Muscone ameliorates cerebral ischemia-reperfusion-induced BBB injury through PKA/RHOA/MLC pathway.

BackgroundIntravenous tissue plasminogen activator (tPA) is currently the only FDA-approved thrombolytic therapy for acute ischemic stroke (AIS), however, relative narrow therapeutic time window (within 4.5 h of AIS onset) and high risk of hemorrhagic transformation due to blood–brain barrier (BBB) disruption limit tPA therapeutic benefits for patients. In this study, we extended the time window of tPA administration (5 h after the occurrence of AIS) and investigated whether Chinese medicine classical formula Shengui Sansheng San (SSS) administration was able to alleviate BBB integrity worsening, and the mechanism was related to vasoactive intestinal peptide (VIP)/ VIP receptor 1 (VIPR1) pathway.MethodsSSS was extracted using aqueous heating method and SFE-CO2 technology, and quality control was performed using UHPLC/MS analysis. Male C57BL/6 mice were suffered from middle cerebral artery occlusion (MCAo), followed by the removal of a silicone filament after 5 h, then, t-PA was administered via tail vein injection at once, along with SSS administration by gavage. Hemoglobin levels and Evans blue leakage were measured to assess brain hemorrhagic transformation and BBB permeability, respectively. Transmission electron microscope (TEM) was utilized to present brain microvascular endothelial cells (BMECs) tight junction morphology. TTC staining and laser speckle contrast imaging were employed for infarct volume and cerebral blood flow measurements. The modified neurological severity score (mNSS) test was conducted to evaluate neurological function. The expressions of VIP, VIPR1, ZO-1, Occludin, Lectin, GFAP, NeuN were detected by immunofluorescence staining or western blotting. In vitro, bEnd.3 and N2a cells were insulted by oxygen–glucose deprivation (OGD), and VIPR1 siRNA, and VIP shRNA transfection were respectively performed, and the molecular docking was applied to verify the SSS in-serum active compounds interacted with VIPR1. The transwell system was utilized to detect OGD-insulted BMECs permeability.ResultsSSS treatment significantly reduced the infarct area, cerebral hemorrhage, and neurological deficits, and enhanced cerebral blood flow in AIS mice received intravenous tPA beyond 4.5 h time window. Simultaneously, the permeability of BBB declined, with increased expressions of tight junction proteins ZO-1, and Occludin and proper BMECs tight junction morphology, and it suggested that VIP was released by neurons rather than astrocytes or BMECs. It also showed high expressions of VIP and VIPR1 in the penumbra area. The inhibition of VIP in N2a cells or VIPR1 in bEnd.3 cells abolished the viability and integrity of OGD-insulted bEnd.3 cells treated by tPA after SSS-containing serum administration, and the SSS in-serum active compounds were proved have high affinity to VIPR1 by molecular docking.ConclusionSSS alleviates the worsening of BBB integrity resulted from delayed tPA administration, reduces hemorrhagic transformation and infarction volume, and ameliorates brain blood flow and neurological function in AIS mice. The mechanisms are associated with the activation of VIP/VIPR1 pathway to enhance BMECs viability and maintain tight junction phenotype.Graphical

Endothelium protection is critical, because of the impact of vascular leakage and edema on pathological conditions such as brain ischemia. Whereas deficiency of class II phosphoinositide 3-kinase alpha (PI3KC2α) results in an increase in vascular permeability, we uncover a crucial role of the beta isoform (PI3KC2β) in the loss of endothelial barrier integrity following injury. Here, we studied the role of PI3KC2β in endothelial permeability and endosomal trafficking in vitro and in vivo in ischemic stroke. Mice with inactive PI3KC2β showed protection against vascular permeability, edema, cerebral infarction, and deleterious inflammatory response. Loss of PI3KC2β in human cerebral microvascular endothelial cells stabilized homotypic cell-cell junctions by increasing Rab11-dependent VE-cadherin recycling. These results identify PI3KC2β as a potential new therapeutic target to prevent aggravating lesions following ischemic stroke.

Background/Aims: Natural killer (NK) cells are among the first immune cells that respond to an ischemic insult in human brains. The infiltrated NK cells damage blood-brain barrier (BBB) and exacerbate brain infarction. Buyang Huanwu Decoction (BHD), a classic Chinese traditional herbal prescription, has long been used for the treatment of ischemic stroke. The present study investigated whether BHD can prevent brain infiltration of NK cells, attenuate BBB disruption and improve ischemic outcomes. Methods: Transient focal cerebral ischemia was induced in rats by a 60-minute middle cerebral artery occlusion, and BHD was orally administrated at the onset of reperfusion, 12 hours later, then twice daily. Assessed parameters on Day 3 after ischemia were: neurological and motor functional deficits through neurological deficit score and rotarod test, respectively; brain infarction through TTC staining; BBB integrity through Evans blue extravasation; matrix metalloproteinase-2/9 activities through gelatin zymography; tight junction protein, nuclear factor-kB (NF-kB) p65 and phospho-p65 levels through Western blotting; NK cell brain infiltration and CXCR3 levels on NK cells through flow cytometry; interferon-γ production through ELISA; CXCL10 mRNA levels through real-time PCR; CXCL10 expression and p65 nuclear translocation through immunofluorescence staining. Results: BHD markedly reduced brain infarction, improved rotarod performance, and attenuated BBB breakdown. Concurrently, BHD attenuated the upregulation of matrix metalloproteinase-2/9 activities and the degradation of tight junction proteins in the ischemic brain. Infiltration of NK cells was observed in the ischemic hemisphere, and this infiltration was blunted by treatment with BHD. BHD suppressed brain ischemia-induced interferon-γ and chemokine CXCL10 production. Furthermore, BHD significantly reduced the expression of CXCR3 on brain-infiltrated NK cells. Strikingly, BHD did not affect NK cell levels or its CXCR3 expression in the spleen or peripheral blood after brain ischemia. The nuclear translocation of NF-kB p65 and phospho-p65 in the ischemic brain was inhibited by BHD. Conclusion: Our findings suggest that BHD prevents brain infiltration of NK cells, preserves BBB integrity and eventually improves ischemic outcomes. The inhibitory effects of BHD on NK cell brain invasion may involve its ability of suppressing NF-kB-associated CXCL10-CXCR3-mediated chemotaxis. Notably, BHD only suppresses NK cells and their CXCR3 expression in the ischemic brain, but not those in periphery.

Enolase-Phosphatase 1 (Enoph1), a newly discovered enzyme of the methionine salvage pathway, has been identified as a candidate gene involved in the modulation of stress responses. In the present study, we investigated the effect of Enoph1 on ischemic blood brain barrier (BBB) injury on an in vitro model of oxygen-glucose deprivation (OGD) and an in vivo rat model of middle cerebral artery occlusion (MCAO). Cell death and apoptosis were assessed by measuring 3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide formation, lactate dehydrogenase release and TdT-mediated dUTP-biotin nick end labeling staining. BBB disruption was evaluated based on fluorescein-labeled albumin (FITC-albumin) extravasation. ROS generation was assessed by DCFH staining. Real time-PCR and western blot were used to measure mRNA and protein expression, respectively. CRISPR-activated plasmid and siRNA were applied to manipulate Enoph1 expression in brain microvascular endothelial cells (BMVECs). Exposure of BMVECs to OGD for 6 hours markedly increased Enoph1 expression and decreased the protein levels of its substrate aci-reductone dioxygenase 1 (ADI1) protein, which was accompanied by membrane type 1 matrix metalloproteinase (MT1-MMP) upregulation, increased apoptotic cell death and ROS generation. Increased Enoph1 expression was also observed in ischemic cerebromicrovassels where FITC-albumin extravasation was observed, indicating the co-localization of BBB disruption and increased Enoph1 expression. Knockdown of Enoph1 expression with siRNA significantly inhibited OGD-induce apoptosis, ROS generation, ADI1 protein reduction and MT1-MMP upregulation in BMVECs, while overexpression of Enoph1 CRISPR-activated plasmids exacerbated OGD-induced cell death and ROS generation. Of note, overexpression of ADI1 or knockdown of MT1-MMP with siRNA significantly blocked OGD-induced BMVECs apoptosis. In conclusion, our data demonstrate for the first time that cerebral ischemia activates Enoph1-ADI1-MT1-MMP axis to mediate BMVEC apoptosis and BBB disruption, and Enoph1 may represent a new therapeutic target for ischemic stroke.

BackgroundImpairment of the blood-brain barrier (BBB) in severe acute pancreatitis (SAP) could result in life-threatening pancreatic encephalopathy. Interleukin-10 (IL-10) is a classical cytokine that is well-known for its strong immunoregulatory and anti-inflammatory abilities. However, whether and how IL-10 protects the BBB in SAP are still unclear.MethodsThis study includes in vivo experiments using a SAP rat model and in vitro experiments using an in vitro BBB model consisting of a monolayer of brain microvascular endothelial cells (BMECs). The study groups are divided into the control, SAP (in vivo)/TNF-α (in vitro), IL-10 treatment, IL-10 + signal transducer and activator of transcription 3 (STAT3) inhibitor S3I-201 treatment groups. Pancreatic pathological scores, serum amylase, serum TNF-α levels and BBB permeability by Evan’s blue assay in SAP rat models were evaluated. BMEC apoptosis in SAP rats or induced by TNF-αin vitro was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and flow cytometry, separately. Expression levels of claudin-5 and proteins involved in the STAT3 signaling pathway were measured by Western blotting. Location and changes of junctional structure of claudin-5 on BMECs were assessed by immunohistochemistry and immunofluorescence.ResultsIn vivo, IL-10 alleviated the severity of inflammation, attenuated the increased BBB permeability in SAP rat models by reducing BMEC apoptosis via the STAT3 pathway and ameliorated the down-regulation of claudin-5 expression in BMECs; in vitro, IL-10 improved BBB integrity against TNF-α by attenuating BMEC apoptosis via the STAT3 pathway, the impairment of tight junction structure and the down-regulation of claudin-5 expression in BMECs.ConclusionsIL-10 improves BBB properties in SAP by attenuating the down-regulation of claudin-5 expression and the impairment of tight junctions and by STAT3 pathway-mediated anti-apoptotic effects on BMECs.

MicroRNAs (miRNAs) are highly expressed in the brain and represent promising therapeutic targets for the treatment of ischemic stroke. Previous studies have shown that microRNA-195 (miR-195) is associated with apoptosis and is significantly upregulated in the serum of patients with ischemic stroke. We aimed to confirm the role of miR-195 in brain microvascular endothelial cell (BMEC) apoptosis and blood-brain barrier (BBB) integrity. bEnd.3 cells were exposed to oxygen-glucose deprivation/reperfusion (OGD/R). RT-qPCR was used to determine the relative expression of miRNA-195. Bioinformatics analysis using the TargetScan database predicted BCL2L2 as a potential target of miR-195. A BBB model was constructed by culturing bEnd.3 cells in the upper Transwell chambers. Transepithelial/transendothelial electrical resistance (TEER) and the fluorescein isothiocyanate (FITC)-dextran assay were used to assess BBB permeability. Immunofluorescence staining for caspase-3, TdT-mediated dUTP nick end labeling (TUNEL) staining, and flow cytometric analysis were used to measure bEnd.3 cell apoptosis. Tight junction proteins (TJPs) expression was determined using western blot analysis. miR-195 expression was upregulated in the in vitro OGD/R model. miR-195 mimics exacerbated cellular apoptosis and BBB disruption following OGD/R, whereas the miR-195 inhibitor alleviated OGD/R-induced apoptosis and BBB impairment. Overexpression of miR-195 significantly reduced BCL2L2 expression, and luciferase reporter assays confirmed that miR-195 directly binds to BCL2L2. Co-transfection of miR-195 mimics and BCL2L2 partially reversed the effects of miR-195 mimics on cell survival and barrier function. Our results suggest that the miR-195/BCL2L2 axis plays a critical role in the regulation of bEnd.3 cell apoptosis. Modulation of miR-195 may represent a novel therapeutic strategy for targeting BMEC apoptosis in ischemic stroke.

This study was undertaken to investigate the role of apoptosis in the integrity of blood-brain barrier (BBB) in subarachnoid hemorrhage (SAH). BBB permeability changes were examined and found increased on day 7 in a double hemorrhage rat model using Evans blue dye. The BBB permeability increase is coincidental to brain microvascular endothelial cell apoptosis (expression of caspase-8 and -9) occurring on Day 7. However, caspase-8 and caspase-9 inhibitors failed to protect the BBB. Considering that treatment did not completely inhibit apoptosis in brain microvascular endothelial cells, higher doses, earlier and/or multiple applications, and, possibly, more potent caspase inhibitors may be needed.

BackgroundTraumatic brain injury (TBI) is a significant worldwide public health concern that necessitates attention. Apoptosis signal-regulating kinase 1 (ASK1), a key player in various central nervous system (CNS) diseases, has garnered interest for its potential neuroprotective effects against ischemic stroke and epilepsy when deleted. Nonetheless, the specific impact of ASK1 on TBI and its underlying mechanisms remain elusive. Notably, mutation of ATP-binding sites, such as lysine residues, can lead to catalytic inactivation of ASK1. To address these knowledge gaps, we generated transgenic mice harboring a site-specific mutant ASK1 Map3k5-e (K716R), enabling us to assess its effects and elucidate potential underlying mechanisms following TBI.MethodsWe employed the CRIPR/Cas9 system to generate a transgenic mouse model carrying the ASK1-K716R mutation, aming to investigate the functional implications of this specific mutant. The controlled cortical impact method was utilized to induce TBI. Expression and distribution of ASK1 were detected through Western blotting and immunofluorescence staining, respectively. The ASK1 kinase activity after TBI was detected by a specific ASK1 kinase activity kit. Cerebral microvessels were isolated by gradient centrifugation using dextran. Immunofluorescence staining was performed to evaluate blood–brain barrier (BBB) damage. BBB ultrastructure was visualized using transmission electron microscopy, while the expression levels of endothelial tight junction proteins and ASK1 signaling pathway proteins was detected by Western blotting. To investigate TBI-induced neuroinflammation, we conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry analyses. Additionally, immunofluorescence staining and electrophysiological compound action potentials were conducted to evaluate gray and white matter injury. Finally, sensorimotor function and cognitive function were assessed by a battery of behavioral tests.ResultsThe activity of ASK1-K716R was significantly decreased following TBI. Western blotting confirmed that ASK1-K716R effectively inhibited the phosphorylation of ASK1, JNKs, and p38 in response to TBI. Additionally, ASK1-K716R demonstrated a protective function in maintaining BBB integrity by suppressing ASK1/JNKs activity in endothelial cells, thereby reducing the degradation of tight junction proteins following TBI. Besides, ASK1-K716R effectively suppressed the infiltration of peripheral immune cells into the brain parenchyma, decreased the number of proinflammatory-like microglia/macrophages, increased the number of anti-inflammatory-like microglia/macrophages, and downregulated expression of several proinflammatory factors. Furthermore, ASK1-K716R attenuated white matter injury and improved the nerve conduction function of both myelinated and unmyelinated fibers after TBI. Finally, our findings demonstrated that ASK1-K716R exhibited favorable long-term functional and histological outcomes in the aftermath of TBI.ConclusionASK1-K716R preserves BBB integrity by inhibiting ASK1/JNKs pathway in endothelial cells, consequently reducing the degradation of tight junction proteins. Additionally, it alleviates early neuroinflammation by inhibiting the infiltration of peripheral immune cells into the brain parenchyma and modulating the polarization of microglia/macrophages. These beneficial effects of ASK1-K716R subsequently result in a reduction in white matter injury and promote the long-term recovery of neurological function following TBI.

The present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxic-ischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O(2) for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury.

High-frequency rTMS inhibits astrocyte reactive activation and protects blood-brain barrier function after cerebral infarction via the miR-665/STAT3/MMP-9 axis.

The protective effects of Axitinib on blood-brain barrier dysfunction and ischemia-reperfusion injury in acute ischemic stroke

Background: Microvascular thromboinflammation is a major pathomechanism underlying vaso-occlusive crisis in patients with sickle cell disease (SCD), yet its role underlying the elevated stroke risk in SCD is unclear. Tissue-based blood brain barrier (BBB) imaging, as a metric of cerebral thromboinflammation, has not been well studied in SCD. We hypothesized that BBB permeability would be increased in patients with SCD and associated with ischemic burden. Methods: Ten young adults with SCD and 17 controls underwent dynamic contrast-enhanced and multimodal MRI to quantify BBB gadolinium leakage rates (Ktrans), white matter microstructural disruption (increased mean diffusivity, MD), and volume of silent cerebral infarcts (SCI). Infarct voxels were removed to avoid the confounding effects of measuring Ktrans in previously infarcted tissue. Whole brain mean Ktrans measures were compared between SCD vs. controls. Bivariate Spearman’s rank correlations measured relationships between Ktrans and SCI volume / MD. Results: BBB permeability, measured by whole brain Ktrans, was elevated in SCD vs. controls (Fig A). Compared to controls, Ktrans was elevated in SCD with infarcts (B), while SCD without infarcts did not differ from controls. In participants with infarcts, Ktrans, measured within non-infarcted tissue, positively correlated with SCI volume (Rho=0.6, p =0.015, C). Furthermore, whole brain Ktrans, positively correlated with MD in normal appearing white matter (Rho=0.5, p =0.01). Conclusion: Our preliminary data suggest BBB permeability is elevated and associated with stroke and microstructural injury in young adults with SCD. We are enrolling more participants. Children with SCD may also have BBB injury but will require a novel non-contrasted MR approach to assess. BBB permeability may provide new insight into the increased stroke risk in SCD. Targeting thromboinflammation and preserving BBB integrity may lead to novel neuroprotective pathways.

The blood-brain barrier (BBB) plays a critical role in the development and outcome of subarachnoid hemorrhage (SAH). This study focuses on the potential mechanism by which G-protein-coupled estrogen receptor 30 (GPR30) affects the BBB after SAH. A rat SAH model was established using an intravascular perforation approach. G1 (GPR30 agonist) was administered to investigate the mechanism of BBB damage after SAH. Brain water content, Western blotting, Evans blue leakage, and immunofluorescence staining were performed. Brain microvascular endothelial cells were induced by hemin to establish SAH model in vitro. By adding LY294002 [a phosphatidylinositol 3-kinase (PI3K) blocker] and zinc protoporphyrin IX (ZnPP IX) [a heme oxygenase 1 (HO-1) antagonist], the mechanism of improving BBB integrity through the activation of GPR30 was studied. In vivo, GPR30 activation improved BBB disruption, as evidenced by decreased cerebral edema, downregulated albumin expression, and reduced extravasation of Evans blue and IgG after G1 administration in SAH rats. Moreover, SAH downregulated the levels of tight junction (TJ) proteins, whereas treatment with G1 reversed the effect of SAH. The protective effect of G1 on BBB integrity in vitro was consistent with that in vivo, as evidenced by G1 reducing the impact of hemin on transendothelial electrical resistance (TEER) value, dextran diffusivity, and TJ protein levels in brain microvascular endothelial cells. In addition, G1 activated the PI3K/ protein kinase B (Akt) and nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathways both in vivo and in vitro. Furthermore, the administration of LY294002 and ZnPP IX partially reversed the protective effect of G1 on BBB integrity in hemin-stimulated cells. We demonstrated that the activation of GPR30, at least partly through the PI3K/Akt and Nrf2/HO-1 pathways, alleviated BBB damage both in vivo and in vitro. This study introduced a novel therapeutic approach for protecting the BBB after SAH.NEW & NOTEWORTHY The PI3K/Akt and Nrf2/HO-1 pathways might be potential mechanisms by which GPR30 protected the integrity of the BBB in SAH models. Therefore, treatment of SAH with GPR30 activator might be a promising therapeutic strategy.

This study investigated whether oxLDL and/or angiotensin (Ang) II signaling pathways mediate traffic-generated air pollution- exposure induced alterations in blood-brain barrier (BBB) integrity and permeability in a healthy wild type (C57Bl/6) mouse model; additionally, whether these outcomes are exacerbated by a high fat-diet investigated. An environmentally relevant concentration of a mixture of vehicle engine exhaust (MVE) was used. To investigate the hypotheses, 12 wk old male C57Bl/6 mice on either a high fat (HF) or low fat (LF) diet were randomly assigned to inhalational exposure of either filtered-air (FA) or 30 µg PM/m3 diesel exhaust + 70 µg PM/m3 gasoline exhaust (MVE) for 6 hr/day for 30 days. Additionally, we examined mechanisms involved in MVE-mediated alterations BBB integrity using a novel BBB co-culture in vitro model, consisting of mouse primary cerebral vascular endothelial cells on an apical transwell and astrocytes in the basal compartment, which was treated with plasma from the mice on our exposure study. Our in vivo exposure study results showed that MVE inhalation resulted in increased circulating plasma oxLDL and Ang II, compared to FA controls. Additionally, we observed increased cerebral microvascular expression of oxLDL receptors, LOX-1 and CD-36, and Ang II receptor subtype 1 (AT1) in MVE-exposed C57Bl/6 mice, which was further exacerbated with consumption of an HF diet. Increased signaling of both Ang II and oxLDL was associated with decreased BBB integrity, as evidenced by the concurrent reduction in expression of tight junction (TJ) protein claudin-5 and increased permeability of sodium fluorescein (Na-F) from the blood into the cerebral parenchyma. Our results suggest that possible mechanisms involved in oxLDL and/or Ang II-mediated alterations in BBB integrity include oxidative stress and upregulated expression and activity of matrix metalloproteinase (MMP)-9, which is associated with degradation of TJ proteins in the BBB. Our in vitro BBB co-culture results confirm our in vivo findings, as we observe increased BBB permeability (TEER) and decreased integrity (decreased expression of TJ proteins) in the endothelial (apical) layer when treated with plasma from MVE-exposed mice, which was further exacerbated when treated with plasma from MVE-exposed mice on an HF diet. Pre-treatment of the endothelial cells with the AT1 receptor antagonist, Losartan, prior to applying plasma, resulted in attenuation of the alterations observed in endothelial integrity in the BBB co-culture treated with plasma from either MVE+LF or MVE+HF animals. These results suggest Ang II – AT1 signaling mediate, at least in part, the alterations in the BBB integrity observed after exposure to MVE. Moreover, we observed that treatment of the endothelial (apical) layer with plasma from MVE-exposed animals resulted in increased production of inflammatory mediators interleukin-6 (IL-6) and transforming growth factor-β in the astrocyte media (basal compartment). Additionally, these same astrocytes also displayed increased production of angiotensin-converting enzyme (ACE) and also AT1 receptor mRNA expression, while showing decreased expression of the aryl hydrocarbon receptor (AhR) and glutathione peroxidase (GPx). Collectively, these results suggest that exposure to the ubiquitous environmental air pollutant, vehicle engine emissions, results in increased oxLDL and Ang II signaling in the cerebral microvasculature, which is associated with decreased vessel integrity and increased oxidative stress and inflammatory signaling in the CNS. The observed detrimental outcomes are even further exacerbated when coupled with the consumption of an HF diet.

Activated neutrophil-derived exosomes contribute to blood–brain barrier damage and hemorrhagic transformation after cerebral ischemia/reperfusion