Dodging blood brain barrier with "nano" warriors: Novel strategy against ischemic stroke.
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ABSTRACT:
SUBMITTER: Parvez S
PROVIDER: S-EPMC8692911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The inflammatory response plays a pivotal role in Blood-Brain Barrier (BBB) destruction following ischemic brain injury. Enhanced leukocyte adhesion to vascular endothelial cells is an essential event in the inflammatory process. TMEM16A, a newly discovered protein regulating calcium-activated chloride channels, is widely expressed in eukaryotes. Recent studies have suggested that upregulated expression of TMEM16A is associated with the occurrence and development of many diseases. However, the role of TMEM16A in regulating BBB integrity after ischemic stroke has not been fully investigated. In this study, we found that TMEM16A is mainly expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. Caccinh-A01, an TMEM16A inhibitor that reduced its upregulation, attenuated brain infarct size and neurological deficits after ischemic stroke. ICAM-1 and MPO expression and BBB permeability were decreased after TMEM16A inhibitor administration. In addition, TMEM16A silencing rescued oxygen-glucose deprivation/reoxygenation (OGD/R)-induced transendothelial permeability in vitro accompanied by decreased ICAM-1 expression and leukocyte adhesion. Furthermore, our mechanistic study showed that TMEM16A knockdown alleviated NF-κB activation and nuclear translocation, indicating that TMEM16A knockdown downregulated OGD/R-induced ICAM-1 expression in an NF-κB-dependent manner. Finally, NF-κB inhibitor treatment also alleviated OGD/ R-induced BBB permeability, confirming that activated NF-κB and increased ICAM-1 are essential factors involved in ischemia-induced BBB damage. Thus, our research provides a promising treatment strategy against BBB destruction after ischemic stroke, and TMEM16A may become a potential target for the treatment of ischemic stroke.
| S-EPMC6691060 | biostudies-literature
Project description:The dynamics of BBB permeability after AIS in humans are not well understood. In the present study we measured the evolution of BBB permeability after AIS in humans using MRI. Patients presenting to our institution with a diagnosis of AIS underwent a single dynamic contrast-enhanced MRI (DCE-MRI) sequence to measure BBB permeability during their initial workup. Forty-two patients were included in the final analysis. The patient sample underwent DCE-MRI at a mean time of 23.8hrs after the onset of AIS symptoms (range: 1.3-90.7hrs). At all time-points the BBB permeability within the infarct region of the brain as defined on DWI/ADC was higher compared to the homologous region of the contralateral hemisphere (p<0.005). BBB permeability, expressed as a ratio of infarct permeability to contralateral permeability, was greatest at 6-48hrs after the onset of AIS. Although the data was not acquired longitudinally, these findings suggest that the permeability of the BBB is continually elevated following AIS, which contradicts previous assertions that BBB permeability after AIS follows a biphasic course. Knowledge of BBB dynamics following AIS may provide insight into future treatments for AIS, especially BBB stabilizing agents.
| S-EPMC5313141 | biostudies-literature
Project description:AimsIschemic stroke is a life-threatening disease with limited therapeutic strategies. Blood-brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.MethodsMiddle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.ResultsAIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM-1 and decreased those of the tight junction (TJ) proteins ZO-1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM-1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R-induced increases in ICAM-1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p-STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.ConclusionOur findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
| S-EPMC8446221 | biostudies-literature
Project description:Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood-brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor ? (PDGFR-?) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-?- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.
| S-EPMC6110873 | biostudies-literature
Project description:Integrity of the blood-brain barrier structure is essential for maintaining the internal environment of the brain. Development of cerebral infarction and brain edema is strongly associated with blood-brain barrier leakage. Therefore, studies have suggested that protecting the blood-brain barrier may be an effective method for treating acute stroke. To examine this possibility, stroke model rats were established by middle cerebral artery occlusion and reperfusion. Remote ischemic postconditioning was immediately induced by three cycles of 10-minute ischemia/10-minute reperfusion of bilateral hind limbs at the beginning of middle cerebral artery occlusion reperfusion. Neurological function of rat models was evaluated using Zea Longa's method. Permeability of the blood-brain barrier was assessed by Evans blue leakage. Infarct volume and brain edema were evaluated using 2,3,5-triphenyltetrazolium chloride staining. Expression of matrix metalloproteinase-9 and claudin-5 mRNA was determined by real-time quantitative reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-9 and claudin-5 protein was measured by western blot assay. The number of matrix metalloproteinase-9- and claudin-5-positive cells was analyzed using immunohistochemistry. Our results showed that remote ischemic postconditioning alleviated disruption of the blood-brain barrier, reduced infarct volume and edema, decreased expression of matrix metalloproteinase-9 mRNA and protein and the number of positive cells, increased expression of claudin-5 mRNA and protein and the number of positive cells, and remarkably improved neurological function. These findings confirm that by suppressing expression of matrix metalloproteinase-9 and claudin-5 induced by acute ischemia/reperfusion, remote ischemic postconditioning reduces blood-brain barrier injury, mitigates ischemic injury, and exerts protective effects on the brain.
| S-EPMC6126140 | biostudies-literature
Project description:Ischemic stroke is a devastating disease with limited therapeutic options. It is very urgent to find a new target for drug development. Here we found that the blood level of MIF in ischemic stroke patients is upregulated. To figure out the pathological role of MIF in ischemic stroke, both in vitro and in vivo studies were conducted. For in vitro studies, primary cortical neuron cultures and adult rat brain endothelial cells (ARBECs) were subjected to oxygen-glucose deprivation (OGD)/reoxygenation. Middle cerebral artery occlusion (MCAo) rodent models were used for in vivo studies. The results show that MIF exerts no direct neuronal toxicity in primary culture but disrupts tight junction in ARBECs. Furthermore, administration of MIF following MCAo shows the deleterious influence on stroke-induced injury by destroying the tight junction of blood-brain barrier and increasing the infarct size. In contrast, administration of MIF antagonist ISO-1 has the profound neuroprotective effect. Our results demonstrate that MIF might be a good drug target for the therapy of stroke.
| S-EPMC5768806 | biostudies-literature
Project description:ObjectiveIn patients with acute ischemic stroke, we aimed to investigate the relation between preexisting small vessel disease (SVD) and the amount of blood-brain barrier (BBB) leakage in ischemic and nonischemic area before IV thrombolysis.MethodsWe retrospectively accessed anonymous patient-level data from the Stroke Imaging Repository and the Virtual International Stroke Trials Archive resources and included patients treated with IV thrombolysis with pretreatment MRI. We rated SVD features using validated qualitative magnetic resonance (MR) scales. Leakage of BBB was assessed with postprocessing of perfusion-weighted images. We evaluated associations between SVD features (individually and summed in a global SVD score) and BBB leakage using linear regression analysis, adjusting for major clinical confounders.ResultsA total of 212 patients, mean age (±SD) 69.5 years (±16.1), 102 (48%) male, had available MR before IV thrombolysis. Evidence of BBB leakage was present in 175 (80%) and 205 (94%) patients in the ischemic and nonischemic area, respectively. Lacunar infarcts (β = 0.17, p = 0.042) were associated with BBB leakage in the ischemic area, and brain atrophy was associated with BBB leakage in both ischemic (β = 0.20, p = 0.026) and nonischemic (β = 0.27, p = 0.001) areas. Increasing SVD grade was independently associated with BBB leakage in both ischemic (β = 0.26, p = 0.007) and nonischemic (β = 0.27, p = 0.003) area.ConclusionsGlobal SVD burden is associated with increased BBB leakage in both acutely ischemic and nonischemic area. Our results support that SVD score has construct validity, and confirm a relation between SVD and BBB disruption also in patients with acute stroke.
| S-EPMC5696647 | biostudies-literature
Project description:Ischemic stroke occurs when a clot forms in the brain vasculature that starves downstream tissue of oxygen and nutrients resulting in cell death. The tissue immediately downstream of the blockage, the core, dies within minutes, but the surrounding tissue, the penumbra is potentially salvageable. Prostaglandin E2 binds to four different G-protein coupled membrane receptors EP1-EP4 mediating different and sometimes opposing responses. Pharmacological activation of the EP4 receptor has already been established as neuroprotective in stroke, but the mechanism(s) of protection are not well-characterized. In this study, we hypothesized that EP4 receptor activation reduces ischemic brain injury by reducing matrix metalloproteinase (MMP)-3/-9 production and blood-brain barrier (BBB) damage. Rats underwent transient ischemic stroke for 90 min. Animals received an intravenous injection of either the vehicle or L-902,688, a highly specific EP4 agonist, at the onset of reperfusion. Brain tissue was harvested at 24 h. We established a dose-response curve and used the optimal dose that resulted in the greatest infarct reduction to analyze BBB integrity compared to vehicle-treated rats. The presence of IgG, a blood protein, in the brain parenchyma is a marker of BBB damage, and L-902,688 (1 mg/kg; i.v.) dramatically reduced IgG extravasation (P < 0.05). Consistent with these data, we assessed zona occludens-1 and occludin, tight junction proteins integral to the maintenance of the BBB, and found reduced degradation with L-902,688 administration. With immunoblotting, qRT-PCR, and/or a fluorescence resonance energy transfer (FRET)-based activity assay, we next measured MMP-3/-9 since they are key effectors of BBB breakdown in stroke. In the cerebral cortex, not only was MMP-3 activity significantly decreased (P < 0.05), but L-902,688 treatment also reduced MMP-9 mRNA, protein, and enzymatic activity (P < 0.001). In addition, post-ischemic administration of the EP4 agonist significantly reduced pro-inflammatory cytokines IL-1β (P < 0.05) and IL-6 (P < 0.01) in the ischemic cerebral cortex. Most importantly, one injection of L-902,688 (1 mg/kg; i.v) at the onset of reperfusion significantly reduces neurological deficits up to 3 weeks later (P < 0.05). Our data show for the first time that pharmacological activation of EP4 with L-902,688 is neuroprotective in ischemic stroke by reducing MMP-3/-9 and BBB damage.
| S-EPMC5829545 | biostudies-literature
Project description:Blood-brain barrier (BBB) damage after ischemia significantly influences stroke outcome. Compound LFHP-1c was previously discovered with neuroprotective role in stroke model, but its mechanism of action on protection of BBB disruption after stroke remains unknown. Here, we show that LFHP-1c, as a direct PGAM5 inhibitor, prevented BBB disruption after transient middle cerebral artery occlusion (tMCAO) in rats. Mechanistically, LFHP-1c binding with endothelial PGAM5 not only inhibited the PGAM5 phosphatase activity, but also reduced the interaction of PGAM5 with NRF2, which facilitated nuclear translocation of NRF2 to prevent BBB disruption from ischemia. Furthermore, LFHP-1c administration by targeting PGAM5 shows a trend toward reduced infarct volume, brain edema and neurological deficits in nonhuman primate Macaca fascicularis model with tMCAO. Thus, our study identifies compound LFHP-1c as a firstly direct PGAM5 inhibitor showing amelioration of ischemia-induced BBB disruption in vitro and in vivo, and provides a potentially therapeutics for brain ischemic stroke.
| S-EPMC8343116 | biostudies-literature
Project description:Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation.
| S-EPMC6007054 | biostudies-literature