Ac2-26 activated the AKT1/GSK3ß pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. METHODS: Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups were injected with shRNA, inhibitor and agonist of GSK3ß respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein ß(S100ß) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. RESULTS: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3ß. The agonist of GSK3ß recovered the protection of Ac2-26 in presence of shRNA. CONCLUSIONS: Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3ß pathway.

Progesterone induces neuroprotection associated with immune/inflammatory modulation in experimental traumatic brain injury.

An imbalance of immune/inflammatory reactions aggravates secondary brain injury after traumatic brain injury (TBI) and can deteriorate clinical prognosis. So far, not enough therapeutic avenues have been found to prevent such an imbalance in the clinical setting. Progesterone has been shown to regulate immune/inflammatory reactions in many diseases and conveys a potential protective role in TBI. This study was designed to investigate the neuroprotective effects of progesterone associated with immune/inflammatory modulation in experimental TBI. A TBI model in adult male C57BL/6J mice was created using a controlled contusion instrument. After injury, the mice received consecutive progesterone therapy (8 mg/kg per day, i.p.) until euthanized. Neurological deficits were assessed via Morris water maze test. Brain edema was measured via the dry-wet weight method. Immunohistochemical staining and flow cytometry were used to examine the numbers of immune/inflammatory cells, including IBA-1 + microglia, myeloperoxidase + neutrophils, and regulatory T cells (Tregs). ELISA was used to detect the concentrations of IL-1ß, TNF-α, IL-10, and TGF-ß. Our data showed that progesterone therapy significantly improved neurological deficits and brain edema in experimental TBI, remarkably increased regulatory T cell numbers in the spleen, and dramatically reduced the activation and infiltration of inflammatory cells (microglia and neutrophils) in injured brain tissue. In addition, progesterone therapy decreased the expression of the pro-inflammatory cytokines IL-1ß and TNF-α but increased the expression of the anti-inflammatory cytokine IL-10 after TBI. These findings suggest that progesterone administration could be used to regulate immune/inflammatory reactions and improve outcomes in TBI.

Efficacy of propofol-based anesthesia against risk of brain swelling during craniotomy: A meta-analysis of randomized controlled studies.

STUDY OBJECTIVE: This meta-analysis aimed to compare the risk of brain swelling during craniotomy between propofol-based and volatile-based anesthesia. DESIGN: Meta-analysis of randomized controlled trials (RCTs). SETTING: Operating room. INTERVENTION: Propofol-based anesthesia. PATIENTS: Adult patients undergoing craniotomy. MEASUREMENTS: Databases, including EMBASE, MEDLINE, Google Scholar, and Cochrane Library, were searched from inception to April 2023. The primary outcome was the risk of brain swelling, while the secondary outcomes included the impact of anesthetic regimens on surgical and recovery outcomes, as well as the risk of hemodynamic instability. MAIN RESULTS: Our meta-analysis of 17 RCTs showed a significantly lower risk of brain swelling (risk ratio [RR]: 0.85, p = 0.03, I2 = 21%, n = 1976) in patients receiving propofol than in those using volatile agents, without significant differences in surgical time or blood loss between the two groups. Moreover, propofol was associated with a lower intracranial pressure (ICP) (mean difference: -4.06 mmHg, p < 0.00001, I2 = 44%, n = 409) as well as a lower risk of tachycardia (RR = 0.54, p = 0.005, I2 = 0%, n = 822) and postoperative nausea/vomiting (PONV) (RR = 0.59, p = 0.002, I2 = 19%, n = 1382). There were no significant differences in other recovery outcomes (e.g., extubation time), risk of bradycardia, hypertension, or hypotension between the two groups. Subgroup analysis indicated that propofol was not associated with a reduced risk of brain swelling when compared to individual volatile agents. Stratified by craniotomy indications, propofol reduced brain swelling in elective craniotomy, but not in emergency craniotomy (e.g., traumatic brain injury), when compared to volatile anesthetics. CONCLUSIONS: By reviewing the available evidence, our results demonstrate the beneficial effects of propofol on the risk of brain swelling, ICP, PONV, and intraoperative tachycardia. In emergency craniotomy for traumatic brain injury and subarachnoid hemorrhage, brain swelling showed no significant difference between propofol and volatile agents. Further large-scale studies are warranted for verification.

Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema.

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI)1. Noradrenaline levels are increased after TBI2-4, and the amplitude of the increase in noradrenaline predicts both the extent of injury5 and the likelihood of mortality6. Glymphatic impairment is both a feature of and a contributor to brain injury7,8, but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.

Acute Mountain Sickness and High Altitude Cerebral Edema in Women: A Scoping Review-UIAA Medical Commission Recommendations.

Derstine, Mia, Dominique Jean, Beth A. Beidleman, Jacqueline Pichler Hefti, David Hillebrandt, Lenka Horakova, Susi Kriemler, Kasté Mateikaité-Pipiriené, Peter Paal, Alison Rosier, Marija Andjelkovic, and Linda E. Keyes. Acute mountain sickness and high altitude cerebral edema in women: A scoping review-UIAA Medical Commission recommendations. High Alt Med Biol. 24:259-267, 2023. Background: Acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) are illnesses associated with rapid ascent to altitudes over 2,500 m in unacclimatized lowlanders. The aim of this scoping review is to summarize the current knowledge on sex differences in the epidemiology, pathophysiology, symptomatology, and treatment of AMS and HACE, especially in women. Methods and Results: The UIAA Medical Commission convened an international author team to review women's health issues at high altitude and to publish updated recommendations. Pertinent literature from PubMed and Cochrane was identified by keyword search combinations (including AMS, HACE, and high altitude), with additional publications found by hand search. The primary search focus was for articles assessing lowland women sojourning at high altitude. Results: The literature search yielded 7,165 articles, 37 of which were ultimately included. The majority of publications included did not find women at increased risk for AMS or HACE. There was extremely limited sex-specific data on risk factors or treatment. Conclusions: There is a limited amount of data on female-specific findings regarding AMS and HACE, with most publications addressing only prevalence or incidence with regard to sex. As such, general prevention and treatment strategies for AMS and HACE should be used regardless of sex.

Early posttraumatic brain injury tranexamic acid prevents blood-brain barrier hyperpermeability and improves surrogates of neuroclinical recovery.

BACKGROUND: Tranexamic acid (TXA) given early, but not late, after traumatic brain injury (TBI) appears to improve survival. This may be partly related to TXA-driven profibrinolysis and increased leukocyte (LEU)-mediated inflammation when administered late post-injury. We hypothesized that early TXA (1 hour post-TBI), blunts penumbral, blood-brain barrier (BBB) leukocyte-endothelial cell (LEU-EC) interactions and microvascular permeability, in vivo when compared with late administration (24 hours post-TBI). METHODS: CD1 male mice (n = 35) were randomized to severe TBI (injury by controlled cortical impact; injury: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy followed by intravenous saline (placebo) at 1 hour, or TXA (30 mg/kg) at 1 hour or 24 hours. At 48 hours, in vivo pial intravital microscopy visualized live penumbral LEU-EC interactions and BBB microvascular fluorescent albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (motor, sensory, reflex, and balance assessments) and body weight loss recovery at 1 and 2 days after injury. Analysis of variance with Bonferroni correction assessed intergroup differences ( p < 0.05). RESULTS: One-hour, but not 24-hour, TXA improved Garcia Neurological Test performance on day 1 post-TBI compared with placebo. Both 1 hour and 24 hours TXA similarly improved day 1 weight loss recovery, but only 1 hour TXA significantly improved weight loss recovery on day 2 compared with placebo ( p = 0.04). No intergroup differences were found in LEU rolling or adhesion between injured animal groups. Compared with untreated injured animals, only TXA at 1 hour reduced BBB permeability. CONCLUSION: Only early post-TBI TXA consistently improves murine neurological recovery. Tranexamic acid preserves BBB integrity but only when administered early. This effect appears independent of LEU-EC interactions and demonstrates a time-sensitive effect that supports only early TXA administration.

Short-term topiramate treatment prevents radiation-induced cytotoxic edema in preclinical models of breast-cancer brain metastasis.

BACKGROUND: Brain edema is a common complication of brain metastases (BM) and associated treatment. The extent to which cytotoxic edema, the first step in the sequence that leads to ionic edema, vasogenic edema, and brain swelling, contributes to radiation-induced brain edema during BM remains unknown. This study aimed to determine whether radiation-associated treatment of BM induces cytotoxic edema and the consequences of blocking the edema in preclinical models of breast-cancer brain metastases (BCBM). METHODS: Using in vitro and in vivo models, we measured astrocytic swelling, trans-electric resistance (TEER), and aquaporin 4 (AQP4) expression following radiation. Genetic and pharmacological inhibition of AQP4 in astrocytes and cancer cells was used to assess the role of AQP4 in astrocytic swelling and brain water intake. An anti-epileptic drug that blocks AQP4 function (topiramate) was used to prevent cytotoxic edema in models of BM. RESULTS: Radiation-induced astrocytic swelling and transient upregulation of AQP4 occurred within the first 24 hours following radiation. Topiramate decreased radiation-induced astrocytic swelling and loss of TEER in astrocytes in vitro, and acute short-term treatment (but not continuous administration), prevented radiation-induced increase in brain water content without pro-tumorigenic effects in multiple preclinical models of BCBM. AQP4 was expressed in clinical BM and breast-cancer cell lines, but AQP4 targeting had limited direct pro-tumorigenic or radioprotective effects in cancer cells that could impact its clinical translation. CONCLUSIONS: Patients with BM could find additional benefits from acute and temporary preventive treatment of radiation-induced cytotoxic edema using anti-epileptic drugs able to block AQP4 function.

Ischemic Preconditioning Alleviates Cerebral Ischemia-Reperfusion Injury by Interfering With Glycocalyx.

Ischemic preconditioning (IPC) could protect the blood-brain barrier (BBB), but the underlying mechanism is not well understood. This preclinical study aimed to investigate whether glycocalyx could be involved in the neuroprotective effect of IPC on cerebral ischemia-reperfusion injury (IRI) and the possible mechanism in rat middle cerebral artery occlusion/reperfusion (MCAO/R) model. Neurological deficit scores, infarct volume, and brain edema were measured to assess the neuroprotection of IPC. Several serum biomarkers related to glycocalyx damage, such as hyaluronic acid (HA), heparan sulfate (HS), and syndecan-1 (SYND1), were evaluated, and their changes were normalized to the ratio of postoperative/preoperative concentration. Western blot and immunofluorescence were used to evaluate the content and cellular location of HA-related metabolic enzymes. This study found that (1) IPC improved brain infarction and edema, neurological impairment, and BBB disruption in IRI rats; (2) IPC significantly up-regulated HA ratio and down-regulated HS ratio, but did not affect SYND1 ratio compared with the IRI group. Moreover, the increased HA ratio was negatively related to brain edema and neurological deficit score. (3) IPC affected HA metabolism by up-regulating hyaluronate synthase-1 and matrix metalloproteinase-2, and down-regulating hyaluronidase-1 in brain tissue. Together, this is the first report that the neuroprotective effect of IPC on IRI may be mediated through interfering with glycocalyx in the MCAO/R model.

Effect of intraoperative goal-directed fluid therapy on the postoperative brain edema in patients undergoing high-grade glioma resections: a study protocol of randomized control trial.

INTRODUCTION: Brain edema is the most frequent postoperative complication after brain tumor resection, especially in patients with high-grade glioma. However, the effect of SVV-based goal-directed fluid therapy (GDFT) on postoperative brain edema and the prognosis remain unclear. METHODS AND ANALYSIS: This is a prospective, randomized, double-blinded, parallel-controlled trial aiming to observe whether stroke volume variation (SVV)-based GDFT could improve the postoperative brain edema in patients undergoing supratentorial high-grade gliomas compared with traditional fluid therapy. The patient will be given 3 ml/kg hydroxyethyl starch solution when the SVV is greater than 15% continuously for more than 5 min intraoperatively. The primary outcome will be postoperative cerebral edema volume on brain CT within 24 h. ETHICS AND DISSEMINATION: This trial has been registered at ClinicalTrials.gov (NCT03323580) and approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (reference number: KY2017-067-02). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to the subject fields. TRIAL REGISTRATION: ClinicalTrials.gov NCT03323580 (First posted: October 27, 2017; Last update posted: February 11, 2022).

(-)-Epicatechin gallate prevents inflammatory response in hypoxia-activated microglia and cerebral edema by inhibiting NF-κB signaling.

High-altitude cerebral edema (HACE), a potentially lethal disease, is associated with a time-dependent exposure to altitude-related hypobaric hypoxia (HH) and has reportedly been associated with microglia hyperactivation. Catechins are substances with good antioxidant properties, among which (-)-epigallocatechin gallate (EGCG) may play a neuroprotective role through the inhibition of microglia overactivation; however, the function of its analog- (-)-epicatechin gallate (ECG)-requires further elucidation. The aim of the present study was to investigate whether ECG prevented HACE by inhibiting HH-activated microglia. Primary microglia exposed to lipopolysaccharide (LPS)/ATP were co-treated with EGCG, ECG, and (-)-epigallocatechin, and ECG and EGCG exerted significant anti-inflammatory and neuroprotective effects. ECG inhibited the NF-κB pathway to prevent the activation of microglia induced by 1% O2. In addition, ECG ameliorated the increase in brain water content and aquaporin 4 expression induced by HH in mice. ECG also reduced the number of Iba1+ microglia in the brain, the release of proinflammatory factors, and the recruitment of microglia to blood vessels in HH-exposed mice. The outcomes of the present study revealed that ECG alleviated hypoxic hyperactivated microglia, reduced the neuroinflammation and blood-brain barrier permeability, and prevented HACE by inhibiting NF-κB signaling.

Mild Hypothermia Protects Brain Injury After Intracerebral Hemorrhage in Mice Via Enhancing the Nrdp1/MyD88 Signaling Pathway.

BACKGROUND: Mild hypothermia has been identified to reduce brain injury following intracerebral hemorrhage (ICH) by protecting neuron cells through several pathways. However, the role of hypothermia in brain function following ICH and the related mechanisms have not been well identified. Ubiquitination-mediated inflammation plays important roles in the pathogenesis of immune diseases. The experiment analyzed anti-inflammatory effects of mild hypothermia following ICH. METHODS: The model of ICH was induced by injecting autologous blood. Neuregulin receptor degradation protein-1 (Nrdp1) and downstream molecule were analyzed. In addition, brain inflammatory response, brain edema, and neurological functions of ICH mice were also assessed. RESULTS: We found that mild hypothermia attenuated proinflammatory factors production after ICH. Mild hypothermia significantly inhibited BBB injury, water content, and neurological damage following ICH in vivo. Moreover, mild hypothermia also increased Nrdp1/MyD88 levels and thus affect neuronal apoptosis and inflammation. CONCLUSIONS: Taken together, these results suggest that mild hypothermia can attenuate the neuroinflammatory response and neuronal apoptosis after ICH through the regulation of the Nrdp1 levels.

Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats.

High altitude cerebral edema (HACE) is a potentially life-threatening disease encountered at high altitudes. However, effective methods for HACE prophylaxis are limited. Convincing evidence confirms that oxidative stress induced by hypobaric hypoxia (HH) is one of the main factors that account for the development of HACE. 5,6,7,8-Tetrahydroxyflavone (THF), a flavone with four consecutive OH groups in ring A, exhibited excellent antioxidant activity in vitro and could attenuate HH induced injury in vivo. The aim of this study was to investigate the protective effect of THF against HACE and its underlying mechanisms. THF administration significantly suppressed HH induced oxidative stress by reducing the formation of hydrogen peroxide and malondialdehyde, by increasing the levels of glutathione and superoxide dismutase in brain tissue. Simultaneously, THF administration inhibited inflammatory responses by decreasing the levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in serum and brain tissue. In addition, THF administration mitigated the energy metabolism disorder induced by HACE as evidenced by decreased levels of lactic acid, lactate dehydrogenase and pyruvate kinase as well as increased ATP levels and ATPase activities. Furthermore, THF administration decreased the expression of matrix metalloproteinase-9, aquaporin 4, hypoxia-inducible factor-1α and vascular endothelial growth factor, which attenuated blood-brain barrier (BBB) disruption and brain edema. Additionally, THF administration improved HACE induced cognitive dysfunction. These results show that THF is a promising agent in the prevention and treatment of HACE.

Acutely Inhibiting AQP4 With TGN-020 Improves Functional Outcome by Attenuating Edema and Peri-Infarct Astrogliosis After Cerebral Ischemia.

Background: Ischemic stroke is one of the leading causes of human death and disability. Brain edema and peri-infarct astrocyte reactivity are crucial pathological changes, both involving aquaporin-4 (AQP4). Studies revealed that acute inhibition of AQP4 after stroke diminishes brain edema, however, its effect on peri-infarct astrocyte reactivity and the subacute outcome is unclear. And if diffusion-weighted imaging (DWI) could reflect the AQP4 expression patterns is uncertain. Methods: Rats were subjected to middle cerebral artery occlusion (MCAO) and allocated randomly to TGN 020-treated and control groups. One day after stroke, brain swelling and lesion volumes of the rats were checked using T2-weighted imaging (T2-WI). Fourteen days after stroke, the rats successively underwent neurological examination, T2-WI and DWI with standard b-values and ultra-high b-values, apparent diffusion coefficient (ADC) was calculated correspondingly. Finally, the rats' brains were acquired and used for glial fibrillary acidic protein (GFAP) and AQP4 immunoreactive analysis. Results: At 1 day after stroke, the TGN-020-treated animals exhibited reduced brain swelling and lesion volumes compared with those in the control group. At 14 days after stroke, the TGN-020-treated animals showed fewer neurological function deficits and smaller lesion volumes. In the peri-infarct region, the control group showed evident astrogliosis and AQP4 depolarization, which were reduced significantly in the TGN-020 group. In addition, the ultra-high b-values of ADC (ADCuh) in the peri-infarct region of the TGN-020 group was higher than that of the control group. Furthermore, correlation analysis revealed that peri-infarct AQP4 polarization correlated negatively with astrogliosis extent, and ADCuh correlated positively with AQP4 polarization. Conclusion: We found that acutely inhibiting AQP4 using TGN-020 promoted neurological recovery by diminishing brain edema at the early stage and attenuating peri-infarct astrogliosis and AQP4 depolarization at the subacute stage after stroke. Moreover, ADCuh could reflect the AQP4 polarization.

Downregulation of NF-κB by Shp-1 Alleviates Cerebral Venous Sinus Thrombosis-Induced Brain Edema Via Suppression of AQP4.

Aquaporin 4 (AQP4), a water channel protein, has been well studied in arterial stroke-induced brain edema. However, the role of AQP4 in cerebral venous sinus thrombosis (CVST) has not been reported. Here, we showed that AQP4 expression was increased in the brain of a rat CVST model, whereas inhibition of AQP4 decreased cerebral edema. Subsequent experiments showed that Shp-1 (Src homology 2-containing phosphatase-1) expression and NF-κB phosphorylation were upregulated after CVST. We found that Shp-1 inhibition resulted in enhancement of NF-κB activation and increased AQP4 expression accompanied by aggravated brain edema. We further showed that NF-κB inhibition led to decreased AQP4 expression and subsequent attenuation of brain edema but had no significant effect on Shp-1 expression. These results provide the first evidence suggesting that downregulation of NF-κB by Shp-1 alleviates CVST-induced brain edema through suppression of AQP4.

Protection of Vasoactive Intestinal Peptide on the Blood-Brain Barrier Dysfunction Induced by Focal Cerebral Ischemia in Rats.

OBJECTIVE: To investigate the effects of vasoactive intestinal peptide on the blood brain barrier function after focal cerebral ischemia in rats. MATERIALS AND METHODS: Rats were intracerebroventricular injected with vasoactive intestinal peptide after a two hours middle cerebral artery occlusion. Functional outcome was studied with the neurological severity score. The brain edema and the infarction were evaluated via histology. The blood brain barrier permeability was assessed using Evans Blue dye injection method. We also measure the apoptosis of brain microvascular endothelial cells and brain levels of B-cell leukemia-2 protein by immunohistochemical analysis and western blotting, respectively. RESULTS: In contrast to the cases treated with vehicle at 72 h after middle cerebral artery occlusion, the treatment with vasoactive intestinal peptide significantly (P < 0.05) reduced the neurological severity score, the brain edema and infarct volume. The Evans Blue leakage and brain water content were obviously reduced (P < 0.05) in vasoactive intestinal peptide-treated rats compared with those of control rats at 72 and 96 h after stroke. In addition, vasoactive intestinal peptide decreased the numbers of terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling positive endothelial cells and increased the protein levels of B-cell leukemia-2 in the ischemic hemisphere at 72 h after ischemia. CONCLUSIONS: Our data suggest that treatment with vasoactive intestinal peptide ameliorates the blood brain barrier function, contributing to reduce in brain damage both morphologically and functionally in the ischemic rat. This amelioration may be associated with attenuation in apoptosis of brain microvascular endothelial cells by increased B-cell leukemia-2 expression.

Beta blockade in TBI: Dose-dependent reductions in BBB leukocyte mobilization and permeability in vivo.

BACKGROUND: Traumatic brain injury (TBI) is accompanied by a hyperadrenergic catecholamine state that can cause penumbral neuroinflammation. Prospective human studies demonstrate improved TBI survival with beta blockade (bb), although mechanisms remain unclear. We hypothesized that deranged post-TBI penumbral blood brain barrier (BBB) leukocyte mobilization and permeability are improved by bb. METHODS: CD1 male mice (n = 64) were randomly assigned to severe TBI-controlled cortical impact: 6 m/s velocity, 1 mm depth, 3 mm diameter-or sham craniotomy, and IP injection of either saline or propranolol (1, 2, or 4 mg/kg) every 12 hours for 2 days. At 48 hours, in vivo pial intravital microscopy visualized live endothelial-leukocyte (LEU) interactions and BBB microvascular leakage. Twice daily clinical recovery was assessed by regaining of lost body weight and the Garcia Neurological Test (motor, sensory, reflex, balance assessments). Brain edema was determined by hemispheric wet-to-dry ratios. RESULTS: Propranolol after TBI reduced both in vivo LEU rolling and BBB permeability in a dose-dependent fashion compared with no treatment (p < 0.001). Propranolol reduced cerebral edema (p < 0.001) and hastened recovery of lost body weight at 48 hours (p < 0.01). Compared with no treatment (14.9 ± 0.2), 24-hour Garcia Neurologic Test scores were improved with 2 (15.8 ± 0.2, p = 0.02) and 4 (16.1 ± 0.1, p = 0.001) but not with 1 mg/kg propranolol. CONCLUSION: Propranolol administration reduces post-TBI LEU mobilization and microvascular permeability in the murine penumbral neurovasculature and leads to reduced cerebral edema. This is associated with hastened recovery of post-TBI weight loss and neurologic function with bb treatment. Dose-dependent effects frame a mechanistic relationship between bb and improved human outcomes after TBI.

Inhibition of AMPA (α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate) Receptor Reduces Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice.

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) is thought to cause acute brain injury, but the role remains poorly understood in subarachnoid hemorrhage (SAH). This study was conducted to evaluate if AMPAR activation induces acute blood-brain barrier (BBB) disruption after SAH. C57BL/6 male adult mice (n = 117) underwent sham or filament perforation SAH modeling, followed by a random intraperitoneal injection of vehicle or two dosages (1 mg/kg or 3 mg/kg) of a selective noncompetitive AMPAR antagonist perampanel (PER) at 30 min post-modeling. The effects were evaluated by mortality, neurological scores, and brain water content at 24-48 h and video electroencephalogram monitoring, immunostaining, and Western blotting at 24 h post-SAH. PER significantly suppressed post-SAH neurological impairments, brain edema, and BBB disruption. SAH developed epileptiform spikes without obvious convulsion, which were also inhibited by PER. Western blotting showed that the expression of AMPAR subunits GluA1 and GluA2 was unchanged after SAH, but they were significantly activated after SAH. PER prevented post-SAH activation of GluA1/2, associated with the suppression of post-SAH induction of tenascin-C, a causative mediator of post-SAH BBB disruption. Meanwhile, an intracerebroventricular injection of a subtype-selective GluA1/2 agonist augmented the activation of GluA1/2 and the induction of tenascin-C in brain capillary endothelial cells and aggravated post-SAH BBB disruption without increases in epileptiform spikes. Neurological impairments and brain edema were not correlated with the occurrence of epileptiform spikes. This study first showed that AMPAR plays an important role in the development of post-SAH BBB disruption and can be a novel therapeutic target against it.

Perihematomal Edema After Intracerebral Hemorrhage: An Update on Pathogenesis, Risk Factors, and Therapeutic Advances.

Intracerebral hemorrhage (ICH) has one of the worst prognoses among patients with stroke. Surgical measures have been adopted to relieve the mass effect of the hematoma, and developing targeted therapy against secondary brain injury (SBI) after ICH is equally essential. Numerous preclinical and clinical studies have demonstrated that perihematomal edema (PHE) is a quantifiable marker of SBI after ICH and is associated with a poor prognosis. Thus, PHE has been considered a promising therapeutic target for ICH. However, the findings derived from existing studies on PHE are disparate and unclear. Therefore, it is necessary to classify, compare, and summarize the existing studies on PHE. In this review, we describe the growth characteristics and relevant underlying mechanism of PHE, analyze the contributions of different risk factors to PHE, present the potential impact of PHE on patient outcomes, and discuss the currently available therapeutic strategies.

Protective mechanism of FoxO1 against early brain injury after subarachnoid hemorrhage by regulating autophagy.

INTRODUCTION: Early brain injury (EBI) plays a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). Autophagy and apoptosis may share a common molecular inducer that regulates the process of cell death. FoxO1, as a key regulator of neuronal autophagy which is involved in apoptosis, has not been reported in SAH rats. This work was to investigate the protective and anti-inflammatory effects of FoxO1 on EBI after SAH by regulating autophagy. METHODS: In this study, we constructed the SAH model. In experiment I, low dose (50 µl of 1 × 108  IU/ml) or high dose (50 µl of 1 × 1010  IU/ml) of FoxO1 gene overexpressed adenovirus vector was injected into the lateral ventricle of rats before SAH. In experiment II, we reported the effect of FoxO1 overexpress on nerve function recovery, oedema, BBB leakage, neuronal death in rats after SAH through autophagy regulation. Post-SAH evaluation included neurological function score, brain water content, evans blue exosmosis, pathological changes, inflammatory response and apoptosis. RESULTS: The experiment I showed that either low or high dose of ad-FoxO1 could significantly improve nerve function, reduce cerebral water content and reduce blood-brain barrier (BBB) destruction in rats, indicating that ad-FoxO1 had a protective effect on brain injury in rats EBI after SAH. In addition, ad-FoxO1 promoted autophagy in rat hippocampal tissue, as evidenced by accumulation of LC3II/I and Beclin-1 and degradation of p62. Furthermore, ad-FoxO1 inhibited the inflammatory response and apoptosis of rat hippocampal neurons after SAH. The experiment II showed that both ad-FoxO1 and rapamycin attenuated the injury of nerve function in rats after SAH, and this synergistic effect further reduced cerebral edema and evansblue extravasation, decreased hippocampus neuronal cell apoptosis, and declined inflammatory response. However, this was contrary to the results of chloroquine. These findings suggested that FoxO1 regulated the neural function of EBI after SAH through the autophagy pathway. CONCLUSIONS: The findings in this study was beneficial for identifying the novel therapeutic target for the treatment of SAH.