Identification of Inflammatory Neuronal Injury and Prevention of Neuronal Damage in Multiple Sclerosis

Zipp, Frauke; Gold, Ralf; Wiendl, Heinz

doi:10.1001/jamaneurol.2013.4391

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS), where immune cells specific to CNS antigens damage the CNS, resulting in paralysis [64][65][66][67][68][69][70][71][72][73]. Autoimmune T cells traffic to the brain and cross the BBB and causes damage [74], thus preventing T cell migration to the CNS is a therapeutic target.…”

Section: Potential Role Of Cns Lymphatics In Health and Diseasementioning

confidence: 99%

Revisiting the Mechanisms of CNS Immune Privilege

Louveau

Harris

Kipnis

2015

Trends in Immunology

554

399

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Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders.

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Section: Potential Role Of Cns Lymphatics In Health and Diseasementioning

confidence: 99%

Revisiting the Mechanisms of CNS Immune Privilege

Louveau

Harris

Kipnis

2015

Trends in Immunology

554

399

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“…Nonetheless, some new small‐molecule‐based oral therapies that can directly cross the blood–brain barrier may be promising as direct neuroprotective agents (Zipp et al . ). One of these, fingolimod (FTY720), is a sphingosine analog that once phosphorylated to FTY720‐phosphate (FTY720‐P), an analog to sphingosine 1‐phosphate (S1P), engages five subtypes of S1P receptors (S1P1R to S1P5R).…”

mentioning

confidence: 97%

In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity

Luchtman

Gollan

Ellwardt

et al. 2016

Journal of Neurochemistry

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In multiple sclerosis (MS), a candidate downstream mechanism for neuronal injury is glutamate (Glu)-induced excitotoxicity, leading to toxic increases in intraneuronal Ca 2+ . Here, we used in vivo two-photon imaging in the brain of TN-XXL transgenic Ca 2+ reporter mice to test whether promising oral MS therapeutics, namely fingolimod, dimethyl fumarate, and their respective metabolites fingolimod-phosphate and monomethyl fumarate, can protect neurons against acute glutamatergic excitotoxic damage. We also assessed whether these drugs can protect against excitotoxicity in vitro using primary cortical neurons, and whether they can directly inhibit Glu release from pathogenic T-helper 17 lymphocytes. In vivo, direct and acute (1 h) administration of 100 mM Glu to the brainstem resulted in a rapid and significant up-regulation in neuronal Ca 2+ signaling as well as morphological excitotoxic changes that were attenuated by the NMDA-receptor antagonist MK801. Direct CNS administration of MS drugs prior to Glu significantly delayed or reduced, but did not prevent the neuronal Ca 2+ increase or morphological changes. In vitro,prolonged (24 h) treatment of primary neurons with the fumarates significantly protected against neurotoxicity induced by Glu as well as NMDA, similar to MK801. Furthermore, monomethyl fumerate significantly reduced Glu release from pathogenic T-helper 17 lymphocytes. Overall, these data suggest that MS drugs may mediate neuroprotection via excitotoxicity modulating effects.

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“…Acute inflammation and chronic neuronal cell loss contribute differently to disease progression and disability. 1,2 Cortical gray matter (GM) atrophy starts at or before clinical disease onset, and the initial extent has robust associations with functional deterioration and cognitive impairment. 3 It reliably predicts and is a relevant marker of disease progression.…”

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confidence: 99%

Covarying patterns of white matter lesions and cortical atrophy predict progression in early MS

Fleischer

Kroth

Ciolac

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveWe applied longitudinal 3T MRI and advanced computational models in 2 independent cohorts of patients with early MS to investigate how white matter (WM) lesion distribution and cortical atrophy topographically interrelate and affect functional disability.MethodsClinical disability was measured using the Expanded Disability Status Scale Score at baseline and at 1-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Covarying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel independent component analysis. Predictive power of covarying patterns for disability progression was tested by receiver operating characteristic analysis at the group level and support vector machine for individual patient outcome.ResultsIn the study cohort, we identified 3 distinct distribution types of WM lesions (cerebellar, bihemispheric, and left lateralized) that were associated with characteristic cortical atrophy distributions. The cerebellar and left-lateralized patterns were reproducibly detected in the second cohort. Each of the patterns predicted to different extents, short-term disability progression, whereas the cerebellar pattern was associated with the highest risk of clinical worsening, predicting individual disability progression with an accuracy of 88% (study cohort) and 89% (replication cohort), respectively.ConclusionThese findings highlight the role of distinct spatial distribution of cortical atrophy and WM lesions predicting disability. The cerebellar involvement is shown as a key determinant of rapid clinical deterioration.

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Identification of Inflammatory Neuronal Injury and Prevention of Neuronal Damage in Multiple Sclerosis

Cited by 18 publications

References 33 publications

Revisiting the Mechanisms of CNS Immune Privilege

Revisiting the Mechanisms of CNS Immune Privilege

In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity

Covarying patterns of white matter lesions and cortical atrophy predict progression in early MS

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