Frequency and clinical characteristics of Multiple Sclerosis rebounds after withdrawal of Fingolimod

Evangelopoulos, Maria-Eleftheria; Miclea, Andrei; Schrewe, Lisa; Briner, Myriam; Salmen, Anke; Engelhardt, Britta; Huwiler, Andrea; Chan, Andrew; Hoepner, Robert

doi:10.1111/cns.12992

Cited by 19 publications

(18 citation statements)

References 7 publications

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“…Although our model was based on a mitochondrial oxidative damage, we saw a decrease in glycolytic function that was recovered in the presence of FP. Some authors have demonstrated that withdrawal of FP after a period of treatment could trigger relapses in MS patients [ 61 ], and thus we decided to maintain FP in one of the groups, extending the study time to determine the need of FP in the medium to maintain its beneficial effects. In these experiments, we found a decrease in ECAR compared to control neurons; FP almost totally reverted the damage produced by VitK3, thus maintaining glycolytic activity to levels close to control up to the maximum time studied, whereas in those neurons not in presence of FP, the damage was maintained over time ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

Gil

Martín-Montañez

Valverde

et al. 2020

Cells

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Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from oxidative damage, and the preservation of different sources of energy production is essential to preserve neuronal function. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of multiple sclerosis. This work was performed in a model of oxidative damage on neuronal cell cultures exposed to menadione in the presence or absence of fingolimod phosphate. We studied the mitochondrial function, antioxidant enzymes, protein nitrosylation, and several pathways related with glucose metabolism and glycolytic and pentose phosphate in neuronal cells cultures. Our results showed that menadione produces a decrease in mitochondrial function, an imbalance in antioxidant enzymes, and an increase in nitrosylated proteins with a decrease in glycolysis and glucose-6-phosphate dehydrogenase. All these effects were counteracted when fingolimod phosphate was present in the incubation media. These effects were mediated, at least in part, by the interaction of this drug with its specific S1P receptors. These actions would make this drug a potential tool in the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

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Section: Resultsmentioning

confidence: 99%

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

Gil

Martín-Montañez

Valverde

et al. 2020

Cells

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“…In clinical practice, bridging with a depleting agent or natalizumab should be considered. When fingolimod is withdrawn before pregnancy, the risk of disease activity rebound must be taken into account, even if the magnitude of this risk is not known yet, as well as the successful strategies to minimize the risk ( 109 , 110 ). Natalizumab might be considered for bridging strategies, and an extended dosing regimen is usually proposed in order to guarantee a lower exposure of the fetus to the drug and a lower PML risk for the mother.…”

Section: Impact Of Disease-modifying Therapiesmentioning

confidence: 99%

Influence of Pregnancy in Multiple Sclerosis and Impact of Disease-Modifying Therapies

2021

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Purpose of this Review: This article is a systematic review on the influence pregnancy has on multiple sclerosis and the resulting impact of disease-modifying therapies.Findings: Multiple sclerosis predominantly affects young women with a clinical onset most often during the child-bearing age. The impact of multiple sclerosis and disease-modifying therapies on fertility, pregnancy, fetal outcome, and breastfeeding is a pivotal topic when it comes to clinical practice. The introduction of disease-modifying therapies has changed not only the natural history of the disease but also the perspective of pregnancy in women with multiple sclerosis. Family planning requires careful consideration, especially because many disease-modifying drugs are contraindicated during pregnancy. In this article, we review current evidence collected from published literature and drug-specific pregnancy registers on the use of disease-modifying therapies. Additionally, we discuss safety profiles for each drug and correlate them to both risk for the exposed fetus and risk for the mothers interrupting treatments when seeking pregnancy.

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“…Although our model is based in a mitochondrial oxidative damage, we see a decrease in glycolytic function, recovered in presence of FP. Some authors have demonstrated that withdrawal of FP after a period of treatment, could trigger relapses in MS patients [54], so we decided to maintain FP in one of the groups; and extend the study time, to determine the need of FP in the medium to maintain its beneficial effects. In these experiments, we found a decrease in ECAR compared to control neurones; FP almost totally reverted the damage produced by VitK3, so maintaining glycolytic activity to levels close to control up to the maximum time studied, whereas in those neurones not in presence of FP the damage was maintained over time (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

Neuronal Metabolism and Neuroprotection. Neuroprotective Effect of Fingolimod on Menadione Induced Mitochondrial Damage

Gil

Martín-Montañez

Valverde

et al. 2020

Preprint

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Imbalance in the oxidative status in neurons, along with mitochondrial damage, are common characteristics in some neurodegenerative diseases. The maintenance in energy production is crucial to face and recover from the oxidative damage and the coexistence of different sources of energy production, such as mitochondrial and glycolytic ATP, allows faster adaptative mechanisms to situations of high energy demand and may help in the maintenance of neuronal function in stress situations. Fingolimod phosphate is a drug with neuroprotective and antioxidant actions, used in the treatment of Multiple Sclerosis. This work has been performed in a model of oxidative damage on neuronal cell cultures exposed to menadione, in presence or absence of fingolimod phosphate. We have studied the mitochondrial function and several pathways related with glucose metabolism, including oxidative, glycolytic and pentose phosphate in neuronal cells cultures. Our results showed a beneficial effect on neuronal survival probably based in the recovery of all, oxidative balance, glycolysis and pentose phosphate, promoted by fingolimod phosphate. These effects are mediated, at least in part by the interaction with its specific receptor. These actions would make this drug a potential tool to the treatment of neurodegenerative processes, either to slow progression or alleviate symptoms.

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Frequency and clinical characteristics of Multiple Sclerosis rebounds after withdrawal of Fingolimod

Cited by 19 publications

References 7 publications

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage

Influence of Pregnancy in Multiple Sclerosis and Impact of Disease-Modifying Therapies

Neuronal Metabolism and Neuroprotection. Neuroprotective Effect of Fingolimod on Menadione Induced Mitochondrial Damage

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