Reduced Blood-brain Barrier Permeability Research Articles

Intergenerational crosstalk of brain-gut axis in parental Nd2O3 exposure-induced offspring neurotoxicity and cognitive dysfunction: a mechanistic study.

Rare earth elements (REEs) are widely used in plenty of fields. REEs have significant neurotoxicity and it may adversely affect the development of cognitive. For example, neodymium will causing neurological damage through penetrate the blood-brain barrier (BBB). However, whether it disrupts the balance of brain-gut axis (BGA) crosstalk and affects the intestinal microecology disorder of host is still unclear. This study investigated the neural damage on children caused by maternal exposure to Neodymium oxide (Nd2O3) during pregnancy, and its involved mechanism of BGA injury. We used rat model to investigated the mechanisms of the offspring's neural damage that Nd2O3 exposure in pregnancy. To verify the neural damage of offspring rats, we examed BBB-related factors, such like glutamate and ROS levels in brain tissue, behavioral tests, hippocampal and cortical damage, as well as changes in gut microbiota, intestinal mucosal barrier, and SCFAs in the intestine. Also, we observed some specific indicators of intestinal immune barrier function and gut nerve-related indicators. Maternal Nd2O3 exposure reduced the content of offspring tight junction proteins, increased BBB permeability, leading to Nd accumulation and brain tissue inflammation, affecting offspring's neural development and weakening their spatial learning ability. Nd2O3 also disrupted BBB integrity by regulating SCFAs and BGA. Probiotic intervention in the offspring rats exposed to 2% Nd2O3 showed significant recovery of inflammation in both brain and colon tissues, and reduced BBB permeability. Maternal exposure to Nd2O3 affects the offspring's BGA, targeting brain and colon tissues, increasing BBB permeability, affecting neural development, causing damage to the intestinal mucosa, and impacting children's gut development. Probiotics can alleviate these effects. These findings provide valuable insights into understanding the neurodevelopmental and intestinal developmental toxicity of Nd2O3 and its prevention and treatment. It also calls for a comprehensive assessment of the health risks of susceptible populations to Nd2O3, such as pregnant women. It may providing theoretical basis for preventing and controlling neodymium-induced harm in children by examing the repair mechanism of the damage through probiotic intervention.

Understanding the Importance of Blood-Brain Barrier Alterations in Brain Arteriovenous Malformations and Implications for Treatment: A Dynamic Contrast-Enhanced-MRI-Based Prospective Study.

The major clinical implication of brain arteriovenous malformations (bAVMs) is spontaneous intracranial hemorrhage. There is a growing body of experimental evidence proving that inflammation and blood-brain barrier (BBB) dysfunction are involved in both the clinical course of the disease and the risk of bleeding. However, how bAVM treatment affects perilesional BBB disturbances is yet unclear. We assessed the permeability changes of the BBB using dynamic contrast-enhanced MRI (DCE-MRI) in a series of bAVMs (n = 35), before and at a mean of 5 (±2) days after treatment. A set of cerebral cavernous malformations (CCMs) (n = 16) was used as a control group for the assessment of the surgical-related collateral changes. The extended Tofts pharmacokinetic model was used to extract permeability (Ktrans) values in the lesional, perilesional, and normal brain tissues. In patients with bAVM, the permeability of BBB was higher in the perilesional of bAVM tissue compared with the rest of the brain parenchyma (mean Ktrans 0.145 ± 0.104 vs 0.084 ± 0.035, P = .004). Meanwhile, no significant changes were seen in the perilesional brain of CCM cases (mean Ktrans 0.055 ± 0.056 vs 0.061 ± 0.026, P = .96). A significant decrease in BBB permeability was evident in the perilesional area of bAVM after surgical resection (mean Ktrans 0.145 ± 0.104 vs 0.096 ± 0.059, P = .037). This benefit in BBB permeability reduction after surgery seemed to surpass the relative increase in permeability inherent to the surgical manipulation. In contrast to CCMs, BBB permeability in patients with bAVM is increased in the perilesional parenchyma, as assessed using DCE-MRI. However, bAVM surgical resection seems to reduce BBB permeability in the perilesional tissue. No evidence of the so-called breakthrough phenomenon was detected in our series. DCE-MRI could become a valuable tool to follow the longitudinal course of BBB damage throughout the natural history and clinical course of bAVMs.

Non-saponin from Panax ginseng maintains blood-brain barrier integrity by inhibiting NF-κB and p38 MAP kinase signaling pathways to prevent the progression of experimental autoimmune encephalomyelitis

BackgroundThe non-saponin (NS) fraction is an important active component of Panax ginseng, with multifunctional pharmacological activities including neuroprotective, immune regulatory, anti-inflammatory, and antioxidant effects. However, the effects of NSs on multiple sclerosis (MS), a chronic and autoimmune demyelinating disorder, have not yet been demonstrated. Purposeand Methods: The goal of the present study was to demonstrate the pharmacological actions of NSs on movement dysfunctions and the related mechanisms of action using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. ResultsNSs (p.o.) alleviated movement dysfunctions in EAE mice related to reduced demyelination in the lumbar spinal cord (LSC). NSs attenuated the recruitment of microglia (CD11b+/CD45low) and macrophages (CD11b+/CD45high) in LSCs from EAE model mice, consistent with the decreased mRNA expression levels of the main proinflammatory mediators (IL-1β, COX-2, MCP-1, MIP-1α, and RANTES). NSs blocked the migration of Th17 cells (CD4+/IL17A+) and mRNA expression levels of IL-17A (product of Th17 cells) in LSCs from EAE mice. NSs suppressed alterations in blood-brain barrier (BBB) components, such as astrocytes and cell adhesion molecules, associated with inhibiting NF-κB and p38 MAPK pathways in LSCs of EAE mice and lipopolysaccharide-induced bEND.3 cells. ConclusionsNSs could attenuate movement dysfunctions and related pathological/inflammatory changes by reducing BBB permeability through NF-κB and p38 MAPK pathway inhibition in LSCs of EAE model mice. These are the first results suggesting that NSs can be potential therapeutic agents for MS by reducing BBB permeability.

PD-1 mediates microglia polarization via the MAPK signaling pathway to protect blood-brain barrier function during cerebral ischemia/reperfusion

BackgroundCerebral ischemia is characterized by its rapid onset and high rates of recurrence, morbidity, and mortality, with blood-brain barrier (BBB) permeability playing a vital role in brain injury. Therefore, it is important to understand the molecular mechanism which regulates the BBB during cerebral ischemia. Materials and methodsAn in vitro model of oxygen-glucose deprivation (OGD) and an in vivo model of cerebral ischemia/reperfusion (I/R) were constructed. PD-1 overexpression vectors and vectors containing si-RNA were transfected and injected into in vitro and in vivo models. Western blotting, real-time quantitative PCR (qPCR), immunofluorescence (IF) analysis, and immunohistochemical staining were employed to evaluate the expression levels of programmed cell death-1 (PD-1), microglia M1 and M2 biomarkers, and tight junction proteins. Flow cytometry and ELISA were used to measure the levels of pro-inflammatory cytokines. The BBB permeability of brain tissues was evaluated by Evans blue dye (EBD) extravasation and transendothelial electrical resistance (TEER). Brain water content was measured to assess the extent of inflammatory exudation. The infarct volume and neurological severity score (NSS) were used to assess the severity of brain injury. Brain cell apoptosis was assessed by the TUNEL assay and hematoxylin-eosin (H&E) staining. ResultsPD-1 helped to convert the microglia M1 phenotype to the M2 phenotype and to reduce BBB permeability both in vitro and in vivo. Overexpression of PD-1 promoted a shift of the M1 phenotype to the M2 phenotype and reduced BBB permeability via the ERK and p38 MAPK signaling pathways. PD-1 reduced inflammatory exudation, BBB permeability, cell apoptosis, and brain injury in vivo. ConclusionOur present study verified that PD-1 exerts an anti-inflammatory effect by converting the microglia M1 phenotype to the M2 phenotype, reducing BBB permeability, and thereby relieves brain injury caused by cerebral ischemia. PD-1 is potential therapeutic target for brain injury caused by cerebral ischemia.

Dose-Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood-Brain Barrier Permeability Following Traumatic Brain Injury: An In Vivo Murine Study.

Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery. CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60mg/kg). At 48h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia NeurologicalTest scores and animal weight changes at 24h and 48h after injury. I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24h and 48h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I +TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group. Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to blunting of leukocyte-mediated penumbral cerebrovascular inflammation.

ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment.

The permeability of the blood-brain barrier (BBB) is increased in Alzheimer's disease (AD). This plays a key role in the instigation and maintenance of chronic inflammation during AD. Experiments using AD models showed that the increased permeability of the BBB was mainly caused by the decreased expression of tight junction-related proteins occludin and claudin-5. In this study, we found that ZNF787 and HDAC1 were upregulated in β-amyloid (Aβ)1-42-incubated endothelial cells, resulting in increased BBB permeability. Conversely, the silencing of ZNF787 and HDAC1 by RNAi led to reduced BBB permeability. The silencing of ZNF787 and HDAC1 enhanced the expression of occludin and claudin-5. Mechanistically, ZNF787 binds to promoter regions for occludin and claudin-5 and functions as a transcriptional regulator. Furthermore, we demonstrate that ZNF787 interacts with HDAC1, and this resulted in the downregulation of the expression of genes encoding tight junction-related proteins to increase in BBB permeability. Taken together, our study identifies critical roles for the interaction between ZNF787 and HDAC1 in regulating BBB permeability and the pathogenesis of AD.

Aloe vera Leaf Extract Reduced BBB Permeability and Improved Neurological Results after Traumatic Brain Injury: The Role of Oxidative Stress.

Recognizing the importance of medicinal plants and the absence of specific medications for traumatic brain injury (TBI) treatment, this study was conducted to evaluate the effects of an aqueous extract of Aloe vera on oxidative stress, blood-brain barrier (BBB) permeability, and neurological scores following TBI. Adult male rats were categorized into five groups: sham, TBI, vehicle, low-dose Aloe vera (LA), and high-dose Aloe vera (HA). We induced diffuse TBI using the Marmaro model and administered the aqueous Aloe vera leaf extract, as well as vehicle, via intraperitoneal injection half an hour after TBI. Neurological outcomes were assessed both before and several hours after TBI. Additionally, oxidative stress factors were measured 24 hr after TBI, and Evans blue content (a BBB permeability index) was determined 5 hr after TBI in both serum and brain. Both LA and HA reduced the increase in BBB permeability after TBI, with HA having a more pronounced effect than LA. Both Aloe vera doses decreased brain MDA levels, increased brain TAC, and lowered both serum and brain PC levels. The impact of Aloe vera on brain oxidative parameters was more significant than on serum. HA also counteracted the declining effects of TBI on neurological outcomes at 4 and 24 hr post-TBI. This study suggests that Aloe vera extract may reduce BBB permeability and improve neurological outcomes after TBI by decreasing oxidative factors and increasing antioxidant factors.

Interfering TRIB3 protects the blood brain barrier through PI3K/Akt pathway to alleviate cerebral ischemia-reperfusion injury in diabetes mellitus mice

This study aimed to treat diabetic cerebral ischemia-reperfusion injury (CI/RI) by affecting blood brain barrier (BBB) permeability and integrity. The CI/RI model in DM mice and a high glucose (HG) treated oxygen and glucose deprivation/reoxygenation (OGD/R) brain endothelial cell model were established for the study. Evans blue (EB) staining was used to evaluate the permeability of BBB in vivo. TTC staining was used to analyze cerebral infarction. The location and expression of tribbles homolog 3 (TRIB3) in endothelial cells were detected by immunofluorescence. Western blotting was used to detect the protein expressions of TRIB3, tight junction molecules, adhesion molecules, phosphorylated protein kinase B (p-AKT) and AKT. The levels of pro-inflammatory cytokines were detected by qRT-PCR. Trans-epithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran were used to measure vascular permeability in vitro. TRIB3 ubiquitination and acetylation levels were detected. Acetyltransferase bound to TRIB3 were identified by immunoprecipitation. TRIB3 was localized in cerebral endothelial cells and was highly expressed in diabetic CI/R mice. The BBB permeability in diabetic CI/R mice and HG-treated OGD/R cells was increased, while the junction integrity was decreased. Interference with TRIB3 in vitro reduces BBB permeability and increases junction integrity. In vivo interfering with TRIB3 reduced cerebral infarction volume, BBB permeability and inflammation levels, and upregulated p-AKT levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin reversed the effects of TRIB3-interfering plasmid. In vitro HG treatment induced TRIB3 acetylation through acetyltransferase p300, which in turn reduced ubiquitination and stabilized TRIB3. Interfering TRIB3 protects BBB by activating PI3K/AKT pathway and alleviates brain injury, which provides a new target for diabetic CI/RI.

A review on recent advances on nobiletin in central and peripheral nervous system diseases

In recent years, the role of nobiletin in neuronal disorders has received extensive attention. However, the study of nobiletin in the peripheral nervous system is limited. Nobiletin, as a compound with high fat solubility, high bioavailability and low toxicity, has been extensively studied. Accumulating scientific evidence has shown that nobiletin has a variety of biological functions in the nervous system, such as inhibiting the expression of inflammatory factors, reducing the neurotoxic response, improving the antioxidant capacity, promoting the survival of nerve cells, promoting axon growth, reducing blood‒brain barrier permeability, reducing brain oedema, promoting cAMP response element binding protein expression, improving memory, and promoting mild depolarization of nerve cell mitochondria to improve antioxidative stress capacity. Accumulating studies have shown that nobiletin also protects enteric nervous system, spinal cord and sciatic nerve. To explore the new therapeutic potential of nobiletin in the nervous system, recent and relevant research progress is reviewed in this article. This will provide a new research idea for nobiletin in the nervous system.

BCL-3 Promotes Intracerebral Hemorrhage Progression by Increasing Blood-Brain Barrier Permeability, Inflammation, and Cell Apoptosis via Endoplasmic Reticulum Stress.

Intracerebral hemorrhage (ICH) is among the common types of stroke with high mortality and morbidity. Molecular biomarker selection is crucial for ICH diagnosis and treatment. However, the identification of ICH-related biomarkers remains inadequate. In vivo and in vitro ICH models were generated and transfected with silenced B-cell lymphoma-3 (BCL-3 and siRNA BCL-3), overexpressed BCL-3, and endoplasmic reticulum stress (ERS) agonist (2-CLHA). Hematoxylin-eosin staining and transmission electron microscopy were used to observe the transfected cells. RNA sequencing was performed in vivo on the sham and ICH groups. The blood-brain barrier (BBB) permeability was evaluated by determining Evans blue dye extravasation, transendothelial electrical resistance, and paracellular permeability. Moreover, tight junction-, cell apoptosis-, and endoplasmic reticulum stress- (ERS-) related proteins were evaluated through real-time quantitative PCR, western blotting, immunohistochemistry, and TUNEL staining. The levels of inflammatory cytokines were measured through the enzyme-linked immunosorbent assay. RNA-seq revealed that BCL-3 acts as a key player. BCL-3 promotes ICH progression by increasing BBB permeability, ERS, inflammation, and cell apoptosis. Silencing of BCL-3 slows ICH progression by reducing BBB permeability and inflammation and terminating cell apoptosis and ERS in vitro and in vivo. Our study identified ICH biomarkers and elucidated the role of BCL-3 in ICH for the first time.

Liensinine, a alkaloid from lotus plumule, mitigates lipopolysaccharide-induced sepsis-associated encephalopathy through modulation of nuclear factor erythroid 2-related factor-mediated inflammatory biomarkers and mitochondria apoptosis.

The present study aims to investigate the role of liensinine in life-threatened sepsis-associated encephalopathy (SAE) mice and the underlying mechanism. Here, seventy-two mice were divided into six groups, including the control group, SAE group, liensinine-treated group, and three doses of liensinine-treated SAE groups. Lipopolysaccharide triggered cerebrum necrosis and disrupted the integrity and permeability of blood-brain barrier (BBB). While liensinine restored cerebrum structure and improved BBB integrity with upregulated tight junction proteins, decreased evans blue leakage and fibrinogen expression with decreased matrix metalloproteinases 2/9 in serum, thereby reducing BBB permeability. Moreover, lipopolysaccharide triggered cerebrum oxidative stress and inflammation, whereas liensinine enhanced antioxidant enzymes activities and weakened malondialdehyde through nuclear factor erythroid 2-related factor. Meanwhile, liensinine inhibited inflammation by activating inducible nitric oxide synthase. Tunel staining combined with transmission electron microscope indicated that lipopolysaccharide induced cerebrum apoptosis, whereas liensinine blocked apoptosis through decreasing B-cell lymphoma-2 associated X (Bax) expression and cytochrome C (Cyto-c) release, increasing B-cell lymphoma-2 (Bcl-2) expression, blocking apoptosome assembly, inhibiting caspase-3 activation, thereby suppressing intrinsic mitochondria apoptosis. Recovering of inflammatory homeostasis and inhibition of mitochondria apoptosis by liensinine ultimately restored cognitive function in SAE mice. Altogether, liensinine attenuated lipopolysaccharide-induced SAE via modulation of Nrf2-mediated inflammatory biomarkers and mitochondria apoptosis.

Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice

Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer’s disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD4-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

MiR-671-5p Upregulation Attenuates Blood–Brain Barrier Disruption in the Ischemia Stroke Model Via the NF-кB/MMP-9 Signaling Pathway

Blood-brain barrier (BBB) disruption can induce further hemorrhagic transformation in ischemic stroke (IS). miR-671-5p, a micro-RNA, is abundant in the cortex of mammalian brains. Herein, we investigated the roles and potential mechanisms for the effects of miR-671-5p on BBB permeability in IS. Results showed that miR-671-5p levels were significantly downregulated in the cerebral cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) C57/BL6 mice in vivo. miR-671-5p agomir administration via right intracerebroventricular injection significantly reduced infarct volume, improved neurological deficits, the axon of neurons and nerve fiber, attenuated cell injury and apoptosis, as well as reduced BBB permeability in MCAO/R mice. Treatment with miR-671-5p agomir alleviated tight junction proteins degradation, including claudin, occludin, and ZO-1 in MCAO/R mice, and these effects were reversed following NF-κB overexpression. Bend.3 brain endothelial cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) treatment in vivo, and then miR-671-5p agomir was transfected into the cells. This resulted in reduction of cytotoxicity, improved cell viability, trans-endothelial electrical resistance, reduced fluorescein sodium permeability, and inhibited tight junction degradation in Bend.3 OGD/R cells. However, these effects were reversed following NF-κB overexpression. These results demonstrated that upregulation of miR-671-5p in IS models in vivo and in vitro alleviated BBB permeability by targeting NF-κB/MMP-9. In summary, miR-671-5p is a potential therapeutic target for protecting BBB permeability in IS to minimize cerebral hemorrhage transformation.

Alpha1-antitrypsin protects the immature mouse brain following hypoxic-ischemic injury.

Introduction: Preterm brain injury often leads to lifelong disabilities affecting both cognitive and motor functions, and effective therapies are limited. Alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteinases with anti-inflammatory, anti-apoptotic, and cytoprotective properties, might be beneficial in treating preterm brain injury. The aim of this study was to investigate whether AAT has neuroprotective effects in a mouse preterm brain injury model. Methods: Preterm brain injury was induced on postnatal day 5, and mouse pups' right common carotid arteries were cut between two ligations followed by hypoxia induction. Brain injury was evaluated through immunohistochemistry staining and magnetic resonance imaging. Fluoro-Jade B and immunohistochemistry staining were performed to investigate the neuronal cell death and blood-brain barrier (BBB) permeability. The motor function and anxiety-like behaviors were revealed by CatWalk gait analysis and the open field test. Results: After hypoxia-ischemia (HI) insult, brain injury was alleviated by AAT treatment, and this was accompanied by reduced BBB permeability, reduced neuronal cell death and caspase-3 activation, and inhibition of microglia activation. In addition, AAT administration significantly improved HI-induced motor function deficiencies in mice. The neuroprotective effect of AAT was more pronounced in male mice. Conclusion: AAT treatment is neuroprotective against preterm brain injury in neonatal mice, and the effect is more pronounced in males.

Apolipoprotein E mimetic peptide COG1410 alleviates blood‑brain barrier injury in a rat model of ischemic stroke.

Blood‑brain barrier (BBB) damage is one of the main causes of poor outcomes and increased mortality rates following cerebral ischemia‑reperfusion injury. ApolipoproteinE (ApoE) and its mimetic peptide have been previously reported to exhibit potent neuroprotective properties in various central nervous system disease models. Therefore, the present study aimed to investigate the possible role of the ApoE mimetic peptide COG1410 in cerebral ischemia‑reperfusion injury and its potential underlying mechanism. Male SD rats were subjected to 2h middle cerebral artery occlusion followed by 22h reperfusion. Evans blue leakage and IgG extravasation assays results revealed that COG1410 treatment significantly reduced BBB permeability. In addition, insitu zymography and western blotting were used to prove that COG1410 was able to downregulate the activities of MMPs and upregulate the expression of occludin in the ischemic brain tissue samples. Subsequently, COG1410 was found to significantly reverse microglia activation while also suppressing inflammatory cytokine production, according to immunofluorescence signal of Iba‑1 and CD68 and protein expression of COX‑2. Consequently, this neuroprotective mechanism mediated by COG1410 was further tested using the BV2 cell line invitro, which was exposed to oxygen glucose deprivation followed by reoxygenation. The mechanism of COG1410 was found to be mediated, as least partly, through the activation of triggering receptor expressed on myeloid cells 2. In conclusion, the data suggest that COG1410 can alleviate BBB injury and neuroinflammation following ischemic stroke.

Resveratrol alleviated neuroinflammation induced by pseudorabies virus infection through regulating microglial M1/M2 polarization

BackgroundPseudorabies virus (PRV) infections in susceptible non-porcine species trigger uncontrolled inflammations and eventually fatal encephalitis. Resveratrol (Res) has broad pharmacological functions including anti-virus, anti-inflammation, and neuroprotective. PurposeWe attempted to investigate the potential of Res in ameliorating PRV infection pathology in mice and decipher the mechanism of Res in treating PRV. MethodsThe mice were infected by PRV to investigate the protective effect of Res. Blood-brain barrier (BBB) permeability, H&E/Nissl/TUNEL staining, Real-time PCR and ELISA analyses were performed. Primary microglia and neuron were isolated from mice and cultured. The co-culture model of microglia and neuron was established by transwell. Immunofluorescence assay and flow cytometry were used. ResultsIn this study, we showed that Res ameliorated brain damage by reducing BBB permeability in PRV-infected mice, and diminished the expressions of MMP-2, MMP-9 and ZO-1 in the cortex. Pathological changes of neurons by H&E/Nissl/TUNEL staining suggested that Res could alleviate neuronal lesions. Moreover, Res inhibited the expressions of pro-inflammatory factors (IL-6, TNF-α) and chemokines (CCL3, CXCL10, MCP-1), but increased the expressions of anti-inflammatory factors (IL-4, IL-10) and neurotrophic factor (TGF-β, NGF and GDNF) in brain. In vitro cultured microglia cells, Res could suppress M1 microglia polarization and activate M2 microglia polarization. Co-culture of PRV-infected microglia with neuron cells by transwell system indicated that Res alleviated inflammatory response and neuronal apoptosis. ConclusionThis study provided evidence that Res could protect mice from PRV-induced encephalitis through regulation of microglia polarization and neuronal apoptosis suggesting the potential for treatment of viral encephalitis.

Curcumin Ameliorates Neurobehavioral Deficits in Ambient Dusty Particulate Matter-Exposure Rats: The Role of Oxidative Stress.

It has been consistently found that exposure to ambient air pollution, such as particulate matter (PM), results in cognitive impairments and mental disorders. This study aimed to investigate the possible neuroprotective effects of curcumin, a polyphenol compound, on the neurobehavioral deficits and to identify the role of oxidative stress in dusty PM exposure rats. Rats received curcumin (50mg/kg, daily, gavage, 2weeks) 30min before placing animals in a clean air chamber (≤ 150µg/m3, 60min daily, 2weeks) or ambient dusty PM chamber (2000-8000µg/m3, 60min daily, 2weeks). Subsequently, the cognitive and non-cognitive functions of the animals were evaluated using standard behavioral tests. Moreover, blood-brain barrier (BBB) permeability, brain water content (BWC), oxidative-antioxidative status, and histological changes were determined in the cerebral cortex and hippocampal areas of the rats. Our results showed that curcumin administration in dusty PM exposure rats attenuates memory impairment, decreases anxiety-/depression-like behaviors, and improves locomotor/exploratory activities. These findings were accompanied by reduced BBB permeability and BWC, decreasing oxidative stress, and lessening neuronal loss in the cerebral cortex and different hippocampal areas. The results of this study suggest that curcumin's antioxidant properties may contribute to its efficacy in improving neurobehavioral deficits and preventing neuronal loss associated with dusty PM exposure.

Effects of Exercise Training on Neurotrophic Factors and Blood–Brain Barrier Permeability in Young-Old and Old-Old Women

Aging and regular exercise may have opposite effects on brain health, and although oxidative stress and sirtuins may be involved in these effects, studies on this topic are limited. Accordingly, the present study aimed to verify the effect of exercise training on oxidant-antioxidant balance, neurotrophic factors, blood-brain barrier permeability, and sirtuins in young-old and old-old women. The study participants were 12 women aged 65-74 years (Young-Old group) and 12 women aged 75-84 years (Old-Old group). All of the selected participants performed exercise training consisting of treadmill walking and resistance band exercise three times a week for 12 weeks. Blood samples were collected before and after exercise training to analyze serum oxidant-antioxidant markers (reactive oxygen species [ROS], superoxide dismutase [SOD]), neurotrophic factor (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) levels, and blood-brain barrier permeability marker (S100 calcium-binding protein β [S100β], matrix metalloproteinase-9 [MMP-9]) levels, and sirtuin (SIRT-1, SIRT-2, SIRT-3) levels. The Young-Old group showed significantly increased SOD, BDNF, VEGF, SIRT-1, and SIRT-3 levels after training in comparison with the levels before training (p < 0.05), and a significantly higher BDNF level than the Old-Old group after training (p < 0.05). On the other hand, the Old-Old group showed significantly higher SIRT-1 levels after training in comparison with the levels before training (p < 0.05). Thus, exercise training may be effective in increasing the levels of neurotropic factors and reducing blood-brain barrier permeability in the elderly women, and increased antioxidant capacity and elevated levels of sirtuins are believed to play a major role in these effects. The positive effect of exercise may be greater in participants of relatively young age.

4-Hydroxynonenal Modulates Blood-Brain Barrier Permeability In Vitro through Changes in Lipid Composition and Oxidative Status of Endothelial Cells and Astrocytes.

Blood brain barrier (BBB) is a dynamic interface responsible for proper functioning of brain, but also a major obstacle for effective treatment of neurological diseases. Increased levels of free radicals, in high ferrous and high lipid content surrounding, induce lipid peroxidation, leading to production of 4-hydroxynonenal (HNE). HNE modifies all key proteins responsible for proper brain functioning thus playing a major role in the onset of neurological diseases. To investigate HNE effects on BBB permeability, we developed two in vitro BBB models-'physiological' and 'pathological'. The latter mimicked HNE modified extracellular matrix under oxidative stress conditions in brain pathologies. We showed that exogenous HNE induce activation of antioxidative defense systems by increasing catalase activity and glutathione content as well as reducing lipid peroxide levels in endothelial cells and astrocytes of 'physiological' model. While in 'pathological' model, exogenous HNE further increased lipid peroxidation levels of endothelial cells and astrocytes, followed by increase in Nrf2 and glutathione levels in endothelial cells. At lipid composition level, HNE caused increase in ω3 polyunsaturated fatty acid (PUFA) level in endothelial cells, followed by decrease in ω3 PUFA level and increase in monounsaturated fatty acid level in astrocytes. Using these models, we showed for the first time that HNE in 'pathological' model can reduce BBB permeability.

A host–gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood–brain barrier integrity in vivo

ABSTRACT The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Male C57Bl/6 J mice were used to assess blood–brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut–brain axis.