Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Gil A

PROVIDER: S-EPMC7824129 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Gil Antonio A Martín-Montañez Elisa E Valverde Nadia N Lara Estrella E Boraldi Federica F Claros Silvia S Romero-Zerbo Silvana-Yanina SY Fernández Oscar O Pavia Jose J Garcia-Fernandez Maria M

Cells 20201229 1

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 ...[more]

PMID: 33383658

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Project description:Fingolimod (FTY720), a structural analogue of sphingosine, targets sphingosine-1-phosphate receptor signaling and is currently an immunomodulatory therapy for multiple sclerosis. Fingolimod accesses the central nervous system (CNS) where its active metabolite, fingolimod phosphate (FTY720-P), has pleotropic neuroprotective effects in an inflammatory microenvironment. To investigate potential neuronal-specific mechanisms of fingolimod neuroprotection, we cultured the human neuronal progenitor cell line, hNP1, in differentiation medium supplemented with HIV- or Mock-infected supernatants, with or without FTY720-P. Gene expression was investigated using microarray and functional genomics. FTY720-P treatment increased differentially expressed (DE) neuronal genes by 33% in HIV-exposed and 40% in Mock-exposed cultures. FTY720-P treatment broadened the functional profile of DE genes in HIV-exposed versus Mock-exposed neurons, including not only immune responses but also transcriptional regulation and cell differentiation, among others. FTY720-P treatment downregulated the gene for follistatin, the antagonist of activin signaling, in all culture conditions. FTY720-P treatment differentially affected both glycolysis-related and immune response genes in Mock- or HIV-exposed cultures, significantly upregulating 11 glycolysis-related genes in HIV-exposed neurons. FTY720-P treatment also differentially upregulated genes related to innate immune responses and antigen presentation in Mock-exposed and more so in HIV-exposed neurons. However, in HIV-exposed neurons, FTY720-P depressed the magnitude of differential expression in almost half the genes, suggesting an anti-inflammatory potential. Moreover, in HIV-exposed neurons, FTY720-P reduced expression of the amyloid precursor protein (APP) gene, resulting in reduced expression of the APP protein. This study provides new evidence that fingolimod alters neuronal gene expression in inflammatory, viral-infected microenvironments, with the potential for neuroprotective effects.

Dataset Information

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

Publications

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

Similar Datasets

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