Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

Fülöp, Gábor; Ahire, Chetan; Csípő, Tamás; Tarantini, Stefano; Kiss, Tamás; Balasubramanian, Priya; Yabluchanskiy, Andriy; Farkas, Eszter; Tóth, Attila; Tóth, Attila; Tóth, Péter; Csiszár, Anna; Ungvári, Zoltán

doi:10.1007/s11357-019-00110-1

Cited by 49 publications

(30 citation statements)

References 97 publications

(114 reference statements)

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“…Burns have been shown to induce cognitive impairment and abnormal behavior (4,(8)(9)(10)(11)(12). Given the fact that BBB dysfunction is the key factor in cognitive impairment (50)(51)(52)(53)(54)(55)(56)(57) and that MSCs can effectively improve the integrity of BBB, we investigated whether burns could induce BBB dysfunction and neuroinflammation as well as evaluated its potential mechanism and the best time point for intervention to improve these effects after burn.…”

Section: Discussionmentioning

confidence: 99%

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Yang

Zhang

et al. 2020

Front. Immunol.

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Neurological syndromes are observed in numerous patients who suffer burns, which add to the economic burden of societies and families. Recent studies have implied that bloodbrain barrier (BBB) dysfunction is the key factor that induces these central nervous system (CNS) syndromes in peripheral traumatic disease, e.g., surgery and burns. However, the effect of burns on BBB and the underlying mechanism remains, largely, to be determined. The present study aimed to investigate the effect of burns on BBB and the potential of umbilical cord-derived mesenchymal stem cells (UC-MSCs), which have strong antiinflammatory and repairing ability, to protect the integrity of BBB. BBB permeability was evaluated using dextran tracer (immunohistochemistry imaging and spectrophotometric quantification) and western blot, interleukin (IL)-6, and IL-1b levels in blood and brain were measured by enzyme-linked immunosorbent assay. Furthermore, transmission electron microscopy (TEM) was used to detect transcellular vesicular transport (transcytosis) in BBB. We found that burns increased mouse BBB permeability to both 10-kDa and 70-kDa dextran. IL-6 and IL-1b levels increased in peripheral blood and CNS after burns. In addition, burns decreased the level of tight junction proteins (TJs), including claudin-5, occludin, and ZO-1, which indicated increased BBB permeability due to paracellular pathway. Moreover, increased vesicular density after burns suggested increased transcytosis in brain microvascular endothelial cells. Finally, administering UC-MSCs at 1 h after burns effectively reversed these adverse effects and protected the integrity of BBB. These results suggest that burns increase BBB permeability through both paracellular pathway and transcytosis, the potential mechanism of which might be through increasing IL-6 and IL-1b levels and decreasing Mfsd2a level, and appropriate treatment with UC-MSCs can reverse these effects and protect the integrity of BBB after burns.

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Section: Discussionmentioning

confidence: 99%

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Yang

Zhang

et al. 2020

Front. Immunol.

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“…Thus, the ICPs in IIH and MS appear to be on a continuum. In a mouse model of IIH, cerebral venous congestion per se was found to cause BBB disruption and neuro-inflammation (Fulop et al, 2019) similar to the earliest manifestations of an MS plaque (Wuerfel et al, 2004).…”

Section: Are Ms and Idiopathic Intracranial Hypertension Related?mentioning

confidence: 97%

The Incidence of Transverse Sinus Stenosis in Multiple Sclerosis: Further Evidence of Pulse Wave Encephalopathy

Bateman

Lechner‐Scott

Bateman

et al. 2020

Multiple Sclerosis and Related Disorders

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Background: Multiple sclerosis (MS) is associated with a breakdown in the intracranial pulse wave dampening or windkessel effect. This is manifest by an increase in the arterial stroke volume and a decrease in the dampening afforded by both the CSF displaced into the spinal canal and the blood displaced by the venous sinus pulsation. There is evidence that the reduction in compliance of the sagittal and straight sinuses in MS is caused by an increase in venous pressure despite the jugular bulb pressures being normal. This implies MS patients have a venous outflow stenosis somewhere between the torcular and jugular bulbs. The purpose of the current study is to define the site, significance and cause of these stenoses. Methods: 50 patients with MS were prospectively recruited from an MS clinic and compared to 50 matched control patients. Using 3DT1 post contrast images, a survey of the venous sinuses was performed looking for the narrowest portion of the sinuses in each of 4 segments from the sagittal sinus to jugular bulbs. The cross sectional areas and wetted circumferences of the venous sinuses were measured at each site to calculate the minimum hydraulic and effective diameters. The BMI, optic nerve sheath diameters and pituitary heights were measured. Statistical analysis was performed using non-parametric methods and was assessed using α≤0.05. Results: Compared to controls, the MS patients' sagittal sinuses were 24% larger in cross-section (p=0.0001) with an 18% larger wetted circumference (p=0.0001). The MS patients' transverse sinuses had an average effective stenosis of 38% by area (p<0.0001) with 8/50 patients having a high grade stenosis of >65% by area and 16/50 a low grade stenosis of between 40-65% by area compared to 1/50 low grade stenoses in this segment in the controls. The commonest cause of the stenosis was a giant arachnoid granulation. The optic nerve sheaths were larger in MS than controls (p=0.0006). Comparing MS patients with transverse sinus stenosis to those without, the pituitary height was 16% smaller and BMI 25% larger (p=0.02 and 0.003 respectively) Conclusion: In patients with MS, the reduction in venous sinus compliance is associated with venous outflow stenoses in the transverse sinuses which increases the upstream venous pressure and dilates the sagittal sinuses. This finding suggests a continuum exists between MS and idiopathic intracranial hypertension.

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“…For example, Huh et al (2008) showed that BBB disruption in their midline CCI rat model of mTBI occurs within 6 h after impact, while glial fibrillary acidic protein (GFAP) immunoreactivity in the cortex at 24 h was comparable to that observed in sham-injured animals, and astrogliosis was only observed on day 3 and day 8 post-injury. As BBB breakdown and extravasation of plasma proteins such as fibrinogen are a driving force of microglia activation after injury ( Davalos et al, 2012 ) and capable of inducing neurotoxic reactive astrocytes after TBI ( Liddelow and Barres, 2017 ; Liddelow et al, 2017 ) and cognitive impairment ( Fulop et al, 2019 ), the vascular link between mTBI and neuroinflammation should be defined in future studies.…”

Section: Blood–brain Barrier Dysfunction and Neuroinflammation In Milmentioning

confidence: 99%

Blood–Brain Barrier Dysfunction in Mild Traumatic Brain Injury: Evidence From Preclinical Murine Models

Guo

et al. 2020

Front. Physiol.

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Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, bloodbrain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases.

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Cerebral venous congestion promotes blood-brain barrier disruption and neuroinflammation, impairing cognitive function in mice

Cited by 49 publications

References 97 publications

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

The Incidence of Transverse Sinus Stenosis in Multiple Sclerosis: Further Evidence of Pulse Wave Encephalopathy

Blood–Brain Barrier Dysfunction in Mild Traumatic Brain Injury: Evidence From Preclinical Murine Models

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