Characterization of blood–brain barrier integrity in a B-cell-dependent mouse model of multiple sclerosis

Bell, Luisa; Koeniger, Tobias; Tacke, Sabine; Küerten, Stefanie

doi:10.1007/s00418-019-01768-6

Cited by 12 publications

(8 citation statements)

References 39 publications

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“…Of note, PTM is suitable for a rapid translation for clinical use, being an already-approved drug. Although PTM has limited capacity to permeate the BBB [53], and although a proportion is retained within the capillary endothelium [54], the BBB damage occurring during demyelinating diseases [55], as also shown by evidences of tracer leakage into the CNS [56], suggests that this drug may be easily available within the inflamed CNS, also when administered systemically, as in this work. Finally, the identification of S100B as a putative therapeutic target of MS pathogenetic processes might likely open novel perspectives for even more efficacious treatments.…”

Section: Discussionmentioning

confidence: 65%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

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Section: Discussionmentioning

confidence: 65%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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“…Counterintuitively, a minor decrease in lymphocyte number was observed in EAE animals treated intrathecally with anti-CD52 mAb, indicating that it did not remain within the CNS in these animals. Given that a recent study reported that the BBB shows signs of leakiness in the chronic stages of the EAE model, 26 these findings might indicate that the observed peripheral immune cell depletion is a consequence of the experimental model. On the other hand, while the venous route for CSF drainage restricts passage of large monoclonal antibodies to the serum, CNS lymphatics can provide aCD52 mAb access to the periphery, 27 in particular in inflammatory settings.…”

Section: Discussionmentioning

confidence: 78%

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis

Bogie

Grajchen

Wouters

et al. 2020

Therapeutic Advances in Chronic Disease

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Background and aims: Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing–remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model. Methods: Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters. Results: We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice. Conclusion: Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.

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“…Evans blue perfusion was performed as previously described [ 46 ]. Briefly, anesthetized mice were perfused with 50 ml of PBS (pH 7.2) followed by 50 ml of 4% PFA containing 1% Evans blue (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Psychological stress induces depressive-like behavior associated with bone marrow-derived monocyte infiltration into the hippocampus independent of blood–brain barrier disruption

Yang

et al. 2022

J Neuroinflammation

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Background Psychological stress is one of the most important factors that trigger emotional disorders, such as depression and anxiety. Emerging evidence suggests that neuroinflammation exacerbated by bidirectional communication between the peripheral immune system and the central nervous system facilitates abnormal psychiatric symptoms. This study aimed to investigate the hippocampal migration of bone marrow (BM)-derived monocytes and its role in regulating depressive-like behaviors using the chronic psychological stress (CPS) mouse model. More importantly, whether the central migration of these peripheral BM-derived cells depend on the disruption of the blood–brain barrier (BBB) was also investigated. Methods and findings Green fluorescent protein-positive (GFP+) BM chimeric mice were used to distinguish BM-derived monocytes within the brain. A CPS mouse model was established to explore the effect of CPS on hippocampal migration of BM-derived monocytes and its role in the regulation of depressive-like behaviors. The results revealed that BM-derived GFP+ cells accumulated in the hippocampus and differentiated into microglia-like cells after exposure to CPS. Interestingly, this migration was not associated with BBB disruption. Furthermore, treatment with C–C chemokine receptor 2 (CCR2) antagonist (RS102895) suppressed the recruitment of BM-derived monocytes to the hippocampus and alleviated depressive-like symptoms. Conclusion These findings indicate that monocyte recruitment to the hippocampus in response to psychological stress may represent a novel cellular mechanism that contributes to the development of depression.

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Characterization of blood–brain barrier integrity in a B-cell-dependent mouse model of multiple sclerosis

Cited by 12 publications

References 39 publications

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis

Psychological stress induces depressive-like behavior associated with bone marrow-derived monocyte infiltration into the hippocampus independent of blood–brain barrier disruption

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