Weight-Drop Method for Inducing Closed Head Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the foremost causes of disability and death globally. Prerequisites for successful therapy of disabilities associated with TBI involved improved knowledge of the neurobiology of TBI, measurement of quantitative changes in recovery dynamics brought about by therapy, and the translation of quantitative methodologies and techniques that were successful in tracking recovery in preclinical models to human TBI. Frequently used animal models of TBI in research and development include controlled cortical impact, fluid percussion injury, blast injury, penetrating blast brain injury, and weight-drop impact acceleration models. Preclinical models of TBI benefit from controlled injury settings and the best prospects for biometric quantification of injury and therapy-induced gradual recovery from disabilities. Impact acceleration closed head TBI paradigm causes diffuse TBI (DTBI) without substantial focal brain lesions in rats. DTBI is linked to a significant rate of death, morbidity, and long-term disability. DTBI is difficult to diagnose at the time of hospitalization with imaging techniques making it challenging to take prompt therapeutic action. The weight-drop method without craniotomy is an impact acceleration closed head DTBI model that is used to induce mild/moderate diffuse brain injuries in rodents. Additionally, we have characterized neuropathological and neurobehavioral outcomes of the weight-drop model without craniotomy for inducing closed head DTBI of graded severity with a range of mass of weights (50-450 gm). This chapter also discusses techniques and protocols for measuring numerous functional disabilities and pathological changes in the brain brought on by DTBI.

MicroRNA-7 attenuates secondary brain injury following experimental intracerebral hemorrhage via inhibition of NLRP3.

BACKGROUND AND PURPOSE: The pathophysiological mechanisms underlying brain injury resulting from intracerebral hemorrhage (ICH) remain incompletely elucidated, and efficacious therapeutic interventions to enhance the prognosis of ICH patients are currently lacking. Previous research indicates that MicroRNA-7 (miR-7) can suppress the expression of Nod-like receptor protein 3 (NLRP3), thereby modulating neuroinflammation in Parkinson's disease pathogenesis. However, the potential regulatory effects miR-7 on NLRP3 inflammasome after ICH are yet to be established. This study aims to ascertain whether miR-7 mitigates secondary brain injury following experimental ICH by inhibiting NLRP3 and to investigate the underlying mechanisms. METHODS: An ICH model was established by stereotaxically injecting 100 µL of autologous blood into the right basal ganglia of Sprague-Dawley (SD) rats. Subsequently, these rats were allocated into three groups: sham, ICH + Vehicle, and ICH + miR-7, each comprising 18 animals. Twelve hours post-modeling, rats received intraventricular injections of 10 µL physiological saline, 10 µL phosphate, and 10 µL phosphate-buffered saline solution containing 0.5 nmol of miR-7 mimics, respectively. Neurological function was assessed on day three post-modeling, followed by euthanasia for brain tissue collection. Brain water content was determined using the dry-wet weight method. The expression of inflammatory cytokines in cerebral tissues surrounding the hematoma was analyzed through immunohistochemistry and Western blot assays. These cytokines were re-evaluated using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Moreover, bioinformatics tools were employed to predict miR-7's binding to NLRP3. A wild-type luciferase reporter gene vector and a corresponding mutant vector were constructed, followed by transfection of miR-7 mimics into HEK293T cells to assess luciferase activity. RESULTS: Our study demonstrates that the administration of miR-7 mimics markedly reduced neurological function scores and attenuated brain edema in rats following ICH. A significant upregulation of NLRP3 expression in microglia/macrophage adjacent to the hematoma was observed, substantially reduced after the treatment with miR-7 mimics. Furthermore, this intervention ameliorated neurodegenerative changes and effectively decreased the protein and mRNA levels of pro-inflammatory cytokines, namely TNF-α, IL-1ß, IL-6, and Caspase1, in the cerebral tissues proximate to the hematomas. In addition, miR-7 mimics distinctly inhibited the luciferase activity associated with the wild-type reporter gene, an effect not mirrored in its mutant variant. CONCLUSIONS: The miR-7 suppressed NLRP3 expression in microglia/macrophage to reduce the production of inflammatory cytokines, leading to conducting certain neuroprotection post-ICH in rats.

Intracerebral hemorrhage-induced brain injury in mice: The role of peroxiredoxin 2-Toll-like receptor 4 inflammatory axis.

BACKGROUND: Peroxiredoxin 2 (Prx2), an intracellular protein that regulates redox reactions, released from red blood cells is involved in inflammatory brain injury after intracerebral hemorrhage (ICH). Toll-like receptor 4 (TLR4) may be crucial in this process. This study investigated the role of the Prx2-TLR4 inflammatory axis in brain injury following experimental ICH in mice. METHODS: First, C57BL/6 mice received an intracaudate injection of autologous arterial blood or saline and their brains were harvested on day 1 to measure Prx2 levels. Second, mice received an intracaudate injection of either recombinant mouse Prx2 or saline. Third, the mice were co-injected with autologous arterial blood and conoidin A, a Prx2 inhibitor, or vehicle. Fourth, the mice received a Prx2 injection and were treated with TAK-242, a TLR4 antagonist, or saline (intraperitoneally). Behavioral tests, magnetic resonance imaging, western blot, immunohistochemistry/immunofluorescence staining, and RNA sequencing (RNA-seq) were performed. RESULTS: Brain Prx2 levels were elevated after autologous arterial blood injection. Intracaudate injection of Prx2 caused brain swelling, microglial activation, neutrophil infiltration, neuronal death, and neurological deficits. Co-injection of conoidin A attenuated autologous arterial blood-induced brain injury. TLR4 was expressed on the surface of microglia/macrophages and neutrophils and participated in Prx2-induced inflammation. TAK-242 treatment attenuated Prx2-induced inflammation and neurological deficits. CONCLUSIONS: Prx2 can cause brain injury following ICH through the TLR4 pathway, revealing the Prx2-TLR4 inflammatory axis as a potential therapeutic target.

Investigating neuropathological changes and underlying neurobiological mechanisms in the early stages of primary blast-induced traumatic brain injury: Insights from a rat model.

The utilization of explosives and chemicals has resulted in a rise in blast-induced traumatic brain injury (bTBI) in recent times. However, there is a dearth of diagnostic biomarkers and therapeutic targets for bTBI due to a limited understanding of biological mechanisms, particularly in the early stages. The objective of this study was to examine the early neuropathological characteristics and underlying biological mechanisms of primary bTBI. A total of 83 Sprague Dawley rats were employed, with their heads subjected to a blast shockwave of peak overpressure ranging from 172 to 421 kPa in the GI, GII, and GIII groups within a closed shock tube, while the body was shielded. Neuromotor dysfunctions, morphological changes, and neuropathological alterations were detected through modified neurologic severity scores, brain water content analysis, MRI scans, histological, TUNEL, and caspase-3 immunohistochemical staining. In addition, label-free quantitative (LFQ)-proteomics was utilized to investigate the biological mechanisms associated with the observed neuropathology. Notably, no evident damage was discernible in the GII and GI groups, whereas mild brain injury was observed in the GIII group. Neuropathological features of bTBI were characterized by morphologic changes, including neuronal injury and apoptosis, cerebral edema, and cerebrovascular injury in the shockwave's path. Subsequently, 3153 proteins were identified and quantified in the GIII group, with subsequent enriched neurological responses consistent with pathological findings. Further analysis revealed that signaling pathways such as relaxin signaling, hippo signaling, gap junction, chemokine signaling, and sphingolipid signaling, as well as hub proteins including Prkacb, Adcy5, and various G-protein subunits (Gnai2, Gnai3, Gnao1, Gnb1, Gnb2, Gnb4, and Gnb5), were closely associated with the observed neuropathology. The expression of hub proteins was confirmed via Western blotting. Accordingly, this study proposes signaling pathways and key proteins that exhibit sensitivity to brain injury and are correlated with the early pathologies of bTBI. Furthermore, it highlights the significance of G-protein subunits in bTBI pathophysiology, thereby establishing a theoretical foundation for early diagnosis and treatment strategies for primary bTBI.

Cannabidiol reduces intraventricular hemorrhage brain damage, preserving myelination and preventing blood brain barrier dysfunction in immature rats.

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. This study assessed the potential neuroprotective effects of cannabidiol (CBD) in an IVH model using immature rats. IVH was induced in 1-day-old (P1) Wistar rats by left periventricular injection of Clostridial collagenase. Some rats received CBD prenatally (10 â€‹mg/kg i.p. to the dam) and then 5 â€‹mg/kg i.p. 6, 30 and 54 â€‹h after IVH (IVH+CBD, n â€‹= â€‹30). Other IVH rats received vehicle (IVH+VEH, n â€‹= â€‹34) and vehicle-treated non-IVH rats served as controls (SHM, n â€‹= â€‹29). Rats were humanely killed at P6, P14 or P45. Brain damage (motor and memory performance, area of damage, Lactate/N-acetylaspartate ratio), white matter injury (ipsilateral hemisphere and corpus callosum volume, oligodendroglial cell density and myelin basic protein signal), blood-brain barrier (BBB) integrity (Mfsd2a, occludin and MMP9 expression, gadolinium leakage), inflammation (TLR4, NFκB and TNFα expression, infiltration of pro-inflammatory cells), excitotoxicity (Glutamate/N-acetylspartate ratio) and oxidative stress (protein nitrosylation) were then evaluated. CBD prevented the long-lasting motor and cognitive consequences of IVH, reduced brain damage in the short- and long-term, protected oligodendroglial cells preserving adequate myelination and maintained BBB integrity. The protective effects of CBD were associated with the modulation of inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, CBD reduced IVH-induced brain damage and its short- and long-term consequences, showing robust and pleiotropic neuroprotective effects. CBD is a potential candidate to ameliorate IVH-induced immature brain damage.

Distant neuroinflammation acutely induced by focal brain injury and its control by endocannabinoid system.

INTRODUCTION: We studied spatiotemporal features of acute transcriptional inflammatory response induced by a focal brain injury in distant uninjured neuronal tissue and a role of endocannabinoid (eCB) system in its control. MATERIALS AND METHODS: A focal excitotoxic lesion was induced by a unilateral injection of kainate in the dorsal hippocampus of awake Wistar rats. During acute post-injury period (3 h and 24 h post-injection), mRNA levels of genes associated with neuroinflammation (Il1b, Il6, Tnf, Ccl2; Cx3cl1, Zc3 h12a, Tgfb1) and eCB receptors of CB1 and CB2 types (Cnr1 and Cnr2) in intact regions of the hippocampus and neocortex were measured using qPCR. Occurrence of acute symptomatic seizures was controlled electrographically. To modulate eCB signaling during injury and acute post-injury period, antagonists (AM251, AM630) and agonist (WIN55-212-2) of eCB receptors were administered before the injury induction. RESULTS: Local intrahippocampal injury triggered widespread time- and region-dependent neuroinflammation in undamaged brain regions remote from the lesion site. The distant areas of the hippocampus and hippocampal meninges exhibited early (3 h) transient upregulation of pro- and anti-inflammatory cytokines simultaneously with occurrence of acute symptomatic seizures. The neocortex and its meninges showed minor neuroinflammation early after injury (3 h) but later (24 h) significantly upregulated several genes, mainly with anti-inflammatory properties. Focal lesion also changed expression of eCB receptors in the distant extra-lesional regions - CB1 receptors at 3 h and both CB1 and CB2 receptors at 24 h. Within the hippocampus, significant regional differences in constitutive and post-injury expression CB1 receptors were found. Pharmacological blockade of eCB receptors during injury and early post-injury period lengthened hippocampal neuroinflammation and reversed upregulation of anti-inflammatory molecules in the neocortex. CONCLUSION: The findings show that focal brain injury rapidly triggers widespread parenchymal and extraparenchymal neuroinflammation. The early injury-induced response is likely to represent neurogenic neuroinflammation produced by network hyperexcitability (acute symptomatic seizures). Activation of eCB signaling during acute phase of the brain injury is important for initiation of adaptive anti-inflammatory processes and prevention of chronic pathologic neuroinflammation in distant uninjured structures. However, the beneficial role of injury-induced eCB activity appears to depend on many factors including time, brain region, eCB tone etc.

A comprehensive predictive model for radiation-induced brain injury in risk stratification and personalized radiotherapy of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.

Neuromonitoring of Pediatric and Adult Extracorporeal Membrane Oxygenation Patients: The Importance of Continuous Bedside Tools in Driving Neuroprotective Clinical Care.

Extracorporeal membrane oxygenation (ECMO) is a form of temporary cardiopulmonary bypass for patients with acute respiratory or cardiac failure refractory to conventional therapy. Its usage has become increasingly widespread and while reported survival after ECMO has increased in the past 25 years, the incidence of neurological injury has not declined, leading to the pressing question of how to improve time-to-detection and diagnosis of neurological injury. The neurological status of patients on ECMO is clinically difficult to evaluate due to multiple factors including illness, sedation, and pharmacological paralysis. Thus, increasing attention has been focused on developing tools and techniques to measure and monitor the brain of ECMO patients to identify dynamic risk factors and monitor patients' neurophysiological state as a function in time. Such tools may guide neuroprotective interventions and thus prevent or mitigate brain injury. Current means to continuously monitor and prevent neurological injury in ECMO patients are rather limited; most techniques provide indirect or postinsult recognition of irreversible brain injury. This review will explore the indications, advantages, and disadvantages of standard-of-care, emerging, and investigational technologies for neurological monitoring on ECMO, focusing on bedside techniques that provide continuous assessment of neurological health.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

Moslosooflavone protects against brain injury induced by hypobaric hypoxic via suppressing oxidative stress, neuroinflammation, energy metabolism disorder, and apoptosis.

OBJECTIVES: To investigate the protect effect of moslosooflavone against brain injury induced by hypobaric hypoxia (HH) in mice. METHODS: Protective effects of moslosooflavone in oxidative stress, neuroinflammation, energy metabolism disorder, and apoptosis were studied in HH-induced brain damage mice. The pathological morphology in the cortex of mice was determined by hematoxylin and eosin staining. The related protein expressions were detected by western blot. KEY FINDINGS: Moslosooflavone improved HH-induced brain histopathological changes, reduced the contents of ROS and MDA, and elevated the levels of antioxidant enzymes and GSH in HH-exposed brains of mice. Moslosooflavone also markedly enhanced the ATPase activities and PK, ATP contents, while reducing LDH activity and the LD, TNF-α, IL-1ß, and IL-6 contents HH-exposed brains of mice. In addition, moslosooflavone notably decreased the expression of HIF-1α, VEGF, Bax, and cleaved caspase-3 dramatically increasing the expression of Bcl-2, Nrf2, and HO­1 in HH-exposed brains of mice. CONCLUSIONS: Our current studies indicate that moslosooflavone protects HH-induced brain injury possibly through alleviating oxidative stress and neuroinflammation, maintaining the balance of energy metabolism, and inhibiting cell apoptosis.

Netrin-1 Alleviates Early Brain Injury by Regulating Ferroptosis via the PPARγ/Nrf2/GPX4 Signaling Pathway Following Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a type of stroke with high morbidity and mortality. Netrin-1 (NTN-1) can alleviate early brain injury (EBI) following SAH by enhancing peroxisome proliferator-activated receptor gamma (PPARγ), which is an important transcriptional factor modulating lipid metabolism. Ferroptosis is a newly discovered type of cell death related to lipid metabolism. However, the specific function of ferroptosis in NTN-1-mediated neuroprotection following SAH is still unclear. This study aimed to evaluate the neuroprotective effects and the possible molecular basis of NTN-1 in SAH-induced EBI by modulating neuronal ferroptosis using the filament perforations model of SAH in mice and the hemin-stimulated neuron injury model in HT22 cells. NTN-1 or a vehicle was administered 2 h following SAH. We examined neuronal death, brain water content, neurological score, and mortality. NTN-1 treatment led to elevated survival probability, greater survival of neurons, and increased neurological score, indicating that NTN-1-inhibited ferroptosis ameliorated neuron death in vivo/in vitro in response to SAH. Furthermore, NTN-1 treatment enhanced the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4), which are essential regulators of ferroptosis in EBI after SAH. The findings show that NTN-1 improves neurological outcomes in mice and protects neurons from death caused by neuronal ferroptosis. Furthermore, the mechanism underlying NTN-1 neuroprotection is correlated with the inhibition of ferroptosis, attenuating cell death via the PPARγ/Nrf2/GPX4 pathway and coenzyme Q10-ferroptosis suppressor protein 1 (CoQ10-FSP1) pathway.

Alpha-Asarone Ameliorates Neurological Dysfunction of Subarachnoid Hemorrhagic Rats in Both Acute and Recovery Phases via Regulating the CaMKII-Dependent Pathways.

Early brain injury (EBI) is the leading cause of poor prognosis for patients suffering from subarachnoid hemorrhage (SAH), particularly learning and memory deficits in the repair phase. A recent report has involved calcium/calmodulin-dependent protein kinase II (CaMKII) in the pathophysiological process underlying SAH-induced EBI. Alpha-asarone (ASA), a major compound isolated from the Chinese medicinal herb Acorus tatarinowii Schott, was proven to reduce secondary brain injury by decreasing CaMKII over-phosphorylation in rats' model of intracerebral hemorrhage in our previous report. However, the effect of ASA on SAH remains unclear, and the role of CaMKII in both acute and recovery stages of SAH needs further investigation. In this work, we first established a classic SAH rat model by endovascular perforation and intraperitoneally administrated different ASA doses (10, 20, and 40 mg/kg) 2 h after successful modeling. Then, the short- and long-term neurobehavioral performances were blindly evaluated to confirm ASA's efficacy against SAH. Subsequently, we explored ASA's therapeutic mechanism in both acute and recovery stages using histopathological examination, TUNEL staining, flow cytometry, Western-blot, double-immunofluorescence staining, and transmission electron microscopy (TEM) observation. Finally, KN93, a selective CaMKII inhibitor, was applied in oxyhemoglobin-damaged HT22 cells to explore the role of CaMKII in ASA's neuroprotective effect. The results demonstrated that ASA alleviated short- and long-term neurological dysfunction, reduced mortality and seizure rate within 24 h, and prolonged 14-day survival in SAH rats. Histopathological examination showed a reduction of neuronal damage and a restoration of the hippocampal structure after ASA treatment in both acute and recovery phases of SAH. In the acute stage, the Western-blot and flow cytometer analyses showed that ASA restored E/I balance, reduced calcium overload and CaMKII phosphorylation, and inhibited mitochondrion-involved apoptosis, thus preventing neuronal damage and apoptosis underlying EBI post-SAH. In the recovery stage, the TEM observation, double-immunofluorescence staining, and Western-blot analyses indicated that ASA increased the numbers of synapses and enhanced synaptic plasticity in the ipsilateral hippocampi, probably by promoting NR2B/CaMKII interaction and activating subsequent CREB/BDNF/TrkB signaling pathways. Furthermore, KN93 notably reversed ASA's neuroprotective effect on oxyhemoglobin-damaged HT22 cells, confirming CaMKII a potential target for ASA's efficacy against SAH. Our study confirmed for the first time that ASA ameliorated the SAH rats' neurobehavioral deterioration, possibly via modulating CaMKII-involved pathways. These findings provided a promising candidate for the clinical treatment of SAH and shed light on future drug discovery against SAH.

Reduction of acute radiation-induced brain injury in rats by anlotinib.

OBJECTIVES: Radiation therapy in the treatment of brain tumors also leads to the occurrence of radiation brain injury (RBI). Anlotinib is a small-molecule inhibitor of multi-receptor tyrosine kinase with high selectivity for vascular endothelial growth factor receptor-2. In this study, we constructed a rat model of RBI and investigated the effect of anlotinib on RBI and its mechanism of action through drug intervention during the acute phase of RBI. METHODS: Six-week-old male (Sprague-Dawley) rats were used to construct an animal model of RBI to evaluate the protective effect of anlotinib on acute RBI by histopathological staining, brain edema determination, blood-brain barrier integrity evaluation and quick real time-polymerase chain reaction , ELISA detection of inflammation-related indexes, and western-blot detection of related gene protein expression. RESULTS: Anlotinib reduced the degree of edema in the hippocampal region of rats, improved the pathological morphology of neural cells and vascular endothelial cells, and decreased blood-brain barrier permeability. Anlotinib reduced glial fibrillary acidic protein protein expression in the hippocampal region of rat brain tissue and inhibited astrocyte activation. It inhibited the release of inflammatory factors (interleukin [IL]-6, IL-8 and vascular endothelial growth factor) and down-regulated the expression of janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3) signaling pathway-related proteins. CONCLUSION: This study found that anlotinib has a protective effect against RBI in rats and anlotinib may be a new candidate for the treatment of RBI.

Protective mechanisms of tea polyphenols regulating the PI3K/Akt pathway on early brain injury after subarachnoid hemorrhage in rats.

In recent years, numerous studies have demonstrated that tea polyphenols (TPPs) can exert neuroprotective effects through the regulation of the PI3K/Akt pathway. The objective of this work was to verify whether TPPs could protect against early brain injury in rats after subarachnoid hemorrhage (SAH) by modulating the PI3K/Akt pathway. A total of 150 rats were randomly rolled into control (C), TPP, and SAH groups. The TPP and SAH groups underwent endovascular perforation to induce SAH, while C group received only endovascular needle puncture and saline injection. Brain water content, Evans Blue (EB) extravasation assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Western blot, and RT-PCR analyses were performed. Relative to SAH group, TPP treatment considerably improved neurological function scores following SAH, reduced brain edema, cortical neuronal apoptosis, and blood-brain barrier damage. Levels of aquaporin-4 (AQP4) and apoptosis-related protein Bax were considerably lower in the TPP group than in SAH group. Conversely, levels of anti-apoptotic protein Bcl-2 and tight junction protein Zona occludens 1 (ZO-1) were considerably higher in the TPP group. Furthermore, TPP treatment was found to activate the PI3K/Akt signaling. TPPs can mitigate early brain injury caused by SAH in rats by reducing AQP4 levels, alleviating cortical damage, and attenuating neuronal apoptosis. These findings elucidate the protective mechanisms of TPPs against early brain injury following SAH through the regulation of the PI3K/Akt signaling.

Treatment of pediatric cerebral radiation necrosis using hyperbaric oxygenation.

Introduction: Cerebral radiation necrosis is rarely encountered in pediatric patients. This case report describes a child with cerebral radiation necrosis who was successfully treated using corticosteroids, bevacizumab, and hyperbaric oxygenation. Case report: A 3-year-old boy developed progressive extremity weakness six months after the completion of radiation therapy for the treatment of a neuroepithelial malignancy. Treatment with corticosteroids and bevacizumab was initiated, but his symptoms did not improve, and he was then referred for hyperbaric oxygen therapy. After completing 60 hyperbaric treatments, he experienced significant improvements in mobility, which remained stable over the next year. Discussion: Cerebral radiation necrosis typically presents in children with symptoms of ataxia or headache. Corticosteroids and bevacizumab are common treatments, but hyperbaric oxygen therapy has also been studied as a therapeutic modality for this condition. When considering the use of hyperbaric oxygenation in pediatric patients, careful attention to treatment planning and patient safety can reduce the risks of adverse events such as middle ear barotrauma and confinement anxiety. Conclusion: In addition to other available pharmacologic therapies, hyperbaric oxygenation should be considered for the treatment of pediatric patients with cerebral radiation necrosis.

Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice.

BACKGROUND: Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. METHODS: A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. RESULTS: The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. CONCLUSIONS: Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Risk factors of prognosis in older patients with severe brain injury after surgical intervention.

BACKGROUND: Older patients (aged ≥ 60 years) with severe brain injury have a high mortality and disability rate. The objective of this retrospective study was to assess the clinical risk factors of prognosis in older patients with severe brain injury after surgical intervention and to analyze the prognosis of the surviving group of patients 1 year after discharge. METHODS: Clinical data of older patients with severe brain injury who were admitted to two neurosurgical centers between January 2010 and December 2020 were collected. Patient age, sex, Glasgow Coma Scale (GCS) score at admission, underlying disease, mechanisms of injury, abnormal pupillary reflex, head computed tomography imaging findings (such as hematoma type),intraoperative brain swelling and other factors were reviewed. All the patients were categorized into a good prognosis (survival) group and a poor prognosis (death) group by the Glasgow Outcome Score (GOS); also, the related factors affecting the prognosis were screened and the independent risk factors were identified by the Binary logistic regression analysis. GOS was used to evaluate the prognosis of the surviving group of patients 1 year after discharge. RESULTS: Out of 269 patients, 171 (63.6%) survived, and 98 (36.4%) died during hospitalization. Univariate analysis showed that age, GCS score at admission, underlying diseases, abnormal pupillary reflex, the disappearance of ambient cistern, the midline structure shift, intraoperative brain swelling, oxygen saturation < 90%, and cerebral hernia were risk factors for the prognosis of older patients with severe brain injury after surgical intervention. Multivariate analysis showed that age, underlying diseases, disappearance of ambient cistern, Oxygen saturation < 90% and intraoperative brain swelling were independent risk factors of the prognosis in the population. The effect of surgical intervention differed among various age groups at 1-year follow-up after surgery. CONCLUSIONS: The results of this retrospective study confirmed that age, underlying diseases, disappearance of ambient cistern, intraoperative brain swelling, and oxygen saturation < 90% are associated with poor prognosis in older postoperative patients with severe brain injury. Surgical intervention may improve prognosis and reduce mortality in older patients (age < 75 years). But for those patients (age ≥ 75 years), the prognosis was poor after surgical intervention.

Commentary on "Brain Injury During Transition in the Newborn With Congenital Heart Disease: Hazards of the Preoperative Period".

BRAIN INJURY DURING TRANSITION IN THE NEWBORN WITH CONGENITAL HEART DISEASE: HAZARDS OF THE PREOPERATIVE PERIOD: Jennifer M. Lynch, J. William Gaynor, Daniel J. Licht Seminars in Pediatric Neurology Volume 28, December 2018, Pages 60-65 Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population.