Focal disturbances in the blood–brain barrier are associated with formation of neuroinflammatory lesions

Alvarez, Jorge Iván; Saint-Laurent, Olivia; Godschalk, Alisha; Terouz, Simone; Briels, Casper T.; Larouche, Sandra; Bourbonnière, Lyne; Larochelle, Catherine; Prat, Alexandre

doi:10.1016/j.nbd.2014.09.016

Cited by 131 publications

(117 citation statements)

References 49 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Interestingly, with our pattern of drug administration we did not detect an increase in general GFAP immunoreactivity, which is in agreement with a previous study that showed no alterations of several proteins, including GFAP, in striatal homogenates of autopsied brains obtained from chronic METH users. 45 Nevertheless, it was possible to observe a specific increase of GFAP immunoreactivity around the microvessels, which indicates an astrocytic recruitment and reorganization around the capillaries highlighting a clear perivascular astrogliosis 31 triggered by METH. In conclusion, the present work shows that at concentrations relevant to human abuse, METH induces the release of TNF-α by both brain ECs and astrocytes with subsequent activation of the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 97%

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Coelho-Santos

Leitão

Cardoso

et al. 2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.

show abstract

Section: Discussionmentioning

confidence: 97%

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Coelho-Santos

Leitão

Cardoso

et al. 2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…These observations suggest that astrocytes become reactive prior to CNS inflammation and that these reactive astrocytes contribute to BBB destabilization and permeability, inducing influx of immune cells into the CNS. The initial signal does however seem to originate in the periphery, as we showed that peripheral immune activation precedes CNS pathology [137].…”

Section: Reactive Astrogliosismentioning

confidence: 79%

“…During the process of transmigration, the barrier function becomes compromised, with alterations in tight junction structures, BBB activation, and leakage [2,136,79]. However, it was shown that changes in the expression of junctional proteins occur very early in MS and spontaneous relapsingremitting EAE lesion formation and that they coincide with perivascular astrogliosis, even before the influx of immune cells [6,2,137]. Similarly, active EAE induction in GFAPluciferase mice already showed bioluminescence in the brain of these animals at day 3 post-induction, approximately a week before infiltration of CD4 + T lymphocytes and onset of clinical signs [138].…”

Section: Reactive Astrogliosismentioning

confidence: 99%

Glial regulation of the blood-brain barrier in health and disease

2015

Self Cite

View full text Add to dashboard Cite

The brain is the organ with the highest metabolic demand in the body. Therefore, it needs specialized vasculature to provide it with the necessary oxygen and nutrients, while protecting it against pathogens and toxins. The blood-brain barrier (BBB) is very tightly regulated by specialized endothelial cells, two basement membranes, and astrocytic endfeet. The proximity of astrocytes to the vessel makes them perfect candidates to influence the function of the BBB. Moreover, other glial cells are also known to contribute to either BBB quiescence or breakdown. In this review, we summarize the knowledge on glial regulation of the BBB during development, in homeostatic conditions in the adult, and during neuroinflammatory responses.

show abstract

“…Indeed, more recent MRI studies suggest that global BBB disruption is an early feature that predicts conversion of optic neuritis to MS,3 and longitudinal studies in mice have shown that BBB disruption occurs before immune cell infiltration in focal lesions 4. However until now, disruption of the BBB has been seen as a step that is required for MS lesion formation but not at the core of its aetiology.…”

Section: Introductionmentioning

confidence: 99%

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

Spencer

Bell

DeLuca

2017

J Neurol Neurosurg Psychiatry

123

View full text Add to dashboard Cite

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

show abstract

Focal disturbances in the blood–brain barrier are associated with formation of neuroinflammatory lesions

Cited by 131 publications

References 49 publications

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Glial regulation of the blood-brain barrier in health and disease

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

Contact Info

Product

Resources

About