Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Hoveizi

Journal Cellular Physiology

et al. 2019

Multiple sclerosis (MS) patients should take medication such as fingolimod (FTY‐720) for a long time, hence pharmaceutical effects on other neural cells such as dopaminergic cells are important. Dopaminergic cell line, BE(2)‐M17, was treated by FTY‐720 and then cell viability and genes involve in neurosurvival were investigated. It was disclosed that FTY‐720 significantly stimulates Bcl2 overexpression. Whereas, it decreased intracellular reactive oxygen species production and cell membrane damage of dopaminergic cells. The increase in Bcl2/Bax ratio increased the cell metabolic activity and decreased propidium iodide‐positive cells. Besides, FTY‐720 induced the overexpression of CACNA1C, nNOS gene, and nitric oxide production. However, FTY‐720 induced GABARA1 overexpression and eventually it could overcame to the cytotoxic effect of intracellular calcium. This cascade led to tyrosine hydroxylase and BDNF genes overexpression whereas FTY‐720 did not change GDNF concentration in BE(2)‐M17 cells. Concluding, it might be said that taking FTY‐720 in MS patients did not induce adverse effect on dopaminergic cells.

Section: Discussionmentioning

confidence: 99%

Small molecule of sphingosine as a rescue of dopaminergic cells: A cell therapy approach in neurodegenerative diseases therapeutics

Hoveizi

Journal Cellular Physiology

et al. 2019

J of Neuroscience Research

“…Remarkably, high 10-100 nM and low 0.01-1 nM concentrations of FTY720 respectively inhibited and induced NPs differentiation (Cipriani et al, 2017;Sun et al, 2016;Tan et al, 2016;Zhang et al, 2017) NPCs treated with FTY720 (100 nmol/L) • Increased MAP Kinase phosphorylation (Blanc et al, 2015) Human oligodendrocyte progenitor cells treated with FTY720 (different exposure times)…”

Section: The Effec T Of F T Y 72 0 On Myelin Reg Ener Ati On In Animentioning

confidence: 99%

“…• Affected membrane elaboration (in a time-and dose-dependent manner) via S1P1 or S1P3/S1P5 • Affected remyelination (Miron, Hall, et al, 2008;Miron et al, 2010) doses (Tan et al, 2016;Zhang et al, 2017). Mechanistically, FTY720…”

Section: The Effec T Of F T Y 72 0 On Myelin Reg Ener Ati On In Animentioning

confidence: 99%

“…Co-administration of FTY720 with transplanted NSCs reduced clinical severity at the later stage in EAE by reducing demyelination and enhancing remyelination. FTY720 increased the survival and proliferation of transplanted NSCs and their differentiation to oligodendrocytes (Yazdi, Mokhtarzadeh Khanghahi, Baharvand, & Javan, 2018;Zhang et al, 2017). Both axonal degradation and astrogliosis occur in MS (Rodriguez et al, 2014).…”

Section: The Effec T Of F T Y 72 0 On Myelin Reg Ener Ati On In Animentioning

confidence: 99%

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Possible regenerative effects of fingolimod (FTY720) in multiple sclerosis disease: An overview on remyelination process

Yazdi

Ghasemi-Kasman

Javan

2019

Fingolimod (FTY720) is a sphingosine 1‐phosphate (S1P) receptor analog, which has been approved as an oral immunomodulator for treating relapsing–remitting multiple sclerosis. This drug prevents lymphocyte egression from lymph nodes and reduces the infiltration of inflammatory mediators into the central nervous system. Based on its lipophilic nature, FTY720 passes through the blood–brain barrier and can directly affect neural cells. A notably different subtype of S1P receptors expresses in neural cells, which suggests FTY720 is a drug capable of affecting neural cells. Oligodendrocytes (OLs) are considered as the primary target cells in MS. Remyelination is a process including the proliferation of neural progenitors and oligodendrocyte precursor cells, their migration to the lesion site and their differentiation to mature oligodendrocytes. Experimental and clinical studies have described the impact of FTY720 on endogenous remyelination elements. In this review, we will explain the current clinical and experimental evidence that exists on the effects of FTY720 on remyelination and the underlying mechanisms.

“…Fingolimod Fingolimod is an FDA-approved disease-modifying therapy for MS whose primary disease-modifying mechanism relies on lymphocyte sequestration within lymph nodes. At nanomolar concentrations, it has been reported to promote the survival of neural stem cells, which the authors suggested may enhance the ultimate development of mature oligodendrocytes in vivo and subsequent remyelination [99]. However, given the need for OPC differentiation the exact mechanisms for this reported effect remain unclear and inadequately described.…”

Section: Compounds With Promising Preclinicalmentioning

confidence: 99%

Remyelinating Pharmacotherapies in Multiple Sclerosis

Bove

Green

2017

Neurotherapeutics

We have witnessed major successes in the development of effective immunomodulatory therapies capable of reducing adaptive immune-mediated myelin damage in MS over the last 30 years. However, until it is possible to prevent MS or initiate treatment before it has already caused lesions there is a need to repair myelin damage to prevent further axonal loss. The past decade has brought remarkable advances in our understanding of oligodendrocyte biology and the related search for remyelinating therapies in humans. In this review, we first outline the basic biology of central nervous system myelin and remyelination, including a discussion of the major identified pathways and targets that might help yield CNS remyelinating drugs. In conjunction, we provide an overview of techniques that have helped identify compounds capable of promoting oligodendrocyte precursor cell differentiation and myelination. This includes the methods for both initial in vitro screening and subsequent in vivo confirmation of the target. We then review methods proposed to quantify human remyelination in vivo, including visual evoked potentials and putative imaging modalities. As the remyelination era approaches, with the announcement of the first positive trial in remyelination, we are now tasked with answering new questions regarding patient-specific factors (e.g., age) that may influence the extent and optimal therapeutic window for remyelination.