Disruption of the Blood-Brain Barrier During Neuroinflammatory and Neuroinfectious Diseases
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ABSTRACT:
SUBMITTER: Mitoma H
PROVIDER: S-EPMC7121618 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Project description:Ginseng has long been considered as an herbal medicine. Recent data suggest that ginseng has anti-inflammatory properties and can improve learning- and memory-related function in the central nervous system (CNS) following the development of CNS neuroinflammatory diseases such as Alzheimer's disease, cerebral ischemia, and other neurological disorders. In this review, we discuss the role of ginseng in the neurovascular unit, which is composed of endothelial cells surrounded by astrocytes, pericytes, microglia, neural stem cells, oligodendrocytes, and neurons, especially their blood-brain barrier maintenance, anti-inflammatory effects and regenerative functions. In addition, cell-cell communication enhanced by ginseng may be attributed to regeneration via induction of neurogenesis and angiogenesis in CNS diseases. Thus, ginseng may have therapeutic potential to exert cognitive improvement in neuroinflammatory diseases such as stroke, traumatic brain injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.
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Project description:The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood-brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.
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Project description:Background and purposeCNS complications are often seen after heart surgery, and postsurgical disruption of the BBB may play an etiologic role. The objective of this study was to determine the prevalence of MR imaging-detected BBB disruption (HARM) and DWI lesions after cardiac surgery.Materials and methodsAll patients had an MRI after cardiac surgery. For half the patients (group 1), we administered gadolinium 24 hours after surgery and obtained high-resolution DWI and FLAIR images 24-48 hours later. We administered gadolinium to the other half (group 2) at the time of the postoperative scan, 2-4 days after surgery. Two stroke neurologists evaluated the images.ResultsOf the 19 patients we studied, none had clinical evidence of a stroke or delirium at the time of the gadolinium administration or the scan, but 9 patients (47%) had HARM (67% in group 1; 30% in group 2; P = .18) and 14 patients (74%) had DWI lesions (70% in group 1; 78% in group 2; P = 1.0). Not all patients with DWI lesions had HARM, and not all patients with HARM had DWI lesions (P = .56).ConclusionsAlmost half the patients undergoing cardiac surgery have evidence of HARM, and three-quarters have acute lesions on DWI after surgery. BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MR imaging can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.
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Project description:Yuzu and its main component, hesperidin (HSP), have several health benefits owing to their anti-inflammatory and antioxidant properties. We examined the effects of yuzu and HSP on blood-brain barrier (BBB) dysfunction during ischemia/hypoxia in an in vivo animal model and an in vitro BBB endothelial cell model, and also investigated the underlying mechanisms. In an in vitro BBB endothelial cell model, BBB permeability was determined by measurement of Evans blue extravasation in vivo and in vitro. The expression of tight junction proteins, such as claudin-5 and zonula occludens-1 (ZO-1), was detected by immunochemistry and western blotting, and the reactive oxygen species (ROS) level was measured by 2'7'-dichlorofluorescein diacetate intensity. Yuzu and HSP significantly ameliorated the increase in BBB permeability and the disruption of claudin-5 and ZO-1 in both in vivo and in vitro models. In bEnd.3 cells, yuzu and HSP were shown to inhibit the disruption of claudin-5 and ZO-1 during hypoxia, and the protective effects of yuzu and HSP on claudin-5 degradation seemed to be mediated by Forkhead box O 3a (FoxO3a) and matrix metalloproteinase (MMP)-3/9. In addition, well-known antioxidants, trolox and N-acetyl cysteine, significantly attenuated the BBB permeability increase, disruption of claudin-5 and ZO-1, and FoxO3a activation during hypoxia, suggesting that ROS are important mediators of BBB dysfunction during hypoxia. Collectively, these results indicate that yuzu and HSP protect the BBB against dysfunction via maintaining integrity of claudin-5 and ZO-1, and these effects of yuzu and HSP appear to be a facet of their antioxidant properties. Our findings may contribute to therapeutic strategies for BBB-associated neurodegenerative diseases.
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Project description:BackgroundPrevious studies demonstrated that cardioembolism (CE) was prone to develop hemorrhagic transformation (HT), whereas hyper-permeability of blood-brain barrier (BBB) might be one reason for the development of HT. We, thus, aimed to investigate whether the BBB permeability (BBBP) was higher in CE stroke than other stroke subtypes in acute ischemic stroke (AIS) patients.MethodsThis study was a retrospective review of prospectively collected clinical and imaging database of AIS patients who underwent CT perfusion. Hypoperfusion was defined as Tmax >6?s. The average relative permeability-surface area product (rPS), reflecting the BBBP, was calculated within the hypoperfusion region (rPShypo). CE was diagnosed according to the international Trial of Org 10172 in Acute Stroke Treatment criteria. Receiver operating characteristics (ROC) curve analysis was used to determine predictive value of rPShypo for CE. Logistic regression was used to identify independent predictors for CE.ResultsA total of 187 patients were included in the final analysis [median age, 73 (61-80) years; 75 (40.1%) females; median baseline National Institutes of Health Stroke Scale score, 12 (7-16)]. Median rPShypo was 65.5 (35.8-110.1)%. Ninety-seven (51.9%) patients were diagnosed as CE. ROC analysis revealed that the optimal rPShypo threshold for CE was 86.71%. The value of rPShypo and the rate of rPShypo>86.71% were significantly higher in patients with CE than other stroke subtypes (p?<?0.05), after adjusting for the potential confounds.ConclusionThe extent of BBB disruption is more severe in CE stroke than other stroke subtypes during the hyperacute stage.
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Project description:The meninges serve as a functional barrier surrounding the brain, critical to the immune response, and can be compromised following head trauma. Meningeal enhancement can be detected on contrast-enhanced MRI in patients presenting with acute traumatic brain injury, even when head CT is negative. Following head trauma, gadolinium-based contrast appears to extravasate from the vasculature, enhancing the dura within minutes, and later permeates the subarachnoid space. The aims of this study were to characterize the initial kinetics of the uptake of contrast agent after injury and the delayed redistribution of contrast enhancement in the subarachnoid space in hyperacute patients. Neuroimaging was obtained prospectively in two large ongoing observational studies of patients aged 18 years or older presenting to the emergency department with suspected acute head injury. Dynamic contrast-enhanced MRI studies in a cohort of consecutively enrolling patients with mild traumatic brain injury (n = 36) determined that the kinetic half-life of dural-related meningeal enhancement was 1.3 ± 0.6 min (95% enhancement within 6 min). The extravasation of contrast into the subarachnoid space was investigated in a cohort of CT negative mild traumatic brain injury patients initially imaged within 6 h of injury (hyperacute) who subsequently underwent a delayed MRI, with no additional contrast administration, several hours after the initial MRI. Of the 32 patients with delayed post-contrast imaging, 18 (56%) had conspicuous expansion of the contrast enhancement into the subarachnoid space, predominantly along the falx and superior sagittal sinus. Patients negative for traumatic meningeal enhancement on initial hyperacute MRI continued to have no evidence of meningeal enhancement on the delayed MRI. These studies demonstrate that (i) the initial enhancement of the traumatically injured meninges occurs within minutes of contrast injection, suggesting highly permeable meningeal vasculature, and that (ii) contrast in the meninges redistributes within the subarachnoid space over the period of hours, suggesting a compromise in the blood-brain and/or blood-cerebrospinal barriers. Data from the parent study indicate that up to one in two patients with mild traumatic brain injury have traumatic brain injury on acute (<48 h) MRI, with a higher prevalence seen in patients with moderate or severe traumatic brain injury. The current study's findings of traumatic meningeal enhancement and the subsequent delayed extravasation of contrast into the subarachnoid spaces indicate that a substantial percentage of patients with even mild traumatic brain injury may have a transient disruption in barriers separating the vasculature from the brain.
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Project description:Viral infections of the central nervous system (CNS) are often associated with blood-brain barrier (BBB) disruption, yet the impact of virus replication and immune cell recruitment on BBB integrity are incompletely understood. Using two-photon microscopy, we demonstrate that Venezuelan equine encephalitis virus (VEEV) strain TC83-GFP, a GFP expressing, attenuated strain with a G3A mutation within the 5' UTR that is associated with increased sensitivity to type I interferons (IFNs), does not directly impact BBB permeability. Following intranasal infection of both wild-type and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1)-deficient mice, which fail to block TC83-specific RNA translation, virus spreads to the olfactory bulb and cortex via migration along axonal tracts of neurons originating from the olfactory neuroepithelium. Global dissemination of virus in the CNS by 2days post-infection (dpi) was associated with increased BBB permeability in the olfactory bulb, but not in the cortex or hindbrain, where permeability only increased after the recruitment of CX3CR1+ and CCR2+ mononuclear cells on 6 dpi, which corresponded with tight junction loss and claudin 5 redistribution. Importantly, despite higher levels of viral replication, similar results were obtained in IFIT1-deficient mice. These findings indicate that TC83 gains CNS access via anterograde axonal migration without directly altering BBB function and that mononuclear and endothelial cell interactions may underlie BBB disruption during alphavirus encephalitis.
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Project description:Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3β inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3β inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier 'leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.
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Project description:Targeted treatment of inflammatory diseases of the central nervous system (CNS) remains problematic due to the complex pathogenesis of these disorders and difficulty in drug delivery. The plant virus, cowpea mosaic virus (CPMV), has recently been explored as a nanoparticle delivery system for therapeutics targeting a number of diseases including cancer and neurodegeneration. To understand the biodistribution of CPMV in the CNS, we examined CPMV uptake during infection of mice with neurotropic mouse hepatitis virus (MHV). CPMV localized mainly to the CNS endothelium in areas that contained an intact blood brain barrier. However, in inflammatory lesions containing macrophage/microglial cell infiltration and IgG, CPMV could be detected in the brain parenchyma. Furthermore, CPMV showed rapid internalization in an in vitro model of the BBB. These results suggest that CPMV particles could be used as a vehicle to deliver therapeutics to the damaged CNS during neurodegenerative and infectious diseases of the CNS.
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Project description:Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies.
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