Process Of Traumatic Brain Injury Research Articles

Astragaloside IV ameliorated neuroinflammation and improved neurological functions in mice exposed to traumatic brain injury by modulating the PERK-eIF2α-ATF4 signaling pathway.

Increasing evidence suggests that endoplasmic reticulum stress (ER stress) and neuroinflammation are involved in the complex pathological process of traumatic brain injury (TBI). However, the pathological mechanisms of their interactions in TBI remain incompletely elucidated. Therefore, investigating and ameliorating neuroinflammation and ER stress post-TBI may represent effective strategies for treating secondary brain injury. Astragaloside IV (AS-IV) has been reported as a potential neuroprotective and anti-inflammatory agent in neurological diseases. This study utilized a mouse TBI model to investigate the pathological mechanisms and crosstalk of ER stress, neuroinflammation, and microglial cell morphology in TBI, as well as the mechanisms and potential of AS-IV in improving TBI. The research revealed that post-TBI, inflammatory factors IL-6, IL-1β, and TNF-α increased, microglial cells were activated, and the specific inhibitor of PERK phosphorylation, GSK2656157, intervened to alleviate neuroinflammation and inhibit microglial cell activation. Post-TBI, levels of ER stress-related proteins (p-PERK, p-eIF2a, ATF4, ATF6, and p-IRE1a) increased. Following AS-IV treatment, neurological dysfunction in TBI mice improved. Levels of p-PERK, p-eIF2a, and ATF4 decreased, along with reductions in inflammatory factors IL-6, IL-1β, and TNF-α. Changes in microglial/macrophage M1/M2 polarization were observed. Additionally, the PERK activator CCT020312 intervention eliminated the impact of AS-IV on post-TBI inflammation and ER stress-related proteins p-PERK, p-eIF2a, and ATF4. These results indicate that AS-IV alleviates neuroinflammation and brain damage post-TBI through the PERK pathway, offering new directions and theoretical insights for TBI treatment.

Loss of AMPK potentiates inflammation by activating the inflammasome after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a significant public health concern characterized by a complex cascade of cellular events. TBI induces adenosine monophosphate-activated protein kinase (AMPK) dysfunction impairs energy balance activates inflammatory cytokines and leads to neuronal damage. AMPK is a key regulator of cellular energy homeostasis during inflammatory responses. Recent research has revealed its key role in modulating the inflammatory process in TBI. Following TBI the activation of AMPK can influence various important pathways and mechanisms including metabolic pathways and inflammatory signaling. Our study investigated the effects of post-TBI loss of AMPK function on functional outcomes inflammasome activation, and inflammatory cytokine production. Male C57BL/6 adult wild-type (WT) and AMPK knockout (AMPK-KO) mice were subjected to a controlled cortical impact (CCI) model of TBI or sham surgery. The mice were tested for behavioral impairment at 24 h post-TBI thereafter, mice were anesthetized, and their brains were quickly removed for histological and biochemical evaluation. In vitro we investigated inflammasome activation in mixed glial cells stimulated with lipopolysaccharides+ Interferon-gamma (LI) (0.1 μg/20 ng/ml LPS/IFNg) for 6 h to induce an inflammatory response. Estimating the nucleotide-binding domain, leucine-rich-containing family pyrin domain containing western blotting ELISA and qRT-PCR performed 3 (NLRP3) inflammasome activation and cytokine production. Our findings suggest that TBI leads to reduced AMPK phosphorylation in WT mice and that the loss of AMPK correlates with worsened behavioral deficits at 24 h post-TBI in AMPK-KO mice as compared to WT mice. Moreover compared with the WT mice AMPK-KO mice exhibit exacerbated NLRP3 inflammasome activation and increased expression of proinflammatory mediators such as IL-1b IL-6 TNF-a iNOS and Cox 2. These results align with the in vitro studies using brain glial cells under inflammatory conditions, demonstrating greater activation of inflammasome components in AMPK-KO mice than in WT mice. Our results highlighted the critical role of AMPK in TBI outcomes. We found that the absence of AMPK worsens behavioral deficits and heightens inflammasome-mediated inflammation thereby exacerbating brain injury after TBI. Restoring AMPK activity after TBI could be a promising therapeutic approach for alleviating TBI-related damage.

EASIX is an effective marker in predicting mortality of traumatic brain injury patients

BackgroundThe Endothelial Activation and Stress Index (EASIX) is a novel marker of endothelial injury and correlates with survival of various patients. The endothelial dysfunction plays an important role on the pathophysiological process of traumatic brain injury (TBI). This study was designed to explore the prognostic value of EASIX on TBI patients.Methods358 TBI patients hospitalized in the West China hospital between October 2018 and October 2022 were enrolled for this study. The EASIX was calculated based on the formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L). The univariate and multivariate logistic regression with forward method was performed to explore the association between EASIX and mortality. A prognostic model was developed combining significant risk factors in the multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to compare the predictive accuracy of the EASIX and the developed model.ResultsThe 30-day mortality of enrolled 358 TBI patients was 51.1%. Non-survivors had higher EASIX than survivors (p < 0.001). The multivariate logistic regression confirmed seven risk factors for mortality of TBI including injury mechanism (p = 0.010), GCS (p < 0.001), glucose (p < 0.001), EASIX (p = 0.017), subdural hematoma (p = 0.012), coagulopathy (p = 0.001). The AUC of EASIX, SOFA, GCS was 0.747, 0.748 and 0.774, respectively. The AUC of developed predictive model was 0.874 with the sensitivity of 0.913 and specificity of 0.686.ConclusionsThe EASIX is a reliable marker for predicting mortality of TBI patients. The predictive model incorporating EASIX is helpful for clinicians to evaluate the mortality risk of TBI patients.

A pre-existing Toxoplasma gondii infection exacerbates the pathophysiological response and extent of brain damage after traumatic brain injury in mice

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity—all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients.

Circulating extracellular vesicles from patients with traumatic brain injury induce cerebrovascular endothelial dysfunction

Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical caspase-1/gasdermin D (GSDMD)-dependent pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.

Brain-specific loss of Abcg1 disturbs cholesterol metabolism and aggravates pyroptosis and neurological deficits after traumatic brain injury.

Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.

Platelet derived growth factor promotes the recovery of traumatic brain injury by inhibiting endoplasmic reticulum stress and autophagy-mediated pyroptosis.

Autophagy and endoplasmic reticulum stress (ER stress) are important in numerous pathological processes in traumatic brain injury (TBI). Growing evidence has indicated that pyroptosis-associated inflammasome is involved in the pathogenesis of TBI. Platelet derived growth factor (PDGF) has been reported to be as a potential therapeutic drug for neurological diseases. However, the roles of PDGF, autophagy and ER stress in pyroptosis have not been elucidated in the TBI. This study investigated the roles of ER stress and autophagy after TBI at different time points. We found that the ER stress and autophagy after TBI were inhibited, and the expressions of pyroptosis-related proteins induced by TBI, including NLRP3, Pro-Caspase1, Caspase1, GSDMD, GSDMD P30, and IL-18, were decreased upon PDGF treatment. Moreover, the rapamycin (RAPA, an autophagy activator) and tunicamycin (TM, an ER stress activator) eliminated the PDGF effect on the pyroptosis after TBI. Interestingly, the sodium 4-phenylbutyrate (4-PBA, an ER stress inhibitor) suppressed autophagy but 3-methyladenine (3-MA, an autophagy inhibitor) not for ER stress. The results revealed that PDGF improved the functional recovery after TBI, and the effects were markedly reversed by TM and RAPA. Taken together, this study provides a new insight that PDGF is a potential therapeutic strategy for enhancing the recovery of TBI.

Histones of Neutrophil Extracellular Traps Induce CD11b Expression in Brain Pericytes Via Dectin-1 after Traumatic Brain Injury.

The brain pericyte is a unique and indispensable part of the blood-brain barrier (BBB), and contributes to several pathological processes in traumatic brain injury (TBI). However, the cellular and molecular mechanisms by which pericytes are regulated in the damaged brain are largely unknown. Here, we show that the formation of neutrophil extracellular traps (NETs) induces the appearance of CD11b+ pericytes after TBI. These CD11b+ pericyte subsets are characterized by increased permeability and pro-inflammatory profiles compared to CD11b- pericytes. Moreover, histones from NETs by Dectin-1 facilitate CD11b induction in brain pericytes in PKC-c-Jun dependent manner, resulting in neuroinflammation and BBB dysfunction after TBI. These data indicate that neutrophil-NET-pericyte and histone-Dectin-1-CD11b are possible mechanisms for the activation and dysfunction of pericytes. Targeting NETs formation and Dectin-1 are promising means of treating TBI.

Construction of a lncRNA-associated competing endogenous RNA regulatory network after traumatic brain injury in mouse

Traumatic brain injury (TBI) is a major public health problem worldwide which causes high mortality and disability. Functioning as microRNA (miRNA) sponges, long non-coding RNA (lncRNA) regulates the expression of protein-coding genes in a competing endogenous RNA (ceRNA) network. However, the lncRNA-associated ceRNA in TBI remains unclear. In this study, we processed the raw SRR files of mice cortex samples of sham injury (n = 3) and TBI groups (n = 3) to count files. Then, the expression profiles of lncRNAs and mRNAs were identified, and 86 differentially expressed (DE) lncRNAs and 1201 DEmRNAs between sham and TBI groups were identified. The DEmRNAs were used to perform enrichment analyses. Next, a lncRNA-miRNA-mRNA regulatory ceRNA network was constructed. The network consisted of 23 mRNAs, 5 miRNAs and 2 lncRNAs. The expression alternations of the 5 miRNAs were validated via qRT-PCR. The subnetwork of hub lncRNA Neat1 was extracted. We identified a potential inflammatory associated regulatory axis: Neat1/miR-31-5p/Myd88 axis. The PPI network based on DEmRNA involved in ceRNA network was constructed PPI networks to identify the hub genes. Finally, DElncRNAs and DEmRNAs were selected randomly and validated by qRT-PCR. In conclusion, with the lncRNA-miRNA-mRNA ceRNA network provided above, we can improve our understanding of the regulatory mechanisms and interaction among lncRNAs, miRNAs and mRNAs in TBI process.

Targeting Nrf2-Mediated Oxidative Stress Response in Traumatic Brain Injury: Therapeutic Perspectives of Phytochemicals.

Traumatic brain injury (TBI), known as mechanical damage to the brain, impairs the normal function of the brain seriously. Its clinical symptoms manifest as behavioral impairment, cognitive decline, communication difficulties, etc. The pathophysiological mechanisms of TBI are complex and involve inflammatory response, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and so on. Among them, oxidative stress, one of the important mechanisms, occurs at the beginning and accompanies the whole process of TBI. Most importantly, excessive oxidative stress causes BBB disruption and brings injury to lipids, proteins, and DNA, leading to the generation of lipid peroxidation, damage of nuclear and mitochondrial DNA, neuronal apoptosis, and neuroinflammatory response. Transcription factor NF-E2 related factor 2 (Nrf2), a basic leucine zipper protein, plays an important role in the regulation of antioxidant proteins, such as oxygenase-1(HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and glutathione peroxidase (GPx), to protect against oxidative stress, neuroinflammation, and neuronal apoptosis. Recently, emerging evidence indicated the knockout (KO) of Nrf2 aggravates the pathology of TBI, while the treatment of Nrf2 activators inhibits neuronal apoptosis and neuroinflammatory responses via reducing oxidative damage. Phytochemicals from fruits, vegetables, grains, and other medical herbs have been demonstrated to activate the Nrf2 signaling pathway and exert neuroprotective effects in TBI. In this review, we emphasized the contributive role of oxidative stress in the pathology of TBI and the protective mechanism of the Nrf2-mediated oxidative stress response for the treatment of TBI. In addition, we summarized the research advances of phytochemicals, including polyphenols, terpenoids, natural pigments, and otherwise, in the activation of Nrf2 signaling and their potential therapies for TBI. Although there is still limited clinical application evidence for these natural Nrf2 activators, we believe that the combinational use of phytochemicals such as Nrf2 activators with gene and stem cell therapy will be a promising therapeutic strategy for TBI in the future.

Deficits in Acoustic Startle Reactivity and Auditory Temporal Processing after Traumatic Brain Injury.

Traumatic brain injury (TBI) exacts significant neurological and financial costs on patients and their families. In adult patients with moderate-to-severe TBI, central auditory impairments have been reported. These auditory impairments may interfere with language receptivity, as observed in children with developmental brain injury. Although rodent models of TBI have been widely used to examine behavioral outcomes, few studies have evaluated how TBI affects higher-order central auditory processing across a range of cue complexities. Here, auditory processing was assessed using a modified acoustic startle paradigm. We used a battery of progressively complex stimuli (single-tone, silent gaps in white noise, and frequency-modulated [FM] sweeps) in adult rats that received unilateral controlled cortical impact injury. TBI subjects showed significant reductions in acoustic startle absolute responses across nearly all stimuli, regardless of cue, duration of stimuli, or cue complexity. Despite this overall reduction of startle magnitudes in injured animals, the detection of single-tone stimuli was comparable between TBI and sham-injured subjects, indicating intact hearing after TBI. TBI subjects showed deficits in rapid gap (5 ms) and FM sweep (175 ms) detection, and, in contrast to shams, they did not improve on detecting silent gaps and FM sweeps across days of testing. Our findings provide evidence for both low-level (brainstem-mediated) and higher-order central auditory processing deficits in a rodent model of TBI, which parallel sensory impairments observed in TBI patients. The present findings support the use of modified pre-pule auditory detection paradigms to investigate clinically relevant processes in TBI.

Propofol effects in rodent models of traumatic brain injury: a systematic review.

Traumatic brain injury (TBI) causes high mortality and disability worldwide. Animal models have been developed to explore the complex processes in TBI. Propofol is used to manage head injuries during surgical intervention and mechanical ventilation in patients with TBI. Many studies have investigated the neuroprotective effect of propofol on TBI. However, other studies have shown neurotoxic effects. To review systematically the literature regarding the neuroprotective and neurotoxic effects of propofol in rodent models of TBI. Data from rodents as models of TBI with propofol as one of the intervention agents, and/or comparing the neuroprotective effects of propofol with the other substances in rodent models of TBI, were obtained from PubMed, EBSCO Host, and ProQuest databases. The PRISMA 2020 statement recommendations were followed and research questions were developed based on PICOS guidelines. Data was extracted from the literature using a standardized Cochrane method. We analyzed data from 12 articles on physiological changes of experimental animals before and after trauma, the effects of propofol administration, and the observed neurotoxic effects. The effects of propofol administration were observed in terms of changes in traumatic lesion volume, the release of antioxidants and inflammatory factors, and the neurological function of rodent models of TBI. Propofol has neuroprotective and neurotoxic effects via several mechanisms, and various doses have been used in research to determine its effects. The timing of administration, the dose administered, and the duration of administration contribute to determine the effect of propofol in rodent models of TBI. However, the doses that produce neuroprotective and neurotoxic effects are not yet clear and further research is needed to determine them.

Вплив Нейромідину® на когнітивні функції і процеси нейропластичності при черепно-мозковій травмі

Легка і середня черепно-мозкова травма (ЧМТ) — це одне з найчастіших захворювань у нейротравматології і важлива проблема сучасної охорони здоров’я усіх країн. Результати нашого дослідження дають підставу проводити пацієнтам комплексну патогенетичну профілактику і лікування виявлених когнітивних порушень уже в гострому періоді ЧМТ з метою запобігання їх прогресуванню в подальшому. Більш високий рівень мозкового гліального нейротрофічного фактора бета-NGF в сироватці крові хворих, які отримували Нейромідин®, свідчив про активний вплив препарату на стимуляцію процесів нейропластичності при травматичному пошкодженні головного мозку. Показана клінічна ефективність Нейромідину® дозволяє рекомендувати його включення в схеми стандартної терапії ЧМТ. А призначення препарату в гострому періоді ЧМТ дозволить уникнути прогресуючого порушення когнітивних функцій у подальшому.

Ability to regulate immunity of mesenchymal stem cells in the treatment of traumatic brain injury.

Traumatic brain injury (TBI) is characterized by broad clinical symptoms in brain insult by external damages to the skull. TBI potentially leads to severe physical, cognitive, and emotional impairment. The complex biochemical reactions of inflammatory processes in TBI significantly influence brain function and clinical sequelae's overall severity. Mesenchymal stem cell therapy has become a promising therapeutic field of treatment for serious injuries due to its ability to regulate the inflammatory microenvironment. In this study, we aimed to investigate MSC's anti-inflammatory ability through regulating leukocyte, neutrophils, and inflammatory factors (IL-6, CRP, and TNF-a), thereby reducing the trauma in the TBI. Biological effects of autologous MNC and MSC cell transplantation have been studied in 40 patients with molded TBI, after being filtered according to appropriate criteria. All patients initially received MNCs and subsequently MSCs (both intravenously) followed by continuous monitoring during treatment (2 months) with clinical cognitive indicators. The results after transplantation MSC indicated that the majority of patients experienced improved health function in different degrees during the follow-up period. Lower serum levels of inflammatory factors, leukocytes, and neutrophils population were detected following the transplantation compared with the levels prior to treatment and with the control patients. No severe symptoms were observed in patients after transplantation, despite 3-4 death cases in each group. Overall, the present study suggests that transplantation of MSC possibly regulates inflammatory factors and appears to be safe in TBI treatment.

Deletion of ferritin H in neurons counteracts the protective effect of melatonin against traumatic brain injury-induced ferroptosis.

Accumulating evidence demonstrates that ferroptosis may be important in the pathophysiological process of traumatic brain injury (TBI). As a major hormone of the pineal gland, melatonin exerts many beneficial effects on TBI, but there is no information regarding the effects of melatonin on ferroptosis after TBI. As expected, TBI resulted in the time-course changes of ferroptosis-related molecules expression and iron accumulation in the ipsilateral cortex. Importantly, we found that treating with melatonin potently rescued TBI induced the changes mentioned above and improved functional deficits versus vehicle. Similar results were obtained with a ferroptosis inhibitor, liproxstatin-1. Moreover, the protective effect of melatonin is likely dependent on melatonin receptor 1B (MT2). Although ferritin plays a vital role in iron metabolism by storing excess cellular iron, its precise function in the brain, and whether it involves melatonin's neuroprotection remain unexplored. Considering ferritin H (Fth) is expressed predominantly in the neurons and global loss of Fth in mice induces early embryonic lethality, we then generated neuron-specific Fth conditional knockout (Fth-KO) mice, which are viable and fertile but have altered iron metabolism. In addition, Fth-KO mice were more susceptible to ferroptosis after TBI, and the neuroprotection by melatonin was largely abolished in Fth-KO mice. In vitro siFth experiments further confirmed the results mentioned above. Taken together, these data indicate that melatonin produces cerebroprotection, at least partly by inhibiting neuronal Fth-mediated ferroptosis following TBI, supporting the notion that melatonin is an excellent ferroptosis inhibitor and its anti-ferroptosis provides a potential therapeutic target for treating TBI.

LncRNA-Meg3 promotes Nlrp3-mediated microglial inflammation by targeting miR-7a-5p

Recent studies have identified neuroinflammation as a significant contributor to the pathological process of traumatic brain injury (TBI) and as a potentially effective target for treatment. LncRNA maternally expressed gene 3 (Meg3) has further been observed to play a critical role in diverse biological processes, including microglial activation and the inflammatory response. However, its target gene and associated signaling pathway require further elucidation. This study found that lipopolysaccharide + ATP upregulated Meg3, promoted microglia activation, Nlrp3/caspase1 activation and inflammation, and markedly reduced miR-7a-5p. Overexpression of miR-7a-5p attenuated Meg3-induced microglial activation, but not Meg3 expression. Bioinformatic analysis and dual-luciferase assays indicated that Meg3 was a direct target of miR-7a-5p that negatively regulates miR-7a-5p expression. Further, we showed that Meg3 acted as a competing endogenous RNA for miR-7a-5p and induced microglial inflammation by regulating nod-like receptor protein 3 (Nlrp3) expression. Our study thus demonstrates Meg3 regulates microglia inflammation by targeting the miR-7a-5p /Nlrp3 pathway.

CXCR7, CXCR4, and Their Ligand Expression Profile in Traumatic Brain Injury

Traumatic brain injury (TBI) is a health problem worldwide, and therapeutic strategies to enhance brain tissue repair to lessen neurologic sequels are imperative. We aimed to analyze the impact of the inflammatory process in TBI through CXCR4 and CXCR7 chemokine receptors and their ligands' CXCL11 and CXCL12 expression profile in search for potential new druggable targets. Twelve pericontusional tissues from severe TBI patients submitted to surgical treatment, and 20 control brain tissues from normal autopsy were analyzed for expression profile by real-time quantitative-polymerase chain reaction. CXCR7 and CXCR4 protein expressions were analyzed by immunohistochemistry. The findings were correlated with the clinical evolution. Increased gene expression of both receptors and their ligands was observed in TBI compared with controls, presenting high sensitivity and specificity to differentiate TBI from normal control (area under the curve ranging from 0.85 to 0.98, P < 0.001). In particular, CXCR7 expression highly correlated with CXCR4 and both ligands' expressions in TBI. Higher immunoreactions for CXCR7 and CXCR4 were identified in neurons and endothelial cells of TBI samples compared with controls. The patients presenting upregulated chemokine expression levels showed a trend toward favorable clinical evolution at up to 6 months of follow-up. The neuroprotective trend of CXCR4, CXCR7, CXCL11, and CXCL12 in TBI observed in this initial analysis warrants further studies with more patients, analyzing the involved signaling pathways for the development of new therapeutic strategies for TBI.

Inhibition of RNF6 alleviates traumatic brain injury by suppressing STAT3 signaling in rats.

BackgroundTraumatic brain injury (TBI) has ranked as one of the leading causes of disability and death in the world. The neuroinflammation mediated by signal transducer and activator of transcription 3 (STAT3) signaling during the progression of TBI leads to long‐term neurodegeneration. Ring finger protein 6 (RNF‐6) is an E3 ubiquitin ligase and can regulate the activity of STAT3 signaling pathway by targeting its inhibitors. However, the mechanism underlying this process in TBI remains poorly understood.MethodsIn this research, cortical impact injury was used to construct the TBI rat model. Western blot assay was performed to evaluate the protein levels of RNF6, Src homology 2 domain‐containing protein tyrosine phosphatase 1 (SHP‐1), and STAT3/pSTAT3. QRT‐PCR assay was performed to assess the RNA levels of RNF6 and other cytokines. The neural function of TBI rats was estimated by modified Neurological Severity Scores test.ResultsThe expression of RNF‐6 was up‐regulated in the brain tissues of TBI rats. Down‐regulation of RNF6 alleviated the symptoms and improved the neural recovery postinjury in TBI rats. Inhibition of RNF6 suppressed the cerebral inflammation by up‐regulating the protein level of SHP‐1 and down‐regulating the phosphorylation level of STAT3.ConclusionInhibition of RNF6 alleviated TBI by suppressing the STAT3 signaling in TBI rats.

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice.

Background Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

How to Translate Time: The Temporal Aspects of Rodent and Human Pathobiological Processes in Traumatic Brain Injury.

Traumatic brain injury (TBI) triggers multiple pathobiological responses with differing onsets, magnitudes, and durations. Identifying the therapeutic window of individual pathologies is critical for successful pharmacological treatment. Dozens of experimental pharmacotherapies have been successfully tested in rodent models, yet all of them (to date) have failed in clinical trials. The differing time scales of rodent and human biological and pathological processes may have contributed to these failures. We compared rodent versus human time scales of TBI-induced changes in cerebral glucose metabolism, inflammatory processes, axonal integrity, and water homeostasis based on published data. We found that the trajectories of these pathologies run on different timescales in the two species, and it appears that there is no universal "conversion rate" between rodent and human pathophysiological processes. For example, the inflammatory process appears to have an abbreviated time scale in rodents versus humans relative to cerebral glucose metabolism or axonal pathologies. Limitations toward determining conversion rates for various pathobiological processes include the use of differing outcome measures in experimental and clinical TBI studies and the rarity of longitudinal studies. In order to better translate time and close the translational gap, we suggest 1) using clinically relevant outcome measures, primarily in vivo imaging and blood-based proteomics, in experimental TBI studies and 2) collecting data at multiple post-injury time points with a frequency exceeding the expected information content by two or three times. Combined with a big data approach, we believe these measures will facilitate the translation of promising experimental treatments into clinical use.