Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice.
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ABSTRACT:
SUBMITTER: Cheng C
PROVIDER: S-EPMC8363504 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTraumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated.MethodsC57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining.ResultsrA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI.ConclusionsSystematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI.
| S-EPMC8353736 | biostudies-literature
Project description:The expression levels of microRNAs (miRNAs) including miR-21, have been reported to change in response to traumatic brain injury (TBI), suggesting that they may influence the pathophysiological process in brain injury. To analyze the potential effect of miR-21 on neurological function after TBI, we employed the fluid percussion injury rat model and manipulated the expression level of miR-21 in brain using intracerebroventricular infusion of miR-21 agomir or antagomir. We found that upregulation of miR-21 level in brain conferred a better neurological outcome after TBI by improving long-term neurological function, alleviating brain edema and decreasing lesion volume. To further investigate the mechanism underlying this protective effect, we evaluated the impact of miR-21 on apoptosis and angiogenesis in brain after TBI. We found that miR-21 inhibited apoptosis and promoted angiogenesis through regulating the expression of apoptosis- and angiogenesis-related molecules. In addition, the expression of PTEN, a miR-21 target gene, was inhibited and Akt signaling was activated in the procedure. Taken together, these data indicate that miR-21 could be a potential therapeutic target for interventions after TBI.
| S-EPMC4208064 | biostudies-literature
Project description:Diagnostic and prognostic biomarkers of traumatic brain injury (TBI) are actively being pursued; potential candidates include glial fibrillary acid protein (GFAP), S100 calcium-binding protein B (S100B), and ubiquitin C-terminal hydrolase L1 (UCHL1), two of which the United States Food and Drug Administration (FDA) recently approved for marketing of blood tests for adult concussion. The relationship between biomarker-encoding genes and TBI outcomes remains unknown. This pilot study explores variation in 18 single nucleotide polymorphisms (SNPs) in biomarker-encoding genes as predictors of neurological outcome in a population of adults with severe TBI. Participants (n = 305) were assessed using the Glasgow Outcome Scale (GOS) at 3, 6, 12, and 24 months post-injury. Multivariate logistical regression was used to calculate the odds ratio (OR) and determine the odds of having a lower score on the GOS ( = 1-2 vs. 3-5) based on variant allele presence, while controlling for confounders. Possession of the variant allele of one S100B SNP (rs1051169) was associated with higher scores on the GOS at 3 months (OR = 0.39; p = 0.04), 6 months (OR = 0.34; p = 0.02), 12 months (OR = 0.32; p = 0.02), and 24 months (OR = 0.30; p = 0.02) post-severe TBI. The relationship among these polymorphisms, protein levels, and biomarker utility, merits examination. These findings represent a novel contribution to the evidence that can inform future studies aimed at enhancing interpretation of biomarker data, identifying novel biomarkers, and ultimately harnessing this information to improve clinical outcomes and personalize care.
| S-EPMC6238603 | biostudies-literature
Project description:Traumatic brain injury (TBI) causes multiple long-term defects including a loss of working memory that is frequently incapacitating. Administrations of mesenchymal stem/stromal cells (MSCs) previously produced beneficial effects in models of TBI as well as other disease models. In several models, the beneficial effects were explained by the MSCs being activated to express TSG-6, a multifunctional protein that modulates inflammation. In a mouse model of TBI, we found the initial mild phase of the inflammatory response persisted for at least 24h and was followed by secondary severe response that peaked at 3days. Intravenous human MSCs or TSG-6 during initial mild phase decreased neutrophil extravasation, expression of matrix metalloproteinase 9 by endothelial cells and neutrophils, and the subsequent blood brain barrier leakage in secondary phase. Administration of TSG-6 also decreased the lesion size at 2weeks. Importantly, the acute administration of TSG-6 within 24h of TBI was followed 6 to 10weeks later by improvements in memory, depressive-like behavior and the number of newly born-neurons. The data suggested that acute administration of TSG-6 may be an effective therapy for decreasing some of the long-term consequences of TBI.
| S-EPMC3790317 | biostudies-literature
Project description:Inflammatory responses are associated with blood-brain barrier (BBB) dysfunction and neurological deficits following traumatic brain injury (TBI). The aim of the present study was to investigate the effects of progesterone on the expression of the inflammatory mediators prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), nuclear factor ?B (NF-?B) and tumor necrosis factor-? (TNF-?) in the brain, BBB permeability, cerebral edema and neurological outcome, as well as to explore the mechanism of its neuroprotective effect. In this study, male rats were randomly divided into three groups: a sham-operated group (SHAM), a TBI group (TBI) and a progesterone treatment group (TBI-PROG). The TBI model was established using a modified Feeney's weight-dropping method. Brain samples were extracted 24 h following injury. The expression levels of COX-2 and NF-?B were examined using immunohistochemistry, whilst the expression levels of PGE2 and TNF-? were detected by enzyme-linked immunosorbent assay. BBB permeability was analyzed using Evans blue and cerebral edema was determined using the dry-wet method. The neurological outcome was evaluated using the modified neurological severity score test. The results revealed that progesterone treatment significantly reduced post-injury inflammatory response, brain edema and Evans blue dye extravasation, and improved neurological scores compared with those in the TBI group. In conclusion, the inhibition of inflammation may be an important mechanism by which progesterone protects the BBB and improves neurological outcome.
| S-EPMC4113529 | biostudies-other
Project description:Traumatic brain injury (TBI) is the leading cause of death and disability for people under the age of 45 years worldwide. Neuropathology after TBI is the result of both the immediate impact injury and secondary injury mechanisms. Secondary injury is the result of cascade events, including glutamate excitotoxicity, calcium overloading, free radical generation, and neuroinflammation, ultimately leading to brain cell death. In this study, the P2X7 receptor (P2X7R) was detected predominately in microglia of the cerebral cortex and was up-regulated on microglial cells after TBI. The microglia transformed into amoeba-like and discharged many microvesicle (MV)-like particles in the injured and adjacent regions. A P2X7R antagonist (A804598) and an immune inhibitor (FTY720) reduced significantly the number of MV-like particles in the injured/adjacent regions and in cerebrospinal fluid, reduced the number of neurons undergoing apoptotic cell death, and increased the survival of neurons in the cerebral cortex injured and adjacent regions. Blockade of the P2X7R and FTY720 reduced interleukin-1?expression, P38 phosphorylation, and glial activation in the cerebral cortex and improved neurobehavioral outcomes after TBI. These data indicate that MV-like particles discharged by microglia after TBI may be involved in the development of local inflammation and secondary nerve cell injury.
| S-EPMC5714842 | biostudies-other
Project description:Background: Thrombospondin-1 (TSP-1) is an extracellular matrix protein that plays multiple physiological and pathophysiological roles in the brain. Experimental reports suggest that TSP-1 may have an adverse role in neuronal function recovery under certain injury conditions. However, the roles of TSP-1 in traumatic brain injury (TBI) have not been elucidated. In this study we for the first time investigated the roles of TSP-1 in a controlled cortical impact (CCI) model of TBI in TSP-1 knockout (TSP-1 KO) and wild type (WT) mice. Methods: We examined blood brain-barrier (BBB) damage using at 1 day post-TBI by measuring Evans Blue leakage, and neurological functional recovery at 3 weeks post-TBI by measuring neurological severity score (NSS), wire gripping, corner test and Morris Water Maze (MWM). Mechanistically, we quantified pro-angiogenic biomarkers including cerebral vessel density, vascular endothelial growth factors (VEGF) and angiopoietin-1 (Ang-1) protein expression, synaptic biomarker synaptophysin, and synaptogenesis marker brain-derived neurotrophic factor (BDNF) protein expression in contralateral and ipsilateral (peri-lesion) cortex at 21 days after TBI using immunohistochemistry and Western Blot. Results: TSP-1 is upregulated at early phase of TBI in WT mice. Compared to WT mice, TSP-1 KO (1) significantly worsened TBI-induced BBB leakage at 1 day after TBI; (2) had similar lesion size as WT mice at 3 weeks after TBI; (3) exhibited a significantly worse neurological deficits in motor and cognitive functions; (4) had no significant difference in cerebral vessel density, but significant increase of VEGF and Ang-1 protein expressions in peri-lesion cortex; (5) significantly increased BDNF but not synaptophysin protein level in peri-lesion cortex compared to sham, but both synaptophysin and BDNF expressions were significantly decreased in contralateral cortex compared to WT. Conclusion: Our results suggest that TSP-1 may be beneficial for maintaining BBB integrity in the early phase and functional recovery in late phase after TBI. The molecular mechanisms of TSP-1 in early BBB pathophysiology, and long-term neurological function recovery after TBI need to be further investigated.
| S-EPMC5599915 | biostudies-literature
Project description:BackgroundInjuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2?, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.MethodsAccordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.ResultsMorphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.ConclusionThis study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.
| S-EPMC3907016 | biostudies-literature
Project description:Pioglitazone, an FDA-approved compound, has been shown to target the novel mitochondrial protein mitoNEET and produce short-term neuroprotection and functional benefits following traumatic brain injury. To expand on these findings, we now investigate the dose- and time-dependent effects of pioglitazone administration on mitochondrial function after experimental traumatic brain injury. We then hypothesize that optimal pioglitazone dosing will lead to ongoing neuroprotection and cognitive benefits that are dependent on pioglitazone-mitoNEET signalling pathways. We show that delayed intervention is significantly more effective than early intervention at improving acute mitochondrial bioenergetics in the brain after traumatic brain injury. In corroboration, we demonstrate that mitoNEET is more heavily expressed, especially near the cortical contusion, in the 18 h following traumatic brain injury. To explore whether these findings relate to ongoing pathological and behavioural outcomes, mice received controlled cortical impact followed by initiation of pioglitazone treatment at either 3 or 18 h post-injury. Mice with treatment initiation at 18 h post-injury exhibited significantly improved behaviour and tissue sparing compared to mice with pioglitazone initiated at 3 h post-injury. Further using mitoNEET knockout mice, we show that this therapeutic effect is dependent on mitoNEET. Finally, we demonstrate that delayed pioglitazone treatment improves serial motor and cognitive performance in conjunction with attenuated brain atrophy after traumatic brain injury. This study illustrates that mitoNEET is the critical target for delayed pioglitazone intervention after traumatic brain injury, mitochondrial-targeting is highly time-dependent after injury and there is an extended therapeutic window to effectively treat mitochondrial dysfunction after brain injury.
| S-EPMC8719838 | biostudies-literature
Project description:ImportanceThe development and expansion of intracranial hematoma are associated with adverse outcomes. Use of tranexamic acid might limit intracranial hematoma formation, but its association with outcomes of severe traumatic brain injury (TBI) is unclear.ObjectiveTo assess whether prehospital administration of tranexamic acid is associated with mortality and functional outcomes in a group of patients with severe TBI.Design, setting, and participantsThis multicenter cohort study is an analysis of prospectively collected observational data from the Brain Injury: Prehospital Registry of Outcome, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) study in the Netherlands. Patients treated for suspected severe TBI by the Dutch Helicopter Emergency Medical Services between February 2012 and December 2017 were included. Patients were followed up for 1 year after inclusion. Data were analyzed from January 10, 2020, to September 10, 2020.ExposuresAdministration of tranexamic acid during prehospital treatment.Main outcomes and measuresThe primary outcome was 30-day mortality. Secondary outcomes included mortality at 1 year, functional neurological recovery at discharge (measured by Glasgow Outcome Scale), and length of hospital stay. Data were also collected on demographic factors, preinjury medical condition, injury characteristics, operational characteristics, and prehospital vital parameters.ResultsA total of 1827 patients were analyzed, of whom 1283 (70%) were male individuals and the median (interquartile range) age was 45 (23-65) years. In the unadjusted analysis, higher 30-day mortality was observed in patients who received prehospital tranexamic acid (odds ratio [OR], 1.34; 95% CI, 1.16-1.55; P < .001), compared with patients who did not receive prehospital tranexamic acid. After adjustment for confounders, no association between prehospital administration of tranexamic acid and mortality was found across the entire cohort of patients. However, a substantial increase in the odds of 30-day mortality persisted in patients with severe isolated TBI who received prehospital tranexamic acid (OR, 4.49; 95% CI, 1.57-12.87; P = .005) and after multiple imputations (OR, 2.05; 95% CI, 1.22-3.45; P = .007).Conclusions and relevanceThis study found that prehospital tranexamic acid administration was associated with increased mortality in patients with isolated severe TBI, suggesting the judicious use of the drug when no evidence for extracranial hemorrhage is present.
| S-EPMC7953275 | biostudies-literature