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Key Points: Question: Is an automated surface temperature management device effective in prevention of fever in patients with acute vascular brain injury, and does it improve functional outcomes compared with standard fever care? Findings: In this randomized clinical trial of 677 critically ill patients with stroke, temperature modulation significantly reduced daily mean fever burden compared with standard fever care (0.37 °C-hour vs 0.73 °C-hour), but there was no significant difference in functional outcomes at 3 months. Meaning: Fever prevention in patients with acute vascular brain injury using an automated surface temperature management device reduced fever burden but did not improve functional outcomes. Importance: Fever is associated with worse outcomes in patients with stroke, but whether preventing fever improves outcomes is unclear. Objective: To determine whether fever prevention after acute vascular brain injury is achievable and impacts functional outcome. Design, Setting, and Participants: Open-label randomized clinical trial with blinded outcome assessment that enrolled 686 of 1176 planned critically ill patients with stroke at 43 intensive care units in 7 countries from March 2017 to April 2021 (last date of follow-up was May 12, 2022). Intervention: Patients randomized to fever prevention (n = 339) were targeted to 37.0 °C for 14 days or intensive care unit discharge using an automated surface temperature management device. Standard care patients (n = 338) received standardized tiered fever treatment on occurrence of temperature of 38 °C or greater. Main Outcomes and Measures: Primary outcome was daily mean fever burden: the area under the temperature curve above 37.9 °C (total fever burden) divided by the total number of hours in the acute phase, multiplied by 24 hours (°C-hour). The principal secondary outcome was 3-month functional recovery by shift analysis of the 6-category modified Rankin Scale, which is scored from 0 (no symptoms) to 6 (death). Major adverse events included death, pneumonia, sepsis, and malignant cerebral edema. Results: Enrollment was stopped after a planned interim analysis demonstrated futility of the principal secondary end point. In total, 686 patients were enrolled, and 9 were consented but not randomized, leaving a primary analysis population of 677 patients (254 ischemic stroke, 223 intracerebral hemorrhage, 200 subarachnoid hemorrhage; 345 were female [51%]; median age, 62 years) with 433 (64%) completing the study through 12 months. Daily mean (SD) fever burden was significantly lower in the fever prevention group (0.37 [1.0] °C-hour; range, 0.0-8.0 °C-hour) compared with the standard care group (0.73 [1.1] °C-hour; range, 0.0-10.3 °C-hour) (difference, −0.35 [95% CI, −0.51 to −0.20]; P <.001). Between-group differences for the primary outcome by stroke subtype were −0.10 (95% CI, −0.35 to 0.15) for ischemic stroke, −0.50 (95% CI, −0.78 to −0.22) for intracerebral hemorrhage, and −0.52 (95% CI, −0.81 to −0.23) for subarachnoid hemorrhage (all P <.001 by Wilcoxon rank-sum test). There was no significant difference in functional recovery at 3 months (median modified Rankin Scale score, 4.0 vs 4.0, respectively; odds ratio for a favorable shift in functional outcome, 1.09 [95% CI, 0.81 to 1.46]; P =.54). Major adverse events occurred in 82.2% of participants in the fever prevention group vs 75.9% in the standard care group, including 33.8% vs 34.5% for infections, 14.5% vs 14.0% for cardiac disorders, and 24.5% vs 20.5% for respiratory disorders. Conclusions and Relevance: In patients with acute vascular brain injury, preventive normothermia using an automated surface temperature management device effectively reduced fever burden but did not improve functional outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02996266 This clinical trial compares fever prevention targeted to 37.0 °C for 14 days vs standardized tiered fever treatment on functional outcomes in critically ill patients with stroke. [ABSTRACT FROM AUTHOR]

Aneurysmal subarachnoid hemorrhage (aSAH) not only causes neurological deficits but also influences extracerebral organ functions. The Logistic Organ Dysfunction System (LODS) reliably captures organ dysfunctions and predicts mortality of critically ill patients. This study investigated LODS in the setting of aSAH as a surrogate marker for early brain injury (EBI). Patients with aSAH treated between 2012 and 2020 were retrospectively analyzed. LODS was calculated within 24 h upon admission applying functional parameters for each organ system. The EBI was evaluated based on 1-persistent loss of consciousness, 2-global cerebral edema, and 3-intracranial blood burden. The outcome was assessed with the modified Rankin scale (mRS) at 3-months after ictus (mRS > 2 = unfavorable outcome). A total of 324 patients with a mean age of 55.9 years were included. Severe EBI (EBI grade ≥ 3) was found in 38% (124/324) of patients. Higher LODS score correlated with severe EBI (p < 0.0001) and poor outcome (p < 0.0001). LODS with a cutoff of 7 allowed a reliable discrimination (AUC 78%, p < 0.0001) of patients with severe from those with mild EBI. The LODS-calculation as an early risk stratification and prognostic tool reliably reflected the severity of EBI after aSAH and correlated with outcome. [ABSTRACT FROM AUTHOR]

Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) has been increasingly recognized as a risk factor for delayed cerebral ischemia (DCI). While several clinical and radiological EBI biomarkers have been identified, no tool for systematic assessment of EBI severity has been established so far. This study aimed to develop an EBI grading system based on clinical signs and neuroimaging for estimation of EBI severity at admission. This is a retrospective observational study assessing imaging parameters (intracranial blood amount, global cerebral edema (GCE)), and clinical signs (persistent loss of consciousness [LOC]) representative for EBI. The intracranial blood amount was semi-quantitatively assessed. One point was added for GCE and LOC, respectively. All points were summed up resulting in an EBI grading ranging from 1 to 5. The estimated EBI severity was correlated with progressive GCE requiring decompressive hemicraniectomy (DHC), DCI-associated infarction, and outcome according to the modified Rankin scale (mRS) at 3-month-follow up. A consecutive cohort including 324 aSAH-patients with a mean age of 55.9 years, was analyzed. The probability of developing progressive GCE was 9% for EBI grade 1, 28% for EBI grade 2, 43% for EBI grade 3, 61% for EBI grade 4, and 89% for EBI grade 5. The EBI grading correlated significantly with the need for DHC (r = 0.25, p < 0.0001), delayed infarction (r = 0.30, p < 0.0001), and outcome (r = 0.31, p < 0.0001). An EBI grading based on clinical and imaging parameters allowed an early systematic estimation of EBI severity with a higher EBI grade associated not only with a progressive GCE but also with DCI and poor outcome. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionAs a prevalent cerebrovascular disorder, cerebral infarction (CI) has garnered extensive attention globally due to its high incidence and substantial fatality rate. Ischemia-reperfusion injury (IRI) exacerbates not only neuronal demise but also amplifies neural functional impairment. Tanshinone IIA (Tan IIA) has been identified to confer protection against IRI, yet the precise underlying mechanisms remain elusive. This work aimed to delve into the mechanistic role of Tan IIA in CI, with the goal of furnishing more distinct theoretical substantiation for its clinical application.Initially, a middle cerebral artery embolization model group (MCAO) model was established, followed by the categorization of rats into distinct groups based on different administration modes. Therapeutic effects were evaluated through indices including mortality rate, cerebral tissue water content, CI proportion, and neural functional scoring. Meanwhile, cellular apoptosis rates in hippocampal and cortical tissues, as well as levels of oxidative stress molecules (OSM), Sirtuin 1 (SIRT1), Forkhead box O3 (FOXO3α), and inflammatory factors, were examined to explore the mechanism of action.This work revealed that within varying doses of Tan IIA groups, as dosage escalated, mortality rate, cerebral edema severity, CI proportion, and neural functional scoring gradually diminished. Notably, the 35 mg/kg dose group exhibited the most significant reductions, with decreases of 74.9%, 12.7%, 47.5%, and 54%, respectively. Cellular apoptosis rates in hippocampal and cortical tissues displayed a stepwise descending trend, with the 35 mg/kg dose group showcasing the largest reduction. SIRT1 and FOXO3α proteins exhibited a steady increase, with the 35 mg/kg dose group manifesting respective elevations of 87.9% and 65.5%, the highest among all groups. Antioxidant molecules glutathione (GSH) and superoxide dismutase (SOD) contents progressively increased, whereas malondialdehyde (MDA) and nitric oxide (NO) content decreased. The 35 mg/kg dose group recorded the highest increments of 49.1% and 58.1% for GSH and SOD content, while achieving the greatest reductions of 55.6% and 56.2% for MDA and NO content. Expression of inflammatory factors, namely tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6), gradually declined, with reductions of 42.1%, 32.2%, and 29.1%, respectively, in the 35 mg/kg dose group, exhibiting drastic differences (p < 0.05).In conclusion, this research elucidates that Tan IIA improves cerebral edema and neural function by elevating intracellular expression of SIRT1 and FOXO3α proteins, modulating OSM and inflammatory factors. These findings yielded robust experimental support for the potential use of Tan IIA as a therapeutic agent for CI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI)-induced intracerebral hematoma is a major driver of secondary injury pathology such as neuroinflammation, cerebral edema, neurotoxicity, and blood–brain barrier dysfunction, which contribute to neuronal loss, motor deficits, and cognitive impairment. Cluster of differentiation 47 (CD47) is an antiphagocytic cell surface protein inhibiting hematoma clearance. This study was designed to evaluate the safety and efficacy of blockade of CD47 via intravenous (i.v.) administration of anti-CD47 antibodies following penetrating ballistic-like brain injury (PBBI) with significant traumatic intracerebral hemorrhage (tICH). The pharmacokinetic (PK) profile of the anti-CD47 antibody elicited that antibody concentration decayed over 7 days post-administration. Blood tests and necropsy analysis indicated no severe adverse events following treatment. Cerebral hemoglobin levels were significantly increased after injury, however, anti-CD47 antibody administration at 0.1 mg/kg resulted in a significant reduction in cerebral hemoglobin levels at 72 h post-administration, indicating augmentation of hematoma clearance. Immunohistochemistry assessment of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) demonstrated a significant reduction of GFAP levels in the lesion core and peri-lesional area. Based on these analyses, the optimal dose was identified as 0.1 mg/kg. Lesion volume showed a reduction following treatment. Rotarod testing revealed significant motor deficits in all injured groups but no significant therapeutic benefits. Spatial learning performance revealed significant deficits in all injured groups, which were significantly improved by the last testing day. Anti-CD47 antibody treated rats showed significantly improved attention deficits, but not retention scores. These results provide preliminary evidence that blockade of CD47 using i.v. administration of anti-CD47 antibodies may serve as a potential therapeutic for TBI with ICH. [ABSTRACT FROM AUTHOR]

The kallikrein–kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of bradykinin 2 receptors (B2R). However, the influence of B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI. B2R KO mice (heterozygous, homozygous) and wild-type (WT) littermates (n = 10/group) were subjected to controlled cortical impact (CCI) TBI. Lesion size was evaluated by magnetic resonance imaging up to 90 days after CCI. Motor and memory function were regularly assessed by Neurological Severity Score, Beam Walk, and Barnes maze test. Ninety days after TBI, brains were harvested for immunohistochemical analysis. There was no difference in cortical lesion size between B2R-deficient and WT animals 3 months after injury; however, hippocampal damage was reduced in B2R KO mice (p = 0.03). Protection of hippocampal tissue was accompanied by a significant improvement of learning and memory function 3 months after TBI (p = 0.02 WT vs. KO), whereas motor function was not influenced. Scar formation and astrogliosis were unaffected, but B2R deficiency led to a gene-dose-dependent attenuation of microglial activation and a reduction of CD45+ cells 3 months after TBI in cortex (p = 0.0003) and hippocampus (p < 0.0001). These results suggest that chronic hippocampal neurodegeneration and subsequent cognitive impairment are mediated by prolonged neuroinflammation and B2R. Inhibition of B2R may therefore represent a novel strategy to reduce long-term neurocognitive deficits after TBI. [ABSTRACT FROM AUTHOR]

Preeclampsia (preE) is a hypertensive disorder in pregnancies. It is the third leading cause of mortality among pregnant women and fetuses worldwide, and there is much we have yet to learn about its pathophysiology. One complication includes cerebral edema, which causes a breach of the blood–brain barrier (BBB). Urinary marinobufagenin (MBG) is elevated in a preE rat model prior to developing hypertension and proteinuria. We investigated what effect MBG has on the endothelial cell permeability of the BBB. Human brain microvascular endothelial cells (HBMECs) were utilized to examine the permeability caused by MBG. The phosphorylation of ERK1/2, Jnk, p38, and Src was evaluated after the treatment with MBG. Apoptosis was evaluated by examining caspase 3/7. MBG ≥ 1 nM inhibited the proliferation of HBMECs by 46–50%. MBG induced monolayer permeability, causing a decrease in the phosphorylation of ERK1/2 and the activated phosphorylation of Jnk, p38, and Src. MBG increased the caspase 3/7 expression, indicating the activation of apoptosis. Apoptotic signaling or the disruption of endothelia tight junction proteins was not observed when using the p38 inhibitor as a pretreatment in MBG-treated cells. The MBG-induced enhancement of the HBMEC monolayer permeability occurs by the downregulation of ERK1/2, the activation of Jnk, p38, Src, and apoptosis, resulting in the cleavage of tight junction proteins, and are attenuated by p38 inhibition. [ABSTRACT FROM AUTHOR]

Hyponatremia is the most common electrolyte abnormality encountered in critically ill patients and is linked to heightened morbidity, mortality, and healthcare resource utilization. However, its causal role in these poor outcomes and the impact of treatment remain unclear. Plasma sodium is the main determinant of plasma tonicity; consequently, hyponatremia commonly indicates hypotonicity but can also occur in conjunction with isotonicity and hypertonicity. Plasma sodium is a function of total body exchangeable sodium and potassium and total body water. Hypotonic hyponatremia arises when total body water is proportionally greater than the sum of total body exchangeable cations, that is, electrolyte-free water excess; the latter is the result of increased intake or decreased (kidney) excretion. Hypotonic hyponatremia leads to water movement into brain cells resulting in cerebral edema. Brain cells adapt by eliminating solutes, a process that is largely completed by 48 h. Clinical manifestations of hyponatremia depend on its biochemical severity and duration. Symptoms of hyponatremia are more pronounced with acute hyponatremia where brain adaptation is incomplete while they are less prominent in chronic hyponatremia. The authors recommend a physiological approach to determine if hyponatremia is hypotonic, if it is mediated by arginine vasopressin, and if arginine vasopressin secretion is physiologically appropriate. The treatment of hyponatremia depends on the presence and severity of symptoms. Brain herniation is a concern when severe symptoms are present, and current guidelines recommend immediate treatment with hypertonic saline. In the absence of significant symptoms, the concern is neurologic sequelae resulting from rapid correction of hyponatremia which is usually the result of a large water diuresis. Some studies have found desmopressin useful to effectively curtail the water diuresis responsible for rapid correction. [ABSTRACT FROM AUTHOR]

Background: Posterior reversible encephalopathy syndrome is a rare neurological syndrome that refers to reversible subcortical vasogenic brain edema disorder in patients with acute neurological symptoms. Case presentation: Whether there is a direct causal relationship between pancreatitis and posterior reversible encephalopathy syndrome needs further study. We here report a 39-year-old Chinese woman who was diagnosed with pancreatitis followed by vision disturbance. The patient was finally diagnosed with posterior reversible encephalopathy syndrome. On the basis of this rare case, we analyzed the causes of visual disturbance and proposed diagnostic ideas. Conclusions: For posterior reversible encephalopathy syndrome, early identification and treatment of the primary disease are particularly important. Imaging and clinical characteristics in posterior reversible encephalopathy syndrome are usually reversible. [ABSTRACT FROM AUTHOR]

Neuronal cytotoxic edema is implicated in neuronal injury and death, yet mitigating brain edema with osmotic and surgical interventions yields poor clinical outcomes. Importantly, neuronal swelling and its downstream consequences during early brain development remain poorly investigated, and new treatment approaches are needed. We explored Ca2+-dependent downstream effects after neuronal cytotoxic edema caused by diverse injuries in mice of both sexes using multiphoton Ca2+ imaging in vivo [Postnatal Day (P)12-17] and in acute brain slices (P8-12). After different excitotoxic insults, cytosolic GCaMP6s translocated into the nucleus after a few minutes in a subpopulation of neurons, persisting for hours. We used an automated morphology-detection algorithm to detect neuronal soma and quantified the nuclear translocation of GCaMP6s as the nuclear to cytosolic intensity (N/C ratio). Elevated neuronal N/C ratios occurred concurrently with persistent elevation in Ca2+ loads and could also occur independently from neuronal swelling. Electron microscopy revealed that the nuclear translocation was associated with the increased nuclear pore size. The nuclear accumulation of GCaMP6s in neurons led to neocortical circuit dysfunction, mitochondrial pathology, and increased cell death. Inhibiting calpains, a family of Ca2+-activated proteases, prevented elevated N/C ratios and neuronal swelling. In summary, in the developing brain, we identified a calpain-dependent alteration of nuclear transport in a subpopulation of neurons after disease-relevant insults leading to long-term circuit dysfunction and cell death. The nuclear translocation of GCaMP6 and other cytosolic proteins after acute excitotoxicity can be an early biomarker of brain injury in the developing brain. [ABSTRACT FROM AUTHOR]

Background and purpose: Early diagnosis and the refinement of treatment of patients with intracranial meningiomas have brought quality of life (QoL) and neurocognitive functioning as outcome measures into focus. The aim of this study is a comprehensive assessment of neurocognitive function, quality of life and the presence of depression in meningioma patients before and after surgery. Methods: Patients with MRI diagnosis of intracranial meningioma and indication for surgery were prospectively included. A clinical neuropsychologist performed neurocognitive assessments within 3 months before and 12 months after surgery. The test battery included investigation of selective and divided attention, verbal and figural memory, executive functioning, and word fluency. Self-report questionnaires to assess depressive symptoms, QoL, and disease coping were administered. Raw values and t-values were compared pre-and postoperatively. Outcome was stratified by tumor- and peritumoral brain edema (PTBE) volumes, postoperative resolution of PTBE and WHO grade. The study included 18 predominantly female patients (83%) with a median age of 59 years and mostly CNS WHO grade 1 meningiomas (83%). Results: There was a significant postoperative improvement in the ability to selectively react under stress, in working memory and improved delayed reproduction of verbal and visual memory content. QoL improved regarding a reduction in physical problems, an improvement in energy, and social functioning. There was a trend towards worse preoperative scores in all tests, and greater postoperative improvement in patients with PTBE. Tumor volume had no effect on the measured outcome. The patients did not suffer from depressive symptoms before the surgery but improved postoperatively and most patients had an active, problem-oriented coping strategy. Conclusion: Resection of intracranial meningiomas leads to an improvement in multiple neurocognitive domains and QoL. There is a trend towards poorer preoperative neurocognitive functioning and greater postoperative improvement in patients with PTBE. Depression appears to play a minor role in the context of neurocognitive functioning and disease coping. [ABSTRACT FROM AUTHOR]

The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-β (Aβ) removal was assessed using a fluorescent Aβ intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aβ clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aβ removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aβ. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's. [ABSTRACT FROM AUTHOR]

Purpose: Acute necrotizing encephalopathy (ANE), a rare and severe brain disorder, is typically linked to prior infections. ANE predominantly affects children, with most reported cases attributed to viral infections. However, instances of bacterial-induced ANE are infrequent. Here, we present a case of adult-onset ANE associated with bacterial infection. Case descriptions: The patient exhibited a hyperinflammatory state following a urinary tract bacterial infection, with neurological function rapidly declining into a coma as the illness progressed. Gram culture of blood suggested Escherichia coli infection. A magnetic resonance imaging (MRI) scan of the brain showed symmetrical hyperintense lesions involving bilateral thalami and pons in T2-weighted and fluid-attenuated inversion recovery images. These lesions also presented with diffuse cerebral edema and diffusion restriction and subacute hemorrhage. Based on clinical symptoms and typical brain MRI, ANE was diagnosed, and the patient underwent immunotherapy. Conclusions: This case underscores the occurrence of ANE triggered by bacterial infection, expanding our understanding of the pathogens associated with this condition. It suggests that ANE may be an immune-mediated disorder rather than solely an infectious disease. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) has high mortality. Early brain injury (EBI) is responsible for unfavorable outcomes for patients with SAH. The protective involvement of autophagy in hemorrhagic stroke has been proposed. The transcription factor EB (TFEB) can increase autophagic flux by promoting autophagosome formation and autophagosome-lysosome fusion, and dysregulation of TFEB activity might induce the development of several diseases. However, the biological functions of TFEB in EBI after SAH remain unknown. We established an animal model of SAH by the modified endovascular perforation method. Expression of TFEB and autophagy required genes was measured by western blotting and immunofluorescence staining. SAH grading, brain water content and neurobehavioral functions were evaluated at 24 h post-SAH. Neuronal apoptosis in cerebral cortex was assessed by TUNEL staining and Fluoro Jade B staining. TFEB was downregulated in SAH rats, and its overexpression reduced brain edema and ameliorated neurological deficits of SAH rats. Additionally, the neuronal apoptosis induced by SAH was inhibited by TFEB overexpression. Moreover, TFEB overexpression promoted autophagy after SAH. TFEB overexpression promotes autophagy to inhibit neuronal apoptosis, brain edema and neurological deficits post-SAH. [ABSTRACT FROM AUTHOR]

Purpose: Acute necrotizing encephalopathy (ANE), a rare and severe brain disorder, is typically linked to prior infections. ANE predominantly affects children, with most reported cases attributed to viral infections. However, instances of bacterial-induced ANE are infrequent. Here, we present a case of adult-onset ANE associated with bacterial infection. Case descriptions: The patient exhibited a hyperinflammatory state following a urinary tract bacterial infection, with neurological function rapidly declining into a coma as the illness progressed. Gram culture of blood suggested Escherichia coli infection. A magnetic resonance imaging (MRI) scan of the brain showed symmetrical hyperintense lesions involving bilateral thalami and pons in T2-weighted and fluid-attenuated inversion recovery images. These lesions also presented with diffuse cerebral edema and diffusion restriction and subacute hemorrhage. Based on clinical symptoms and typical brain MRI, ANE was diagnosed, and the patient underwent immunotherapy. Conclusions: This case underscores the occurrence of ANE triggered by bacterial infection, expanding our understanding of the pathogens associated with this condition. It suggests that ANE may be an immune-mediated disorder rather than solely an infectious disease. [ABSTRACT FROM AUTHOR]

Two rehydration protocols currently exist to treat diabetic ketoacidosis (DKA) in pediatric patients aged <21 years: the traditional "one-bag" system and the more recent "twobag" system. This study aimed to evaluate the safety and efficacy of the newer two-bag system versus the well-established one-bag system. The CiNAHL, Cochrane Library, Embase, PubMed, Scopus, and Web of Science databases were comprehensively searched from inception to June 2023 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis framework. Eligible studies were those that reported participants <21 years of age who presented to the emergency room with a clinical diagnosis of DKA. This review was prospectively registered on PROSPERO (CRD42023427551). From the initial screening of 42 studies, 8 unique studies encompassing 583 patients met the eligibility criteria. The analysis yielded no significant intergroup differences in hypoglycemia (odds ratio, 0.61; 95% confidence interval [CI], 0.20-1.87; I2=3%) or mean glucose correction rate (mean difference [MD], 0.04 mg/dL/hr; 95% CI, -13.10 to 13.17; I2=64%). The incidence of cerebral edema was as low (0.17%) across groups, with only one case reported in the one-bag group. Notably, the mean time to DKA resolution (MD, -3.24 h; 95% CI, -5.57 to -0.91; I2=0%) and mean response time for intravenous fluid changes (MD, -32.75 min; 95% CI, -43.21 to -22.29; I2=59%) was lower for the two-bag system. This meta-analysis presents preliminary evidence suggesting that the two-bag system may confer advantages over the one-bag system for selected patients. However, further studies with greater patient stratification based on DKA severity, fluid composition, and protocol are needed to draw definitive conclusions and elucidate the extent of these advantages. [ABSTRACT FROM AUTHOR]

Cerebral ischemia can lead to destruction of the blood—brain barrier (BBB), the main cause of cerebral edema and cerebral infarction. BBB damage is also one of the key factors affecting the result of drug therapy. We studied the protective effect of 5-day pretreatment with protocatechuic aldehyde (PAL) at doses of 10 and 20 mg/kg on BBB function and structure after middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. The infarct volume, behavioral neurological deficit score, and Evans blue content in the brain were estimated. We also evaluated the content of nitric oxide (NO) and activities of inducible and neuronal NO synthases. Expression of aquaporin-4 (AQP-4), occludin, claudin-5, and MMP-3 in the brain tissues was estimated by Western blotting. The BBB ultrastructure was analyzed under an electron microscope. We revealed that PAL at both used doses significantly reduced the neurological deficit score, brain infarct volume, and Evans blue extravasation. Electron microscopy showed that PAL significantly improved the ultrastructure of BBB and alleviated its injury. Pretreatment with PAL increased expression of occludin and claudin-5 and reduced expression of AQP-4 and MMP-3. At the same time, the release of NO and activities of NO synthases were notably inhibited. Our results suggest that PAL can be a promising compound to attenuate cerebral ischemia resulting from occlusion/reperfusion injury via BBB protection. [ABSTRACT FROM AUTHOR]

Background: Aquaporin‐4 (AQP4), predominantly expressed in astrocytes, has been implicated in the development of brain edema following ischemic events. However, its role in post‐stroke neuroinflammation is not fully understood. Methods: Using a middle cerebral artery occlusion (MCAO) mouse model, we assessed AQP4's role in post‐stroke inflammation. Brain tissue slices from male C57BL/6 mice were subjected to immunohistochemistry and western blot post‐MCAO. Additionally, primary astrocytes were isolated for quantitative real‐time PCR and immunofluorescence assays to evaluate the expression of inflammatory markers glial fibrillary acidic protein (GFAP) and AQP4. AQP4 modulation was achieved using viral knockdown and overexpression methods. Neuronal damage was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) tests in co‐culture studies. Results: MCAO mice exhibited a significant upregulation in GFAP. This reactive astrogliosis corresponded with an elevation in inflammatory markers. AQP4 expression responded to this inflammatory trend, peaking at 6 h after OGD and returning to baseline levels at 24 and 48 h. Co‐culture experiments revealed that AQP4(+) astrocytes exacerbated injury in OGD‐treated neurons, as evidenced by increased TUNEL positivity and apoptotic events. Conversely, AQP4(−) astrocytes appeared to have a protective effect. Knockdown of AQP4 resulted in reduced post‐OGD inflammatory response, whereas AQP4 overexpression intensified the injury to neurons post‐OGD. In vivo experiments also confirmed that AQP4 inhibitor TGN‐020 reduced and overexpression of AQP4 increased behavioral abnormalities and brain infarcts. Conclusion: Our findings underscore AQP4's pivotal role in modulating post‐stroke neuroinflammation. Targeting AQP4 may present a novel therapeutic avenue for mitigating ischemia‐induced neuronal damage. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Parkinson's disease (PD) may benefit from deep brain stimulation (DBS). Perifocal brain edema sometimes occurs after DBS surgery, but it is transient and does not affect the final prognosis. Transient deterioration of cognitive function has been reported in patients with frontal edema in the first postoperative week. This study aimed to investigate the effect of Goreisan in preventing edematous changes after DBS and determine the influence of edema on cognition. Methods: We included 29 patients with PD who underwent bilateral subthalamic nucleus (STN) DBS and who were divided into 2 groups: those using (11 patients) and those not using Goreisan (18 patients). At 1 week postoperatively, all patients underwent magnetic resonance imaging. We measured the volume of edema either in the frontal white matter or STN on fluid‐attenuated inversion recovery (FLAIR) images. Finally, brain edema, motor function, and cognitive function were compared between the groups with and without Goreisan. Results: In the FLAIR image 1 week postoperatively, the average postoperative frontal subcortical edema (FE) volume of the group with Goreisan was significantly lower than that without Goreisan (2249 ± 2186 mm3, 6261 ± 7213 mm3, respectively, p = 0.023). Multivariate analysis with age, preoperative Mini‐Mental State Examination (MMSE) score, FE, and peri‐STN edema (SE) as factors, and MMSE at 1 week postoperatively as the dependent variable showed that preoperative MMSE score and SE were significant as associated factors. Conclusions: FE after DBS surgery may be alleviated using Goreisan. SE and preoperative MMSE scores were associated with MMSE scores 1 week postoperatively. Trial Registration: Not applicable [ABSTRACT FROM AUTHOR]

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1–3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation. [ABSTRACT FROM AUTHOR]

The human brain is highly dependent on oxygen, utilizing approximately 20% of the body's oxygen at rest. Oxygen deprivation to the brain can lead to loss of consciousness within seconds and death within minutes. Recent studies have identified regions of the brain with spontaneous episodic hypoxia, referred to as "hypoxic pockets". Hypoxia can also result from impaired blood flow due to conditions such as heart disease, blood clots, stroke, or hemorrhage, as well as from reduced oxygen intake or excessive oxygen consumption caused by factors like low ambient oxygen, pulmonary diseases, infections, inflammation, and cancer. Severe hypoxia in the brain can manifest symptoms similar to Parkinson's disease (PD), including cerebral edema, mood disturbances, and cognitive impairments. Additionally, the development of PD appears to be closely associated with hypoxia and hypoxic pathways. This review seeks to investigate the molecular interactions between hypoxia and PD, emphasizing the pathological role of hypoxic pathways in PD and exploring their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) scans of acute cerebral hemorrhage are often characterized by high-density imaging with occasional mixed density and low-density imaging features. Possible reasons for this are a lack of blood coagulation, extravasation of cerebrospinal fluid, and brain tissue edema. It is rarely due to the accumulation of lipid components associated with hyperlipidemia. In the present case, preoperative lipid tests and the intraoperative finding of a large amount of milky white fluid surrounding the hematoma confirmed that the low-density imaging surrounding the hematoma visible on the CT scan represented a rare case of lipid accumulation. [ABSTRACT FROM AUTHOR]

Objective: To identify brain edema in fetuses with Chiari II malformation using a multiparametric approach including structural T2-weighted, diffusion tensor imaging (DTI) metrics, and MRI-based radiomics. Methods: A single-center retrospective review of MRI scans obtained in fetuses with Chiari II was performed. Brain edema cases were radiologically identified using the following MR criteria: brain parenchymal T2 prolongation, blurring of lamination, and effacement of external CSF spaces. Fractional anisotropy (FA) values were calculated from regions of interest (ROI), including hemispheric parenchyma, internal capsule, and corticospinal tract, and compared group-wise. After 1:1 age matching and manual single-slice 2D segmentation of the fetal brain parenchyma using ITK-Snap, radiomics features were extracted using pyradiomics. Areas under the curve (AUCs) of the features regarding discriminating subgroups were calculated. Results: Ninety-one fetuses with Chiari II underwent a total of 101 MRI scans at a median gestational age of 24.4 weeks and were included. Fifty scans were visually classified as Chiari II with brain edema group and showed significantly reduced external CSF spaces compared to the nonedema group (9.8 vs. 18.3 mm, p < 0.001). FA values of all used ROIs were elevated in the edema group (p < 0.001 for all ROIs). The 10 most important radiomics features showed an AUC of 0.81 (95%CI: 0.71, 0.91) for discriminating between Chiari II fetuses with and without edema. Conclusions: Brain edema in fetuses with Chiari II is common and radiologically detectable on T2-weighted fetal MRI sequences, and DTI-based FA values and radiomics features provide further evidence of microstructure differences between subgroups with and without edema. Clinical relevance statement: A more severe phenotype of fetuses with Chiari II malformation is characterized by prenatal brain edema and more postnatal clinical morbidity and disability. Fetal brain edema is a promising prenatal MR imaging biomarker candidate for optimizing the risk-benefit evaluation of selection for fetal surgery. Key Points: Brain edema of fetuses prenatally diagnosed with Chiari II malformation is a common, so far unknown, association. DTI metrics and radiomics confirm microstructural differences between the brains of Chiari II fetuses with and without edema. Fetal brain edema may explain worse motor outcomes in this Chiari II subgroup, who may substantially benefit from fetal surgery. [ABSTRACT FROM AUTHOR]

Objectives: Ischemic edema is associated with worse clinical outcomes, especially in large infarcts. Computed tomography (CT)–based densitometry allows direct quantification of absolute edema volume (EV), which challenges indirect biomarkers like midline shift (MLS). We compared EV and MLS as imaging biomarkers of ischemic edema and predictors of malignant infarction (MI) and very poor clinical outcome (VPCO) in early follow-up CT of patients with large infarcts. Materials and methods: Patients with anterior circulation stroke, large vessel occlusion, and Alberta Stroke Program Early CT Score (ASPECTS) ≤ 5 were included. VPCO was defined as modified Rankin scale (mRS) ≥ 5 at discharge. MLS and EV were quantified at admission and in follow-up CT 24 h after admission. Correlation was analyzed between MLS, EV, and total infarct volume (TIV). Multivariable logistic regression and receiver operating characteristics curve analyses were performed to compare MLS and EV as predictors of MI and VPCO. Results: Seventy patients (median TIV 110 mL) were analyzed. EV showed strong correlation to TIV (r = 0.91, p < 0.001) and good diagnostic accuracy to classify MI (EV AUC 0.74 [95%CI 0.61–0.88] vs. MLS AUC 0.82 [95%CI 0.71–0.94]; p = 0.48) and VPCO (EV AUC 0.72 [95%CI 0.60–0.84] vs. MLS AUC 0.69 [95%CI 0.57–0.81]; p = 0.5) with no significant difference compared to MLS, which did not correlate with TIV < 110 mL (r = 0.17, p = 0.33). Conclusion: EV might serve as an imaging biomarker of ischemic edema in future studies, as it is applicable to infarcts of all volumes and predicts MI and VPCO in patients with large infarcts with the same accuracy as MLS. Clinical relevance statement: Utilization of edema volume instead of midline shift as an edema parameter would allow differentiation of patients with large and small infarcts based on the extent of edema, with possible advantages in the prediction of treatment effects, complications, and outcome. Key Points: • CT densitometry–based absolute edema volume challenges midline shift as current gold standard measure of ischemic edema. • Edema volume predicts malignant infarction and poor clinical outcome in patients with large infarcts with similar accuracy compared to MLS irrespective of the lesion extent. • Edema volume might serve as a reliable quantitative imaging biomarker of ischemic edema in acute stroke triage independent of lesion size. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). Methods: Patients with LHI within 24 h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3 months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5 mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. Results: Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82 ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144–6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841–10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56 ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236–6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534–9.637, p = 0.004). Conclusions: Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies. [ABSTRACT FROM AUTHOR]

Background: Patients with traumatic brain injury (TBI) with large contusions make up a specific TBI subtype. Because of the risk of brain edema worsening, elevated cerebral perfusion pressure (CPP) may be particularly dangerous. The pressure reactivity index (PRx) and optimal cerebral perfusion pressure (CPPopt) are new promising perfusion targets based on cerebral autoregulation, but they reflect the global brain state and may be less valid in patients with predominant focal lesions. In this study, we aimed to investigate if patients with TBI with significant contusions exhibited a different association between PRx, CPP, and CPPopt in relation to functional outcome compared to those with small/no contusions. Methods: This observational study included 385 patients with moderate to severe TBI treated at a neurointensive care unit in Uppsala, Sweden. The patients were classified into two groups: (1) significant contusions (> 10 mL) and (2) small/no contusions (but with extra-axial or diffuse injuries). The percentage of good monitoring time (%GMT) with intracranial pressure > 20 mm Hg; PRx > 0.30; CPP < 60 mm Hg, within 60–70 mm Hg, or > 70 mm Hg; and ΔCPPopt less than − 5 mm Hg, ± 5 mm Hg, or > 5 mm Hg was calculated. Outcome (Glasgow Outcome Scale-Extended) was assessed after 6 months. Results: Among the 120 (31%) patients with significant contusions, a lower %GMT with CPP between 60 and 70 mm Hg was independently associated with unfavorable outcome. The %GMTs with PRx and ΔCPPopt ± 5 mm Hg were not independently associated with outcome. Among the 265 (69%) patients with small/no contusions, a higher %GMT of PRx > 0.30 and a lower %GMT of ΔCPPopt ± 5 mm Hg were independently associated with unfavorable outcome. Conclusions: In patients with TBI with significant contusions, CPP within 60–70 mm Hg may improve outcome. PRx and CPPopt, which reflect global cerebral pressure autoregulation, may be useful in patients with TBI without significant focal brain lesions but seem less valid for those with large contusions. However, this was an observational, hypothesis-generating study; our findings need to be validated in prospective studies before translating them into clinical practice. [ABSTRACT FROM AUTHOR]

Background: The Coiled-Coil Domain-Containing Protein 88 A (CCDC88A) gene encodes the actin-binding protein Girdin, which plays important roles in maintaining the actin cytoskeleton and in cell migration and was recently associated with a specific form of epileptic encephalopathy. Biallelic protein-truncating variants of CCDC88A have been considered responsible for progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO)-like syndrome. To date, only three consanguineous families with loss-of-function homozygous variants in the CCDC88A gene have been reported. The described patients share many clinical features, such as microcephaly, neonatal hypotonia, seizures, profound developmental delay, face and limb edema, and dysmorphic features, with a similar appearance of the eyes, nose, mouth, and fingers. Case presentation: We report on a child from a nonconsanguineous family who presented with profound global developmental delay, severe epilepsy, and brain malformations, including subcortical band heterotopia. The patient harbored two heterozygous pathogenic variants in the trans configuration in the CCDC88A gene, which affected the coiled-coil and C-terminal domains. Conclusions: We detail the clinical and cerebral imaging data of our patient in the context of previously reported patients with disease-causing variants in the CCDC88A gene, emphasizing the common phenotypes, including cortical malformations, that warrant screening for sequence variants in this gene. [ABSTRACT FROM AUTHOR]

Background: Early severe cerebral edema and chronic hydrocephalus are the primary cause of poor prognosis in patients with subarachnoid hemorrhage (SAH). This study investigated the role of cerebrospinal fluid (CSF) inflammatory cytokines and coagulation factors in the development of severe cerebral edema and chronic hydrocephalus in patients with SAH. Methods: Patients with SAH enrolled in this study were categorized into mild and severe cerebral edema groups based on the Subarachnoid Hemorrhage Early Brain Edema Score at admission. During long-term follow-up, patients were further classified into hydrocephalus and non-hydrocephalus groups. CSF samples were collected within 48 h post-SAH, and levels of inflammatory cytokines and coagulation factors were measured. Univariate and multivariate logistic regression analyses were performed to identify independent factors associated with severe cerebral edema and chronic hydrocephalus. The correlation between inflammatory cytokines and coagulation factors was further investigated and validated in a mouse model of SAH. Results: Seventy-two patients were enrolled in the study. Factors from the extrinsic coagulation pathway and inflammatory cytokines were associated with both severe cerebral edema and chronic hydrocephalus. Coagulation products thrombin-antithrombin complexes (TAT) and fibrin, as well as inflammatory cytokines IL-1β, IL-2, IL-5, IL-7, and IL-4, were independently associated with severe cerebral edema. Additionally, Factor VII, fibrin, IL-2, IL-5, IL-12, TNF-α, and CCL-4 were independently associated with chronic hydrocephalus. A positive correlation between extrinsic coagulation factors and inflammatory cytokines was observed. In the SAH mouse model, tissue plasminogen activator was shown to alleviate neuroinflammation and cerebral edema, potentially by restoring glymphatic-meningeal lymphatic function. Conclusions: Elevated levels of inflammatory cytokines and extrinsic coagulation pathway factors in the CSF are associated with the development of early severe cerebral edema and chronic hydrocephalus following SAH. These factors are interrelated and may contribute to post-SAH glymphatic-meningeal lymphatic dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Chronic and acute mountain sickness is known worldwide, but most of the available information comes from the eastern continent (Himalayas) without taking into account the west which has the most recent group located at altitude, the Andes. The aim of this study was to synthesize the evidence on the prevalence of acute and chronic mountain sickness in Latin American countries (LATAM). Methods: A systematic search of the variables of interest was performed until July 8, 2023 in the Web of Science, Scopus, PubMed and Embase databases. We included studies that assessed the prevalence of mountain sickness in high-altitude inhabitants (>1500 m.a.s.l) who lived in a place more than 12 months. These were analyzed by means of a meta-analysis of proportions. To assess sources of heterogeneity, subgroup analyses and sensitivity analyses were performed by including only studies with low risk of bias and excluding extreme values (0 or 10,000 ratio). PROSPERO (CRD42021286504). Results: Thirty-nine cross-sectional studies (10,549 participants) met the inclusion criteria. We identified 5 334 and 2 945 events out of 10,000 with acute and chronic mountain sickness in LATAM countries. The most common physiological alteration was polycythemia (2,558 events), while cerebral edema was the less common (46 events). Clinical conditions were more prevalent at high altitudes for both types of MS. Conclusion: Acute mountain sickness (AMS) occurs approximately in 5 out of 10 people at high altitude, while chronic mountain sickness (CMS) occurs in 3 out of 10. The most frequent physiological alteration was polycythemia and the least frequent was cerebral edema. [ABSTRACT FROM AUTHOR]

Brain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na+ and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9‐phenanthrol (9‐Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain‐targeting T7 (HAIYPRH)‐modified lipid nanoparticle (LNP) encapsulated 9‐Phe (9‐Phe@T7‐LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9‐Phe for treating brain edema in vivo. These results demonstrated that 9‐Phe@T7‐LNP can penetrate the intact blood‐brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9‐Phe@T7‐LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9‐Phe@T7‐LNP scavenged oxygen‐free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9‐Phe@T7‐LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema. [ABSTRACT FROM AUTHOR]

Background and Purpose: The optic nerve sheath diameter (ONSD) is a commonly used estimate of intracranial pressure (ICP). The rationale behind this is that pressure changes in the cerebrospinal fluid affect the optic nerve subarachnoid space (ONSAS) thickness. Still, possible effects on other compartments of the optic nerve sheath (ONS) have not been studied. This is the first study ever to analyze all measurable compartments of the ONS for associations with elevated ICP. Methods: We measured changes in ICP and changes in ONS compartments in 75 patients treated with invasive ICP monitoring at the Karolinska University Hospital. Associations between changes in ICP and changes in ONS compartments were estimated with generalized estimating equations. The potential to identify elevated ICP was assessed with the area under the receiver operating characteristic curve (AUROC) for ONS compartments associated with ICP changes. Results: Both ONSAS and perioptic dura mater thickness were significantly associated with changes in ICP in multivariable modeling. ONSAS was the only compartment that independently predicted changes in ICP, with an AUROC of 0.69 for predicting ICP increase. Still, both the perioptic dura mater thickness and the optic nerve diameter added value in predicting ICP changes in multivariable modeling. Conclusions: The results from this study challenge the current understanding of the mechanism behind the association between ICP and ONSD. Contrary to the common opinion that ONSAS is the only affected compartment, this study shows a more complex picture. It suggests that all ONS compartments may add value in predicting changes in ICP. [ABSTRACT FROM AUTHOR]

Stroke is a major contributor to mortality and morbidity worldwide and the most common cause of epilepsy in the elderly in high income nations. In recent years, it has become increasingly evident that both ischemic and hemorrhagic strokes induce dysfunction of the blood–brain barrier (BBB), and that this impairment can contribute to epileptogenesis. Nevertheless, studies directly comparing BBB dysfunction and poststroke epilepsy (PSE) are largely absent. Therefore, this review summarizes the role of BBB dysfunction in the development of PSE in animal models and clinical studies. There are multiple mechanisms whereby stroke induces BBB dysfunction, including increased transcytosis, tight junction dysfunction, spreading depolarizations, astrocyte and pericyte loss, reactive astrocytosis, angiogenesis, matrix metalloproteinase activation, neuroinflammation, adenosine triphosphate depletion, oxidative stress, and finally cell death. The degree to which these effects occur is dependent on the severity of the ischemia, whereby cell death is a more prominent mechanism of BBB disruption in regions of critical ischemia. BBB dysfunction can contribute to epileptogenesis by increasing the risk of hemorrhagic transformation, increasing stroke size and the amount of cerebral vasogenic edema, extravasation of excitatory compounds, and increasing neuroinflammation. Furthermore, albumin extravasation after BBB dysfunction contributes to epileptogenesis primarily via increased transforming growth factor β signaling. Finally, seizures themselves induce BBB dysfunction, thereby contributing to epileptogenesis in a cyclical manner. In repairing this BBB dysfunction, pericyte migration via platelet‐derived growth factor β signaling is indispensable and required for reconstruction of the BBB, whereby astrocytes also play a role. Although animal stroke models have their limitations, they provide valuable insights into the development of potential therapeutics designed to restore the BBB after stroke, with the ultimate goal of improving outcomes and minimizing the occurrence of PSE. In pursuit of this goal, rapamycin, statins, losartan, semaglutide, and metformin show promise, whereby modulation of pericyte migration could also be beneficial. [ABSTRACT FROM AUTHOR]

Introduction: Endovascular treatment (EVT) is a therapeutic option for cerebral venous thrombosis (CVT); however, its benefit over conservative medical management has not been proven. Whether the current patient selection practices are appropriate for EVT is unclear. Methods: This was a nationwide study of the 2016–2020 National Inpatient Sample database. Adult CVT patients and EVT treatments were identified. Patient demographics, medical comorbidities, CVT risk factors, and CVT manifestations were identified. Presence of radiographic signs of advanced and severe CVT (venous infarction, cerebral edema, and intracranial hemorrhage) was recorded. Primary and secondary outcomes were good discharge outcomes and in-hospital mortality, respectively. Results: A total of 17,130 CVT patients were identified, and 56.7% had good discharge outcomes, while 4.6% died during hospitalization. 945 (5.5%) received EVT, and EVT patients were more likely to have cerebral infarction (35.4 vs. 21.8%, p < 0.001), edema (35.4 vs. 20.1%, p < 0.001), and hemorrhage (37.6 vs. 19.7%, p < 0.001). After multivariable adjustments, EVT for patients without infarction, edema, or hemorrhage was moderately associated with higher odds of good outcomes (OR 1.86 [95% CI 0.98–3.53], p = 0.059) and resulted in zero deaths. However, with the increasing burden of radiographic signs of advanced CVT measured by the cumulative presence of infarction, edema, and hemorrhage, EVT was associated with decreasing odds of good outcomes and increasing odds of in-hospital mortality compared to medical management (interaction p = 0.046 and 0.029, respectively). Conclusions: EVT may lead to higher rates of favorable hospitalization outcomes in patients who have not yet developed overt parenchymal manifestations of backpressure changes; presence of infarction, edema, and hemorrhage may diminish the short-term effectiveness of EVT. [ABSTRACT FROM AUTHOR]

Glioblastomas synthesize, bear receptors for, and respond to bradykinin, triggering migration and proliferation. Since centrifugal migration into uninvolved surrounding brain tissue occurs early in the course of glioblastoma, this attribute defeats local treatment attempts and is the primary reason current treatments almost always fail. Stopping bradykinin-triggered migration would be a step closer to control of this disease. The recent approval and marketing of an oral plasma kallikrein inhibitor, berotralstat (Orladeyo™), and pending FDA approval of a similar drug, sebetralstat, now offers a potential method for reducing local bradykinin production at sites of bradykinin-mediated glioblastoma migration. Both drugs are approved for treating hereditary angioedema. They are ideal for repurposing as a treatment adjunct in glioblastoma. Furthermore, it has been established that peritumoral edema, a common problem during the clinical course of glioblastoma, is generated in large part by locally produced bradykinin via kallikrein action. Both brain edema and the consequent use of corticosteroids both shorten survival in glioblastoma. Therefore, by (i) migration inhibition, (ii) growth inhibition, (iii) edema reduction, and (iv) the potential for less use of corticosteroids, berotralstat may be of service in treatment of glioblastoma, slowing disease progression. This paper recounts the details and past research on bradykinin in glioblastoma and the rationale of treating it with berotralstat. [ABSTRACT FROM AUTHOR]

Aims: Incidence of acute mountain sickness (AMS) ranges from 40%–90%, with high‐altitude cerebral edema (HACE) representing a life‐threatening end stage of severe AMS. However, practical and convenient preventive strategies for HACE are lacking. Remote ischemic preconditioning (RIPC) has demonstrated preventive effects on ischemia‐ or hypoxia‐induced cardiovascular and cerebrovascular diseases. This study aimed to investigate the potential molecular mechanism of HACE and the application of RIPC in preventing HACE onset. Methods: A hypobaric hypoxia chamber was used to simulate a high‐altitude environment of 7000 meters. Metabolomics and metabolic flux analysis were employed to assay metabolite levels. Transcriptomics and quantitative real‐time PCR (q‐PCR) were used to investigate gene expression levels. Immunofluorescence staining was performed on neurons to label cellular proteins. The fluorescent probes Mito‐Dendra2, iATPSnFR1.0, and CMTMRos were used to observe mitochondria, ATP, and membrane potential in cultured neurons, respectively. TUNEL staining was performed to detect and quantify apoptotic cell death. Hematoxylin and eosin (H&E) staining was utilized to analyze pathological changes, such as tissue swelling in cerebral cortex samples. The Rotarod test was performed to assess motor coordination and balance in rats. Oxygen–glucose deprivation (OGD) of cultured cells was employed as an in vitro model to simulate the hypoxia and hypoglycemia induced by RIPC in animal experiments. Results: We revealed a causative perturbation of glucose metabolism in the brain preceding cerebral edema. Ischemic preconditioning treatment significantly reprograms glucose metabolism, ameliorating cell apoptosis and hypoxia‐induced energy deprivation. Notably, ischemic preconditioning improves mitochondrial membrane potential and ATP production through enhanced glucose‐coupled mitochondrial metabolism. In vivo studies confirm that RIPC alleviates cerebral edema, reduces cell apoptosis induced by high‐altitude hypoxia, and improves motor dysfunction resulting from cerebral edema. Conclusions: Our study elucidates the metabolic basis of HACE pathogenesis. This study provides a new strategy for preventing HACE that RIPC reduces brain edema through reprogramming metabolism, highlighting the potential of targeting metabolic reprogramming for neuroprotective interventions in neurological diseases caused by ischemia or hypoxia. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Superior vena cava syndrome (SVCS) is commonly caused by mediastinal malignancies. Early identification through clinical signs and imaging is critical to avoid complications including cerebral and laryngeal edema, and cardiogenic shock. We present a case of large cell neuroendocrine carcinoma causing superior and inferior vena cava compression that responded well to radiotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Elevated intracranial pressure (ICP) in patients with cerebral lesions has garnered considerable attention in research. It often manifests as a common symptom in conditions such as intracranial tumors, intracerebral hemorrhage, and cerebral edema. This paper provides an overview of ICP concepts, discusses the advantages and disadvantages of traditional monitoring methods, explores the physiological and anatomical aspects of the optic nerve sheath, examines the utility of ultrasound measurement of optic nerve sheath diameter (ONSD) in both nervous system and nonnervous system disorders, and outlines the cutoff values and normal ranges for assessing elevated ICP using ultrasound measurement of ONSD. The review underscores ultrasound measurement of ONSD as a promising noninvasive, safe, straightforward, and repeatable examination technique for various diseases. Nevertheless, the lack of standardized cutoff values for elevated ICP remains a challenge. Summarizing studies on optic nerve sheaths is crucial for enhancing the efficacy of ultrasound measurement of ONSD in assessing ICP. [ABSTRACT FROM AUTHOR]

Adapting the mechanical strength between the implant materials and the brain tissue is crucial for the postoperative treatment of glioblastoma. However, no related study has been reported. Herein, we report an injectable lipoic acid‑iron (LA-Fe) hydrogel (LFH) that can adapt to the mechanical strength of various brain tissues, including human brain tissue, by coordinating Fe3+ into a hybrid hydrogel of LA and its sodium salt (LANa). When LFH, which matches the mechanical properties of mouse brain tissue (337 ± 8.06 Pa), was injected into the brain resection cavity, the water content of the brain tissue was maintained at a normal level (77%). Similarly, LFH did not induce the activation or hypertrophy of glial astrocytes, effectively preventing brain edema and scar hyperplasia. Notably, LFH spontaneously degrades in the interstitial fluid, releasing LA and Fe3+ into tumor cells. The redox couples LA/DHLA (dihydrolipoic acid, reduction form of LA in cells) and Fe3+/Fe2+ would regenerate each other to continuously provide ROS to induce ferroptosis and activate immunogenic cell death. As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the efficacy of tumor-immunotherapy and promoted tumor ferroptosis. The injectable hydrogel that adapted the mechanical strength of tissues shed a new light for the tumor postoperative treatment. TOC Graph: The first injectable hydrogel that can adapt the mechanical strength of different brain tissues including human brain has been developed for the GBM postoperative treatment without the involvement of anti-tumor drugs by coordinating Fe3+ into the hybrid hydrogel of B vitamin lipoic acid (LA) and its sodium salt (LANa). [Display omitted] • By coordinating Fe3+ into the hybrid hydrogel of lipoic acid (LA) and its sodium salt (LANa) formed an injectable hydrogel. • The LA-Fe hydrogel (LFH) can adapt the mechanical strength of multiple brain tissues including human brain. • The LFH circumvented the foreign body reaction caused by material implantation, and effectively inhibited tumor recurrence. • As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the tumor-immunotherapy efficacy and promoted the tumor ferroptosis. [ABSTRACT FROM AUTHOR]

In patients suffering from focal drug-resistant epilepsy, intracranial explorations are the gold standard for identifying the epileptogenic zone and evaluating the possibility of a surgical resection. Amongst them, stereoelectroencephalography (SEEG), using depth electrodes, is a safe procedure. However, complications occur on average in 2% of cases, notably haemorrhages or infections. Vasogenic cerebral oedema constitutes a rarely reported complication. Amongst the 85 patients explored with SEEG between January 2017 and September 2023, three had a clinically and electrophysiologically relevant vasogenic cerebral oedema. In these three patients, the surgical procedure was uneventful. In all three as well, electrodes exploring areas away from the epileptogenic zone recorded some unexpected focal delta slowing with clinically asymptomatic superimposed discharges, a pattern so far only reported in cases of bleeding. Moreover, one patient experienced confusion 10 days after explantation. Post-explantation magnetic resonance imaging showed, in all three patients, a vasogenic oedema that fully resolved a few months later. We did not identify any contributing factors, and there were no particularities concerning the number of electrodes, their implantation site or the recording duration. Focal delta slowing and rhythmic discharges during SEEG can indicate a vasogenic oedema. Clinical consequences can occur after explantation. Evolution is favourable but this misleading pattern must be identified. [ABSTRACT FROM AUTHOR]

Brain edema is a critical complication arising from stroke and traumatic brain injury (TBI) with an important impact on patient recovery and can lead to long-term consequences. Therapeutic options to reduce edema progression are limited with variable patient outcomes. Aquaporin 4 (AQP4) is a water channel that allows bidirectional water diffusion across the astrocyte membrane and participates in the distinct phases of cerebral edema. The absence or inhibition of this channel has been demonstrated to ameliorate edema and brain damage. The endocannabinoid system (ECS) is a neuromodulator system with a wide expression in the brain and its activation has shown neuroprotective properties in diverse models of neuronal damage. This review describes and discusses the major features of ECS and AQP4 and their role during brain damage, observing that ECS stimulation reduces edema and injury size in diverse models of brain damage, however, the relationship between AQP4 expression and dynamics and ECS activation remains unclear. The research on these topics holds promising therapeutic implications for the treatment of brain edema following stroke and TBI. [ABSTRACT FROM AUTHOR]

A subarachnoid hemorrhage (SAH) is life-threatening bleeding into the subarachnoid space that causes brain damage. Growing evidence has suggested that melatonin provides neuroprotection following SAH. Exploring the mechanisms underlying melatonin-mediated neuroprotection contributes to its clinical application in SAH. The plasma and cerebrospinal fluid (CSF) were collected from SAH patients, and SAH mice were established via pre-chiasmatic injection. Circodz3 expression, levels of IL-1β and TNF-α, brain water content, neurological and beam-waling scores were determined. Ferroptosis was evaluated by analyzing levels of iron, lipid ROS, MDA, and GSH. The colocalization of circodz3 and Iba-1 was analyzed by immunofluorescence staining. Interaction of circodz3 and HuR was determined with RNA pull-down and RNA immunoprecipitation assays. Herein, we found that circodz3 was highly abundant in SAH patients and mice. Colocalization of circodz3 and Iba-1 in the left hemisphere of SAH mice suggested the implication of circodz3 in regulating microglia activation following SAH. Melatonin alleviated brain edema, neurological impairment, and microglia activation and inhibited circodz3 expression in SAH mice. Moreover, melatonin inhibited M1 polarization, oxidative stress and ferroptosis and restrained circodz3 expression in primary microglia following SAH. These effects were abrogated by circodz3 overexpression. Circodz3 knockdown inhibited ferroptosis and M1 polarization of BV2 microglia after SAH. Circodz3 interacted with HuR to facilitate β-Trcp1-mediated ubiquitination and degradation, thus restraining the expression of SLC7A11 and GPX4. Collectively, melatonin exerted neuroprotection following SAH via inhibiting ferroptosis and M1 polarization through the circodz3/HuR axis. Our study suggests potential application of melatonin in the treatment of SAH. Highlights: CircODZ3 is highly abundant in the plasma and cerebrospinal fluid from SAH patients. Melatonin protects against SAH by inhibiting circodz3 expression. Silencing of circodz3 inhibits ferroptosis and M1 polarization of BV2 microglia. Circodz3 interacts with HuR to promote its ubiquitination and degradation. Circodz3 degrades HuR to reduce SLC7A11 and GPX4 expression. [ABSTRACT FROM AUTHOR]

Interest in naturally occurring phytochemicals has been on the increase, they are believed to reduce the risk of brain disorders. Hispidulin (HN) is a phenolic flavonoid compound with various pharmacological and biological effects on the central nervous system. It belongs to the flavone class of flavonoids. It can be found in different plant materials, especially fruits and vegetables. The literature used in this review was collected from credible scientific databases including ScienceDirect, Scopus, PubMed, Google Scholar, and Hindawi without time restriction, using relevant keywords, such as HN, brain, central nervous system, flavonoids, and flavones. HN was discovered to possess pro-apoptotic properties, act as an antioxidant, inhibit cytokine production and toll-like receptor 4 expression, as well as impede nuclear factor kappa beta and mitogen-activated protein kinase B. HN was also found to inhibit lipid peroxidation in vitro and reduce brain edema in mice. These pharmacological potentials suggest that HN is a promising candidate for neuroprotection in CNS disorders like depression and epilepsy. This review provides an update on the scientific literature concerning how these activities could help provide various forms of neuroprotection in the CNS. Additional experimental data on the effects of HN in models of neurological disorders and neuroprotection should be explored further. Based on the current study, HN is a promising candidate for neuroprotection of the CNS. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild‐type (WT) C57BL/6 mice and TRPV1−/− mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood–brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin‐stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post‐ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post‐ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin‐induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin‐stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c‐Jun NH2‐terminal kinase mitogen‐activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria‐related neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Patients undergoing solid-organ transplantation (SOT) face a tumultuous journey. Prior to transplant, their medical course is characterized by organ dysfunction, diminished quality of life, and reliance on organ support, all of which are endured in hopes of reaching the haven of organ transplantation. Peritransplant altered mental status may indicate neurologic insults acquired during transplant and may have long-lasting consequences. Even years after transplant, these patients are at heightened risk for neurologic dysfunction from a myriad of metabolic, toxic, and infectious causes. This review provides a comprehensive examination of causes, diagnostic approaches, neuroimaging findings, and management strategies for altered mental status in SOT recipients. Given their complexity and the numerous etiologies for neurologic dysfunction, liver transplant patients are a chief focus in this review; however, we also review lesser-known contributors to neurological injury across various transplant types. From hepatic encephalopathy to cerebral edema, seizures, and infections, this review highlights the importance of recognizing and managing pre- and posttransplant neurological complications to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Patients with cancer experience high rates of alterations in mental status. The mechanisms for altered mental status (AMS) in this population are manifold. The cancer itself may cause AMS through direct invasion of the central nervous system or as metastatic leptomeningeal spread. However, cancer patients are also vulnerable to tumor-associated complications such as seizures, cerebral edema, strokes, or cancer treatment-related complications such as infections, direct neural injury from radiation or chemotherapy, edema, or dysregulated autoimmune response from immunotherapies. Both during treatment and as sequelae, patients may suffer neurocognitive complications from chemotherapy and radiation, medications or opportunistic infections, as well as toxic–metabolic, nutritional, and endocrine complications. In this review, we describe a clinical approach to the cancer patient presenting with AMS and discuss the differential drivers of AMS in this patient population. While common etiologies of AMS in noncancer patients (toxic–metabolic or infectious encephalopathy, delirium) are also applicable to cancer patients, we additionally provide a cancer-specific differential diagnosis that warrants special consideration in the cancer patient with AMS. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure. [ABSTRACT FROM AUTHOR]

Background: Clinically, ischemic reperfusion injury is the main cause of stroke injury. This study aimed to assess the effectiveness of fingolimod in suppressing inflammation caused by ischemic brain injury and explore its pharmacological mechanisms. Methods: In total, 75 male Sprague-Dawley rats were randomly and equally assigned to five distinct groups: sham, middle cerebral artery occlusion/ reperfusion (MCAO/R) surgery, fingolimod low-dose (F-L), fingolimod medium-dose (F-M), and fingolimod high-dose (F-H). Neurobehavioral tests, 2,3,5-triphenyltetrazolium chloride staining, and the brain tissue drying-wet method were conducted to evaluate neurological impairment, cerebral infarction size, and brain water content. Enzyme-linked immunosorbent assay was employed to quantify pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) protein levels. Western blotting and immunohistochemical staining were performed to assess high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa-B p65 (NF-κBp65) levels. Results: Rats in the F-L, F-M, and F-H groups exhibited lower Longa scores, reduced infarction volumes, and decreased brain edema than those in the MCAO/R group. Additionally, the F-L, F-M, and F-H groups exhibited lower serum levels of IL-1β, IL-6, and TNF-α than those of the MCAO/R group. Additionally, F-L, F-M, and F-H treatments resulted in decreased HMGB1, TLR4, and NF-κBp65 protein expression levels in the hippocampus of MCAO/R rats. Conclusions: Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

• Emodin reduces HIBD in neonatal mice. • Emodin improves neurologic recovery of neonatal mice after HIBD. • Emodin can exert neuroprotective effects on HIBD by inhibiting neuronal apoptosis. Neonatal hypoxic-ischemic brain damage (HIBD) can lead to mortality and severe neurological dysfunction. Emodin is a natural anthraquinone derivative that is easy to obtain and has good neuroprotective effects. This study aimed to investigate the neuroprotective effect of emodin on neonatal mouse HIBD. The modified Rice–Vannucci method was used to induce HIBD in mouse pups. Eighty postnatal 7-day (P7) C57BL/6 neonatal mice were randomly divided into the sham group (sham), vehicle group (vehicle), and emodin group (emodin). TTC staining and whole-brain morphology were used to evaluate the infarct volume and morphology of the brain tissue. The condition of the neurons was observed through Nissl staining, HE staining, FJC staining, immunofluorescence and Western blot for NeuN, IBA-1, and GFAP. The physiological status of the mice was evaluated using weight measurements. The neural function of the mice was assessed using the negative geotaxis test, righting reflex test, and grip test. TUNEL staining was used to detect apoptosis in brain cells. Finally, Western blot and immunofluorescence were used to detect the expression levels of apoptosis-related proteins, such as P53, cleaved caspase-3, Bax and Bcl-2, in the brain. Experiments have shown that emodin can reduce the cerebral infarct volume, brain oedema, neuronal apoptosis, and degeneration and improve the reconstruction of brain tissue morphology, neuronal morphology, physiological conditions, and neural function. Additionally, emodin inhibited the expression of proapoptotic proteins such as P53, Bax and cleaved caspase-3 and promoted the expression of the antiapoptotic protein Bcl-2. Emodin attenuates HIBD by inhibiting neuronal apoptosis in neonatal mice. [ABSTRACT FROM AUTHOR]

Introduction: Peritumoral brain edema (PTBE) has been widely reported with many brain tumors, especially with glioma. Since the blood–brain barrier (BBB) is essential for maintaining minimal permeability, any alteration in the interaction of BBB components, specifically in astrocytes and tight junctions (TJ), can result in disrupting the homeostasis of the BBB and making it severely leaky, which subsequently generates edema. Objective: This study aimed to evaluate the functional gliovascular unit of the BBB by examining changes in the expression of claudin (CLDN) genes and the expression of transient receptor potential (TRP) membrane channels, additionally to define the correlation between their expressions. The evaluation was conducted using in vitro spheroid swelling models and tumor samples from glioma patients with PTBE. Results: The results of the spheroid model showed that the genes TRPC3, TRPC4, TRPC5, and TRPV1 were upregulated in glioma cells either wild‐type isocitrate dehydrogenase 1 (IDH1) or the IDH1 R132H mutant, with or without NaCl treatment. Furthermore, TRP genes appeared to adversely correlate with the up regulation of CLDN1, CLDN3, and CLDN5 genes. Besides, the upregulation of TRPC1 and TRPC4 in IDH1mt‐R132H glioma cells. On the other hand, the correlation analysis revealed different correlations between different proteins in PTBE. CLDN1 exhibits a slight positive correlation with CLDN3. Similarly, TRPV1 displays a slight positive correlation with TRPC1. In contrast, TRPC4 shows a slight negative correlation with TRPC5. On the other hand, TRPC3 demonstrates a slight positive correlation with TRPC5, while the non‐PTBE analysis highlights a moderate positive correlation between CLDN1 and TRPM4 while CLDN3 exhibits a moderate negative correlation with TRPC4. Additionally, CLDN5 demonstrates a slight negative correlation with TRPC4 but a moderate positive correlation with TRPC3. Furthermore, TRPC1 have a slight negative correlation with TRPV1, TRPC3 exhibiting a slight positive correlation with TRPC4, and TRPV1 showing a slight negative correlation with TRPC5. Conclusion: As a conclusion, the current study provided evidence of a slight negative correlation between TRPs and CLDN gene expression in PTBE patients and confirmatory results with some of the genes in cell model of edema. [ABSTRACT FROM AUTHOR]