Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke.

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema.

Sepsis after middle cerebral artery occlusion exacerbates peripheral oxidative stress in a sex-specific manner.

Ischemic stroke occurs due a blockage in the blood flow to the brain, leading to damage to the nervous system. The prevalent morbidities resulting from stroke include post-stroke infection, as sepsis. Additionally, oxidative stress is recognized for inducing functional deficits in peripheral organs during sepsis. Therefore, sex differences in stroke exist and we aimed to investigate the peripheral oxidative stress caused by sepsis after stroke in male and female rats. Wistar rats (male and female) were divided into sham+sham, middle cerebral artery occlusion (MCAO) + sham, sham+ cecal ligation and perforation (CLP) and MCAO+CLP groups to males and female rats. Animals were subjected to MCAO or sham and after 7 days, were subjected to sepsis by CLP or sham. After 24 h, serum, total brain, lung, liver, heart, and spleen were collected. Brain edema, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, oxidative damage to lipids and proteins, and catalase activity were evaluated. Brain edema was observed only in male rats in MCAO+CLP group compared to MCAO+sham. Regarding MPO activity, an increase was verified in male in different organs and serum in MCAO+CLP group. For N/N levels, the increase was more pronounced in females submitted to MCAO+CLP. In general, to oxidative stress, an increase was only observed in animals exposed to MCAO+CLP, or with a greater increase in this group compared to the others. The findings provided the first indication that animals exposed to MCAO exhibit a heightened vulnerability to the harmful impacts of sepsis, as evidenced by brain edema and peripheral oxidative stress, and this susceptibility is dependent of sex.

Evaluating the interaction between hemorrhagic transformation and cerebral edema on functional outcome after ischemic stroke.

BACKGROUND: Hemorrhagic transformation (HT) and cerebral edema (CED) are both major complications following ischemic stroke, but few studies have evaluated their overlap. We evaluated the frequency and predictors of CED/HT overlap and whether their co-occurrence impacts functional outcome more than each in isolation. METHODS: 892 stroke patients enrolled in a prospective study had follow-up CT imaging evaluated for HT and CED; the latter was quantified using the ratio of hemispheric CSF volumes (with hemispheric CSF ratio < 0.90 used as the CED threshold). The interaction between HT and CED on functional outcome (using modified Rankin Scale at 3 months) was compared to that for each condition separately. RESULTS: Among the 275 (31%) who developed HT, 233 (85%) manifested hemispheric CSF ratio < 0.9 (CED/HT), with this overlap group representing half of the 475 with measurable CED. Higher baseline NIHSS scores and larger infarct volumes were observed in the CED/HT group compared with those with CED or HT alone. Functional outcome was worse in those with CED/HT [median mRS 3 (IQR 2-5)] than those with CED [median 2 (IQR 1-4)] or HT alone [median 1 (IQR 0-2), p < 0.0001]. Overlap of CED/HT independently predicted worse outcome [OR 1.89 (95% CI: 1.12-3.18), p = 0.02] while HT did not; however, CED/HT was no longer associated with worse outcome after adjusting for severity of CED [adjusted OR 0.35 (95% CI: 0.23, 0.51) per 0.21 lower hemispheric CSF ratio, p < 0.001]. CONCLUSIONS: Most stroke patients with HT also have measurable CED. The co-occurrence of CED and HT occurs in larger and more severe strokes and is associated with worse functional outcome, although this is driven by greater severity of stroke-related edema in those with HT.

Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies.

Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trials.

Alteration of the translational readthrough isoform AQP4ex induces redistribution and downregulation of AQP4 in human glioblastoma.

Glioblastoma multiforme (GBM) is characterized by a remarkable cellular and molecular heterogeneity that make the behavior of this tumor highly variable and resistant to therapy. In addition, the most serious clinical complication of GBM and other brain tumors is the development of vasogenic edema which dramatically increase the intracranial pressure. In the present study we evaluate the expression, supramolecular organization and spatial distribution of AQP4 and AQP4ex, the new readthrough isoform of AQP4, in relationship with the degree of vasogenic brain edema and tumor progression. To this purpose, tissue samples from regions of tumor core, peritumoral and non-infiltrated tissues of each GBM patient (n = 31) were analyzed. Immunofluorescence experiments revealed that the expression of AQP4ex was almost absent in tumoral regions while the canonical AQP4 isoforms appear mostly delocalized. In peritumoral tissues, AQP4 expression was found altered in those perivascular astrocyte processes where AQP4ex appeared reduced and partially delocalized. Protein expression levels measured by immunoblot showed that global AQP4 was reduced mainly in the tumor core. Notably, the relative amount of AQP4ex was more severely reduced starting from the peritumoral region. BN-PAGE experiments showed that the supramolecular organization of AQP4 is only partially affected in GBM. Edema assessment by magnetic resonance imaging revealed that the level of AQP4ex downregulation correlated with edema severity. Finally, the degree of BBB alteration, measured with sodium fluorescein content in GBM biopsies, correlated with the edema index and AQP4ex downregulation. Altogether these data suggest that the AQP4ex isoform is critical in the triggering event of progressive downregulation and mislocalization of AQP4 in GBM, which may affect the integrity of the BBB and contributes to accumulation of edema in the peritumoral tissue. Thus, AQP4ex could be considered as a potential early biomarker of GBM progression.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1ß production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. METHODS: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. RESULTS: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. CONCLUSIONS: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Subacute phase of subarachnoid haemorrhage in female rats: Increased intracranial pressure, vascular changes and impaired sensorimotor function.

OBJECTIVE: Early brain injury (EBI) and delayed cerebral ischemia (DCI) after subarachnoid haemorrhage (SAH) has devastating consequences but therapeutic options and the underlying pathogenesis remain poorly understood despite extensive preclinical and clinical research. One of the drawbacks of most preclinical studies to date is that the mechanisms behind DCI after SAH are studied only in male animals. In this study we therefore established a female rat model of SAH in order to determine subacute pathophysiological changes that may contribute to DCI in females. METHODS: Experimental SAH was induced in female rats by intracisternal injection of 300 µL of autologous blood. Sham operation served as a control. Neurological deficits and intracranial pressure measurements were evaluated at both 1 and 2 days after surgery. Additionally, changes in cerebral vascular contractility were evaluated 2 days after surgery using wire myography. RESULTS: SAH in female rats resulted in sensorimotor deficits and decreased general wellbeing on both day 1 and day 2 after SAH. Intracranial pressure uniformly increased in all rats subjected to SAH on day 1. On day 2 the intracranial pressure had increased further, decreased slightly or remained at the level seen on day 1. Furthermore, female rats subjected to SAH developed cortical brain edema. Cerebral arteries, isolated 2 days after SAH, exhibited increased vascular contractions to endothelin-1 and 5-carboxamidotryptamine. CONCLUSION: In the subacute phase after SAH in female rats, we observed increased intracranial pressure, decreased wellbeing, sensorimotor deficits, increased vascular contractility and cortical brain edema. Collectively, these pathophysiological changes may contribute to DCI after SAH in females. Previous studies reported similar pathophysiological changes for male rats in the subacute phase after SAH. Thus, prevention of these gender-independent mechanisms may provide the basis for a universal treatment strategy for DCI after SAH. Nevertheless, preclinical studies of potential therapies should employ both male and female SAH models.

Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.

BACKGROUND: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. CASE PRESENTATION: Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. CONCLUSION: This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.

Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema.

Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion. SD triggered a rapid fragmentation of dendritic mitochondria. A large increase in the density of synapses on swollen dendritic shafts implies that some dendritic spines were overwhelmed by swelling or merely retracted. The overall synaptic density was unchanged. The postsynaptic dendritic membranes remained attached to axonal boutons, providing a structural basis for the recovery of synaptic circuits. Upon immediate reperfusion, cytotoxic edema mainly subsides as affirmed by a recovery of dendritic ultrastructure. Dendritic recuperation from swelling and reversibility of mitochondrial fragmentation suggests that neurointensive care to improve tissue perfusion should be paralleled by treatments targeting mitochondrial recovery and minimizing the occurrence of SDs.

Posterior Reversible Encephalopathy Syndrome.

PURPOSE OF REVIEW: This review provides an updated discussion on the clinical presentation, diagnosis and radiographic features, mechanisms, associations and epidemiology, treatment, and prognosis of posterior reversible encephalopathy syndrome (PRES). Headache is common in PRES, though headache associated with PRES was not identified as a separate entity in the 2018 International Classification of Headache Disorders. Here, we review the relevant literature and suggest criteria for consideration of its inclusion. RECENT FINDINGS: COVID-19 has been identified as a potential risk factor for PRES, with a prevalence of 1-4% in patients with SARS-CoV-2 infection undergoing neuroimaging, thus making a discussion of its identification and treatment particularly timely given the ongoing global pandemic at the time of this writing. PRES is a neuro-clinical syndrome with specific imaging findings. The clinical manifestations of PRES include headache, seizures, encephalopathy, visual disturbances, and focal neurologic deficits. Associations with PRES include renal failure, preeclampsia and eclampsia, autoimmune conditions, and immunosuppression. PRES is theorized to be a syndrome of disordered autoregulation and endothelial dysfunction resulting in preferential hyperperfusion of the posterior circulation. Treatment typically focuses on treating the underlying cause and removal of the offending agents.

Idiopathic Intracranial Hypertension: Glymphedema of the Brain.

BACKGROUND: During the last decade, our understanding of cerebrospinal fluid (CSF) physiology has dramatically improved, thanks to the discoveries of both the glymphatic system and lymphatic vessels lining the dura mater in human brains. EVIDENCE ACQUISITION: We detail the recent basic science findings in the field of CSF physiology and connect them with our current understanding of the pathophysiology of idiopathic intracranial hypertension (IIH). RESULTS: Transverse sinus (TS) stenoses seem to play a major causative role in the symptoms of IIH, as a result of a decrease in the pressure gradient between the venous system and the subarachnoid space. However, the intracranial pressure can be highly variable among different patients, depending on the efficiency of the lymphatic system to resorb the CSF and on the severity of TS stenoses. It is likely that there is a subclinical form of IIH and that IIH without papilledema is probably under-diagnosed among patients with chronic migraines or isolated tinnitus. CONCLUSIONS: IIH can be summarized in the following pathological triad: restriction of the venous CSF outflow pathway-overflow of the lymphatic CSF outflow pathway-congestion of the glymphatic system. To better encompass all the stages of IIH, it is likely that the Dandy criteria need to be updated and that perhaps renaming IIH should be considered.

Limiting Brain Shift in Malignant Hemispheric Infarction by Decompressive Craniectomy.

OBJECTIVE: Decompressive craniectomy (DC) improves functional outcomes in selected patients with malignant hemispheric infarction (MHI), but variability in the surgical technique and occasional complications may be limiting the effectiveness of this procedure. Our aim was to evaluate predefined perioperative CT measurements for association with post-DC midline brain shift in patients with MHI. METHODS: At two medical centers we identified 87 consecutive patients with MHI and DC between January 2007 and December 2019. We used our previously tested methods to measure the craniectomy surface area, extent of transcalvarial brain herniation, thickness of tissues overlying the craniectomy, diameter of the cerebral ventricle atrium contralateral to the stroke, extension of infarction beyond the craniectomy edges, and the pre and post-DC midline brain shifts. To avoid potential confounding from medical treatments and additional surgical procedures, we excluded patients with the first CT delayed >30 hours post-DC, resection of infarcted brain, or insertion of an external ventricular drain during DC. The primary outcome in multiple linear regression analysis was the postoperative midline brain shift. RESULTS: We analyzed 72 qualified patients. The average midline brain shift decreased from 8.7 mm pre-DC to 5.4 post-DC. The only factors significantly associated with post-DC midline brain shift at the p<0.01 level were preoperative midline shift (coefficient 0.32, standard error 0.10, p=0.002) and extent of transcalvarial brain herniation (coefficient -0.20, standard error 0.05, p <0.001). CONCLUSIONS: In patients with MHI and DC, smaller post-DC midline shift is associated with smaller pre-DC midline brain shift and greater transcalvarial brain herniation. This knowledge may prove helpful in assessing DC candidacy and surgical success. Additional studies to enhance the surgical success of DC are warranted.

Mesenchymal Stem Cells: The Potential Therapeutic Cell Therapy to Reduce Brain Stroke Side Effects.

Tissue plasminogen activator (tPA) is the gold standard treatment for ischemic stroke in the time window of 3-4.5 hours after the onset of symptoms. However, tPA administration is associated with inflammation and neurotoxic effects. Mesenchymal stem cells (MSC)-based therapy is emerging as a promising therapeutic strategy to control different inflammatory conditions. This project was designed to examine the protective role of MSC administration alone or in combination with royal jelly (RJ) five hours after stroke onset. The mice model of middle cerebral artery occlusion (MCAO) was established and put to six groups, including intact (healthy mice without stroke), control (untreated stroke), treated with mouse MSC (mMSC), Sup (conditioned medium), RJ and combination of mMSC and RJ (mMSC/RJ). Thereafter, behavioral functions, serum and brain (in both infarcted and non-infarcted tissues) levels of interleukin (IL)-1ß, IL-4, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) the sizes of brain infarction have been determined in the groups. Administration of mMSC and mMSC/RJ significantly improved the behavioral functions when compared to the controls. mMSC, RJ and mMSC/RJ significantly decreased the infarcted volumes. RJ and mMSC/RJ, but not mMSC, significantly decreased the brain edema. The infarction increased the serum levels of the cytokines, except TNF-α, and treatment with mMSC, Sup and RJ reduced serum levels of the pro-inflammatory cytokines. mMSC reduced IL-1ß in the non-infarcted brain tissue. To conclude, data revealed that using mMSC/RJ combination significantly reduced stroke side effects, including brain edema and serum levels of pro-inflammatory cytokines, and suggested that combination therapy of MSCs with RJ may be considered as an effective stroke therapeutic strategy.

Bilateral Cerebral Hyperperfusion Syndrome Following Carotid Artery Stenting in Stroke - A Case Report.

BACKGROUND: Revascularization of the symptomatic carotid artery is performed with endarterectomy or stenting. Rarely, patients may develop cerebral hyperperfusion syndrome (CHS) following revascularization. This usually occurs in the cerebral hemisphere ipsilateral to revascularized carotid stenosis. CHS rarely involves the contralateral hemisphere. OBJECTIVE: To present a case of CHS involving bilateral cerebral hemispheres following carotid artery stenting in acute ischemic stroke. CASE DESCRIPTION: A 66-year-old woman presented with right side weakness and aphasia. National Institutes of Health stroke scale score was 27. CT angiogram/perfusion showed high grade left internal carotid artery (ICA) stenosis, left middle cerebral artery (MCA) occlusion, and increased time to peak in left MCA territory. She underwent mechanical thrombectomy with complete reperfusion. Left carotid artery stenting was performed for 85% cervical ICA stenosis with thrombus. She neurologically deteriorated and required intubation after the procedure. Follow-up CT perfusion at 18 hours after thrombectomy showed increased cerebral blood flow and early time to peak in bilateral MCA territories. CT head showed parenchymal hematoma in the left subcortical area with extension to the ventricle. Fluid-attenuated inversion recovery MRI on day 4 showed diffuse white matter hyperintensities in the entire right hemisphere, and left temporal and frontal lobes suggestive of vasogenic edema. CONCLUSION: This case highlights bilateral cerebral hyperperfusion syndrome characterized by neurological worsening, imaging findings of parenchymal hemorrhage, vasogenic edema and increased cerebral blood flow without any new ischemic lesions. The involvement of bilateral hemispheres in the absence of significant contralateral carotid stenosis is unique in this case.

The role of vascular endothelial growth factor in ischemic stroke.

Ischemic stroke is an injury caused by temporary or permanent cerebral vascular occlusion. It has a high incidence, mortality, and disability rate in clinical practice, and thus poses a considerable threat to public health as one of the top three major conditions endangering human health. Vascular endothelial growth factor is a specific mitogen of endothelial cells and a protein factor that is closely related to ischemic stroke. Vascular endothelial growth factor plays an important role in a multitude of physiological and pathological conditions. As a potential angiogenic protein for the treatment of ischemic stroke, vascular endothelial growth factor plays a role in promoting angiogenesis and neuroprotection and regeneration. At the same time, it plays a role in brain edema, collateral artery formation, and atherosclerosis. An increase in vascular endothelial growth factor levels contributes to the early pathological changes in patients with stroke and is closely related to the formation of cerebral edema in ischemic stroke complications. In theory, the neuroprotective and angiogenic effects of vascular endothelial growth factor make it an ideal candidate for the treatment of stroke. Here, we review the mechanism by which vascular endothelial growth factor participates in various stages of ischemic stroke and its prospects for use in the treatment of ischemic stroke.

Estimation of the Morphofunctional Status of the Brain in Hypertensive Wistar Rats Using Diffusion-Weighted MRI.

Morphofunctional changes of the brain tissues of Wistar rats were studied based on the development of a multifactor cardiovasorenal model of arterial hypertension using MRI. An increase of the signal on the diffusion brain maps was recorded in 3 months, which indicated fluid accumulation in the intra- and extracellular space of the brain tissue. The data characterize the development of the pathogenetic mechanism of the hypervolemic variant of experimental arterial hypertension. The development of endothelial dysfunction in the brain vessels was manifested by predominance of abnormal constrictor reactions. In 6 months after arterial hypertension simulation, structural changes in the brain developed, such as leukoareosis, cystic encephalomalacia with dilated cerebrospinal fluid spaces and limited blood supply to brain tissue in the basins of the large cerebral arteries.

Contrast-Induced Encephalopathy After Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Contrast-induced encephalopathy (CIE) is a rare and underrecognized complication after endovascular thrombectomy (EVT) for acute ischemic stroke. This study investigated the incidence and risk factors of CIE in patients who underwent EVT. METHODS: Consecutive patients with acute ischemic stroke who received EVT between September 2014 and December 2019 at 2 medical centers were included. CIE was diagnosed on clinical criteria of neurological deterioration or delayed improvement within 24 hours after the procedure that was unexplained by the infarct or hemorrhagic transformation and radiological criterion of edematous change extending beyond the infarct core accompanied by contrast staining. RESULTS: Of 421 patients with acute ischemic stroke who received EVT, 7 (1.7%) developed CIE. The manifestations included worsening of focal neurological signs, coma, and seizure. Patients with CIE were more likely to experience contrast-induced acute kidney injury than were those without CIE, but the volume of contrast medium was comparable between the two groups. The independent risk factors for CIE included renal dysfunction (defined as an estimated glomerular filtration rate <45 mL/min per 1.73 m2; odds ratio, 5.77 [95% CI, 1.37-24.3]; P=0.02) and history of stroke (odds ratio, 4.96 [95% CI, 1.15-21.3]; P=0.03). Patients with CIE were less likely to achieve favorable functional outcomes (odds ratio, 0.09 [95% CI, 0.01-0.87]; P=0.04). CONCLUSIONS: CIE should be suspected in patients with clinical worsening after EVT accompanied by imaging evidence of contrast staining and edematous changes, especially in patients with renal dysfunction or history of stroke.

Stanniocalcin-1 ameliorates cerebral ischemia by decrease oxidative stress and blood brain barrier permeability.

Blood brain barrier (BBB) permeability and oxidative stress have been reported to be important mechanisms for brain damage following ischemic stroke and stanniocalcin-1 (STC-1), a neuroprotective protein, has anti-inflammatory and anti-oxidative stress properties. Herein, we report the effect of STC-1 on BBB permeability and brain oxidative stress after stroke in an animal model. Male Wistar received an intracerebroventricularly injection of human recombinant STC-1 (100 ng/kg) or saline and were subjected to sham procedure or global cerebral ischemia/reperfusion (I/R) model. Six and 24 h after I/R, neurological evaluation was performed; at 24 h brain water content was evaluated in the total brain, and BBB permeability, nitrite/nitrate (N/N) concentration, lipid peroxidation, protein carbonyls formation, superoxide dismutase (SOD) and catalase (CAT) activity were determined in the hippocampus, cortex, prefrontal cortex, striatum and cerebellum. Rats exhibited neurological deficit at 6 and 24 h after I/R and STC-1 reduction at 24 h. After I/R there were an increase of brain water content, BBB permeability in the hippocampus, cortex and pre-frontal cortex and N/N in the hippocampus, and STC-1 decreased this level only in the hippocampus. STC-1 decreased lipid peroxidation in the hippocampus, cortex and prefrontal cortex and protein oxidative damage in the hippocampus and cortex. SOD activity decreased in the hippocampus, cortex and prefrontal cortex after I/R and STC-1 reestablished these levels in the hippocampus and cortex. CAT activity decreased only in the hippocampus and cortex and STC-1 increased the CAT activity in the hippocampus. Our data provide the first experimental demonstration that STC-1 reduced brain dysfunction associated with cerebral I/R in rats, by decreasing BBB permeability and oxidative stress parameters.

Asiaticoside Alleviates Cerebral Ischemia-Reperfusion Injury via NOD2/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Factor kappa B (NF-κB) Signaling Pathway.

BACKGROUND Cerebral ischemia-reperfusion injury (CIRI) remains a serious health problem. Centella asiatica formulations are used to treat central nervous system disorders. In the present study, asiaticoside, an extract of the plant Centella asiatica, was investigated in CIRI in vivo and vitro. MATERIAL AND METHODS We made a CIRI model in vivo in SD rats treated by middle cerebral artery occlusion, and a cell model of ischemia-reperfusion injury was made in PC12 cells treated by deprivation of oxygen and glucose/restoration. CIRI in vivo was assessed by scores of neurological functions, encephaledema, and cerebral infarction area. Inflammation level and oxidative stress level were detected by the appropriate kits. TUNEL assay was performed for assessment of cell apoptosis and Western blot analysis was performed to assess protein expression levels. CCK8 assay was performed for evaluation of cell survival and flow cytometer was used to detect cell apoptosis in vitro. RESULTS Nervous function injury, brain edema, cell apoptosis, infarct size, apoptosis-related protein expressions, and protein expressions of the NOD2/MAPK/NF-kappaB signaling pathway in the CIRI model were all reversed by asiaticoside in rats. The cell apoptosis, inflammation level, and oxidative stress level in the model of cerebral ischemia-reperfusion injury were reduced by asiaticoside. The effects of asiaticoside on CIRI were reversed by NOD 2 agonists. CONCLUSIONS Asiaticoside showed a protective effect against cerebral ischemia-reperfusion injury via the NOD2/MAPK/NF-kappaB signaling pathway. These findings are vital for future research on use of asiaticoside in CIRI, providing a new avenue for alleviating CIRI.

Basic Fibroblast Growth Factor (bFGF) Protects the Blood-Brain Barrier by Binding of FGFR1 and Activating the ERK Signaling Pathway After Intra-Abdominal Hypertension and Traumatic Brain Injury.

BACKGROUND Intra-abdominal hypertension (IAH) is associated with high morbidity and mortality. IAH leads to intra-abdominal tissue damage and causes dysfunction in distal organs such as the brain. The effect of a combined injury due to IAH and traumatic brain injury (TBI) on the integrity of the blood-brain barrier (BBB) has not been investigated. MATERIAL AND METHODS Intracranial pressure (ICP) monitoring, brain water content, EB permeability detection, immunofluorescence staining, real-time PCR, and Western blot analysis were used to examine the effects of IAH and TBI on the BBB in rats, and to characterize the protective effects of basic fibroblast growth factor (bFGF) on combined injury-induced BBB damage. RESULTS Combined injury from IAH and TBI to the BBB resulted in brain edema and increased intracranial pressure. The effects of bFGF on alleviating the rat BBB injuries were determined, indicating that bFGF regulated the expression levels of the tight junction (TJ), adhesion junction (AJ), matrix metalloproteinase (MMP), and IL-1ß, as well as reduced BBB permeability, brain edema, and intracranial pressure. Moreover, the FGFR1 antagonist PD 173074 and the ERK antagonist PD 98059 decreased the protective effects of bFGF. CONCLUSIONS bFGF effectively protected the BBB from damage caused by combined injury from IAH and TBI, and binding of FGFR1 and activation of the ERK signaling pathway was involved in these effects.