed-head injury (CHI) followed by i.p. injection of ABX-1431 (5 mg/kg) or vehicle 30 min after the insult (10 mice per group). Differences between groups and between time points were determined using two-way repeated measures (ANOVA) for multiple comparisons and post hoc testing with the statistical significance level set at p < 0.05. Optical imaging revealed that CHI caused a decrease in regional CBF, arteriole diameters (vasospasm), and blood flow volume, leading to capillary microthrombosis and a reduction in capillary flow velocity. Compromised cerebral microcirculation led to the development of tissue hypoxia. ABX-1431 application, in a ~30-minute delay, mitigated the development of microvascular dysfunction, microthrombosis formation, and tissue hypoxia compared to the saline control group (p < 0.05, starting 1 hour after CHI). Therefore, MAGL inhibition by ABX-1431 attenuates cerebral ischaemia early after TBI. The observed 2-AG-mediated cerebrovascular relaxation might involve both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium.

Selective neuronal expression of progranulin is sufficient to provide neuroprotective and anti-inflammatory effects after traumatic brain injury.

Progranulin (PGRN), which is produced in neurons and microglia, is a neurotrophic and anti-inflammatory glycoprotein. Human loss-of-function mutations cause frontotemporal dementia, and PGRN knockout (KO) mice are a model for dementia. In addition, PGRN KO mice exhibit severe phenotypes in models of traumatic or ischemic central nervous system (CNS) disorders, including traumatic brain injury (TBI). It is unknown whether restoration of progranulin expression in neurons (and not in microglia) might be sufficient to prevent excessive TBI-evoked brain damage. To address this question, we generated mice with Nestin-Cre-driven murine PGRN expression in a PGRN KO line (PGRN-KONestinGrn) to rescue PGRN in neurons. PGRN expression analysis in primary CNS cell cultures from naïve mice and in (non-) injured brain tissue from PGRN-KONestinGrn revealed expression of PGRN in neurons but not in microglia. After experimental TBI, examination of the structural brain damage at 5 days post-injury (dpi) showed that the TBI-induced loss of brain tissue and hippocampal neurons was exacerbated in PGRN-KOGrnflfl mice (PGRN knockout with the mGrn fl-STOP-fl allele, Cre-negative), as expected, whereas the tissue damage in PGRN-KONestinGrn mice was similar to that in PGRN-WT mice. Analysis of CD68+ immunofluorescent microglia and Cd68 mRNA expression showed that excessive microglial activation was rescued in PGRN-KONestinGrn mice, and the correlation of brain injury with Cd68 expression suggested that Cd68 was a surrogate marker for excessive brain injury caused by PGRN deficiency. The results show that restoring neuronal PGRN expression was sufficient to rescue the exacerbated neuropathology of TBI caused by PGRN deficiency, even in the absence of microglial PGRN. Hence, endogenous microglial PGRN expression was not essential for the neuroprotective or anti-inflammatory effects of PGRN after TBI in this study.

Evaluation of Blood-Brain Barrier Disruption Using Low- and High-Molecular-Weight Complexes in a Single Brain Sample in a Rat Traumatic Brain Injury Model: Comparison to an Established Magnetic Resonance Imaging Technique.

Traumatic brain injury (TBI), a major cause of death and disability among young people, leads to significant public health and economic challenges. Despite its frequency, treatment options remain largely unsuitable. However, examination of the blood-brain barrier (BBB) can assist with understanding the mechanisms and dynamics of brain dysfunction, which affects TBI sufferers secondarily to the injury. Here, we present a rat model of TBI focused on two standard BBB assessment markers, high- and low-molecular-weight complexes, in order to understand BBB disruption. In addition, we tested a new technique to evaluate BBB disruption on a single brain set, comparing the new technique with neuroimaging. A total of 100 Sprague-Dawley rats were separated into the following five groups: naive rats (n = 20 rats), control rats with administration (n = 20 rats), and TBI rats (n = 60 rats). Rats were assessed at different time points after the injury to measure BBB disruption using low- and high-molecular-weight complexes. Neurological severity score was evaluated at baseline and at 24 h following TBI. During the neurological exam after TBI, the rats were scanned with magnetic resonance imaging and euthanized for assessment of the BBB permeability. We found that the two markers displayed different examples of BBB disruption in the same set of brain tissues over the period of a week. Our innovative protocol for assessing BBB permeability using high- and low-molecular-weight complexes markers in a single brain set showed appropriate results. Additionally, we determined the lower limit of sensitivity, therefore demonstrating the accuracy of this method.

Knockout of neutrophil cytosolic factor 1 ameliorates neuroinflammation and motor deficit after traumatic brain injury.

Traumatic brain injury (TBI) is a predominant cause of long-term disability in adults, yet the molecular mechanisms underpinning the neuropathological processes associated with it remain inadequately understood. Neutrophil cytosolic factor 1 (NCF1, also known as p47phox) is one of the cytosolic components of NADPH oxidase NOX2. In this study, we observed a reduction in the volume of TBI-induced brain lesions in NCF1-knockout mice compared to controls. Correspondingly, the neuronal loss induced by TBI was mitigated in the NCF1-knockout mice. Behavioral analysis also demonstrated that the motor coordination deficit following TBI was mitigated by the depletion of NCF1. Mechanistically, our findings revealed that NCF1 deficiency attenuated TBI-induced inflammatory responses by inhibiting the release of proinflammatory factors and reducing neutrophil infiltration into the brain parenchyma. Additionally, our results indicated that NCF1 deficiency significantly decreased the levels of reactive oxygen species in neutrophils. Taken together, our findings indicate that NCF1 plays a crucial role in the regulation of brain injury and secondary inflammation post-TBI.

Microglia-mediated neuroinflammation in traumatic brain injury: a review.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, characterized by a complex interplay of primary and secondary injury mechanisms. Microglia, the resident immune cells of the central nervous system, play a crucial role in the inflammatory response following TBI. To review the current understanding of microglia-mediated neuroinflammation in TBI, exploring its dual nature as a protective and detrimental process. A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Google Scholar. Relevant studies investigating the role of microglia in TBI were included. In the early stages of TBI, microglia exhibit a protective response, releasing cytokines and chemokines to promote neuronal survival and tissue repair. However, prolonged or excessive microglial activation can lead to neurotoxicity and exacerbate secondary injury. Microglia-mediated neuroinflammation involves complex signaling pathways, including Toll-like receptors, purinergic receptors, and the complement system. Microglia-mediated neuroinflammation in TBI is a double-edged sword. While acute microglial activation can promote repair, chronic or excessive inflammation contributes to neuronal damage and functional deficits. Understanding the temporal and molecular dynamics of microglial responses is crucial for developing therapeutic strategies to modulate neuroinflammation and improve outcomes after TBI.

Targeting cis-p-tau and neuro-related gene expression in traumatic brain injury: therapeutic insights from TC-DAPK6 treatment in mice.

BACKGROUND: Traumatic brain injury (TBI) is a significant global health concern and is characterized by brain dysfunction resulting from external physical forces, leading to brain pathology and neuropsychiatric disorders such as anxiety. This study investigates the effects of TC-DAPK6 on tau hyper-phosphorylation, gene expression, anxiety, and behavior impairment in the TBI mice model. METHODS AND RESULTS: A weight drop model induced the TBI and the anxiety levels were evaluated using an elevated plus maze (EPM) test. TC-DAPK6 was intraperitoneally administered one-month post-TBI and continued for two months. The total cis-p-tau ratio in the brain was assessed using western blot and immunofluorescence staining. Molecular analysis was conducted on Aff2, Zkscan16, Kcna1, Pcdhac2, and Pcdhga8 to investigate the function and pathogenic role of TC-DAPK6 in neurological diseases in the cerebral cortex tissues of TBI-model mice, and the results were compared with TC-DAPK6 TBI-treatment group. The anxiety level and phosphorylation of tau protein in the TBI group were significantly increased compared to the sham groups and decreased substantially in the TBI-treatment group after TC-DAPK6 administration; the TBI group mostly spent their time with open arms. TC-DAPK6 decreased the expression level of genes as much as the sham group. Meanwhile, KCNA1 showed the highest fold of changes in the TBI and TBI-treatment groups. CONCLUSIONS: The study demonstrates a clear association between cis-p-tau and neuro-related gene expression levels in TBI-induced mice. Targeting these pathways with DAPK1 inhibitors, shows promise for therapeutic interventions in TBI and related neurodegenerative disorders.

Effective treatment of traumatic brain injury by injection of a selenium-containing ointment.

Traumatic brain injury (TBI) is an incurable and overwhelming disease accompanied with serve disability and huge financial burden, where the overproduced reactive oxygen species (ROS) can exacerbate the secondary injury, leading to massive apoptosis of neurons. In this study, ß-cyclodextrin (CD)-capped hyperbranched polymers containing selenium element (HSE-CD) were crosslinked with CD-modified hyaluronic acid (HA-CD) and amantadine-modified hyaluronic acid (HA-AD) to obtain a ROS-responsive ointment (R-O). The structures of synthesized polymers were characterized with 1H nuclear magnetic resonance, and the properties of ointment were investigated with rheology and antioxidation. Compared to non-ROS-responsive ointment (N-O), the R-O ointment had stronger efficiency in decreasing the ROS level in BV2 cells in vitro. In a controlled rat cortical impact (CCI) model, the R-O ointment could relieve the DNA damage and decrease apoptosis in injured area via reducing the ROS level. Besides, after the R-O treatment, the rats showed significantly less activated astrocytes and microglia, a lower level of pro-inflammatory cytokines and a higher ratio of M2/M1 macrophage and microglia. Moreover, compared to the TBI group the R-O ointment promoted the doublecortin (DCX) expression and tissue structure integrity around the cavity, and promoted the recovery of nerve function post TBI. STATEMENT OF SIGNIFICANCE: Traumatic brain injury (TBI) is an incurable and overwhelming disease, leading to severe disability and huge social burden, where reactive oxygen species (ROS) are considered as one of the most significant factors in the secondary injury of TBI. A ROS responsive supramolecular ointment containing di-selenide bonds was injected in rats with controlled cortical impact. It relieved the DNA damage and decreased apoptosis in the injured area via reducing the ROS levels, downregulated neuroinflammation, and improved neurological recovery of TBI in vivo. This designed self-adaptive biomaterial effectively regulated the pathological microenvironment in injured tissue, and achieved better therapeutic effect.

Implications of Iron in Ferroptosis, Necroptosis, and Pyroptosis as Potential Players in TBI Morbidity and Mortality.

Iron is a critical transition metal required to sustain a healthy central nervous system. Iron is involved in metabolic reactions, enzymatic activity, myelinogenesis, and oxygen transport. However, in several pathological conditions such as cancer, neurodegeneration, and neurotrauma iron becomes elevated. Excessive iron can have deleterious effects leading to reactive oxygen species (ROS) via the Fenton reaction. Iron-derived ROS are known to drive several mechanisms such as cell death pathways including ferroptosis, necroptosis, and pyroptosis. Excessive iron present in the post-traumatic brain could trigger these harmful pathways potentiating the high rates of morbidity and mortality. In the present review, we will discuss how iron plays an intricate role in initiating ferroptosis, necroptosis, and pyroptosis, examine their potential link to traumatic brain injury morbidity and mortality, and suggest therapeutic targets.

Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI. Pharmacologically preventing Fis1 from binding its mitochondrial partner, dynamin-related protein 1 (Drp1), for 2 weeks after TBI normalizes the balance of mitochondrial fission/fusion and prevents chronically impaired mitochondrial bioenergetics, oxidative damage, microglial activation and lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, and cognitive impairment. Delaying treatment until 8 months after TBI offers no protection. Thus, time-sensitive inhibition of acutely elevated mitochondrial fission may represent a strategy to protect human TBI patients from chronic neurodegeneration.