Blood–brain barrier disruption and lesion localisation in experimental autoimmune encephalomyelitis with predominant cerebellar and brainstem involvement

Muller, Diane M.; Pender, Michael P.; Greer, Judith M.

doi:10.1016/j.jneuroim.2004.11.011

Cited by 57 publications

(40 citation statements)

References 24 publications

(18 reference statements)

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“…Experiments performed in the rat using low-molecular mass molecules such as mannitol or radiolabeled ionic tracers revealed a comparable pattern of diffusion, with extravasation of ions from the lumbar spinal cord vasculature before other CNS regions (71,72). Similar observations were made in C3H/He mice, in which ascending paralysis was closely associated with HRP extravasation in the spinal cord, whereas predominant cerebellar involvement was evident only in instances of axial rotatory EAE (11). In the EAE SJL mouse model, it was proposed that the first occurrence of BBB disruption and rabbit IgG leakage occurred in the cerebellum, and then spread to the spinal cord (9).…”

Section: Discussionsupporting

confidence: 58%

“…This leads to immune cell invasion, formation of demyelinated lesions, and axonal damage (4,(6)(7)(8). Early breakdown of the BSCB in EAE has been widely documented, but the precise timing and triggers of this disruption are still a matter of debate (9)(10)(11)(12). This has prompted us to look further into the kinetics of BSCB disruption and the putative cellular candidates involved in this process.…”

mentioning

confidence: 99%

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Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

186

159

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Disruption of the blood–brain and blood–spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP+ myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP+ cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

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Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Aubé

Lévesque

Paré

et al. 2014

The Journal of Immunology

186

159

View full text Add to dashboard Cite

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“…73,115 Considering MS-diseased BBB, it has been shown that disease severitiy could be correlated with alteration of BBB integrity, as confirmed by loss and delocalization of brain endothelilal junction proteins, like occluding., VE-cadherin and others. 67,123 Schmidt and co-workers, in two different works, 100 ; 2003b) demonstrated that long-circulating prednisolone LPs (PL) were able to localize the high tissue therapeutic levels of glucocorticalsteroid in the inflamed cerebral area of autoimmune EAE rats model 39 as compared with an equivalent dose given as free drug with a following reduction of inflammation and a significantly improvement in the disease course of (AT)-EAE.…”

Section: Huntington' S Diseasementioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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“…The development and progression of clinical signs in EAE are associated with loss of blood-brain barrier (BBB) integrity and upregulation of adhesion molecules expression in CNS tissues, resulting in the migration of vascular inflammatory cells into the CNS compartment [2,3]. This inflammatory cascade triggers upregulation of various proinflammatory mediators produced by infiltrating leukocytes and resident glial cells in the CNS, which are determining factors in the tissue damage [4,5].…”

Section: Introductionmentioning

confidence: 99%

Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: A potential therapeutic role

Martín

Carvalho‐Tavares

Hernández

et al. 2010

Biochemical Pharmacology

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Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease for which there exist no therapies without undesired side effects. Thus, the establishment of less toxic treatments is an ongoing challenge. Nowadays, research on medicinal plants has been attracting much attention, since screening of its active principles could prove useful in identification of safe and innovative pharmaceutical molecules. In this study we investigated the therapeutic effect of oleanolic acid (OA) a plant-derived triterpene with potent anti-inflammatory and immunomodulatory activities, whose actions on CNS diseases remain far from completely characterized. We focussed on the potential therapeutic effect of oleanolic acid (OA) on an accepted experimental model of MS, the experimental autoimmune encephalomyelitis (EAE).We have found that OA treatment, before or at the early onset of EAE, ameliorates neurological signs of EAE-mice. These beneficial effects of OA seem to be associated with a reduction of blood-brain barrier leakage and lower infiltration of inflammatory cells within the CNS, as well as with its modulatory role in Th1/Th2 polarization: inhibition of proinflammatory cytokines and chemokines, and stimulation of anti-inflammatory ones.Moreover, EAE-animals that were treated with OA had lower levels of anti-MOG antibodies than untreated EAE-mice.Our findings show that the administration of the natural triterpenoid OA reduces and limits the severity and development of EAE. Therefore, OA therapy might be of clinical interest for human MS and other Th1 cell-mediated inflammatory diseases.

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Blood–brain barrier disruption and lesion localisation in experimental autoimmune encephalomyelitis with predominant cerebellar and brainstem involvement

Cited by 57 publications

References 24 publications

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Neutrophils Mediate Blood–Spinal Cord Barrier Disruption in Demyelinating Neuroinflammatory Diseases

Nanoparticle transport across the blood brain barrier

Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: A potential therapeutic role

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