FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells

Stessin, A.; Gursel, Demirkan; Schwartz, Allie; Parashar, Bhupesh; Kulidzhanov, F; Sabbas, Albert; Boockvar, John A.; Nori, Dattatreyudu; Wernicke, A. Gabriella

doi:10.1016/j.neulet.2012.04.004

Cited by 29 publications

(22 citation statements)

References 46 publications

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“…FTY720 is phosphorylated by Sphingosine kinase (SphK), mainly by SphK2 [339] [340], into the active compound phospho-FTY720, which then acts on 4 of the 5 known S1P receptor subtypes (S1P1, S1P3, S1P4, S1P5), and shows neuroprotective effect against many central nervous system disease including cerebral ischemia [341] [342] [343] [344]. Mechanisms include regulation of myelination and microglial activation following injury, proliferation and migration of neural precursor cells toward injury sites, and potentiation of growth-factor regulated neuronal differentiation, survival, and process extension, and also antiapoptotic and anti-inflammatory pathways [344] [345] [346] [347] [348] [349] [343]. FTY720 also exerts immunomodulatory actions by affecting lymphocyte production, trafficking, and apoptosis through S1P receptors which induces a depletion of circulating lymphocytes by preventing the egress of lymphocytes from the lymph nodes.…”

Section: Fingolimod (Fty 720)mentioning

confidence: 99%

Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets

Kim¹,

Kawabori²,

Yenari³

2014

CMC

229

191

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Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world.

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Section: Fingolimod (Fty 720)mentioning

confidence: 99%

Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets

Kim¹,

Kawabori²,

Yenari³

2014

CMC

229

191

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“…FTY720 enhanced survival, proliferation and migration of NSCs in vitro [18–21]; however, effect on differentiation remains controversial. Our results, demonstrating a positive effect of FTY720 on differentiation of postnatal NSCs, both to neurons and oligodendrocytes, indicate that FTY720 is able to accelerate neurogenesis and oligodendrogenesis from neural precursors and suggest a potential neurogenic role also in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…In our study, we demonstrated the ability of the pro-drug FTY720, in its non-phosphorylated form, to promote differentiation of postnatal NSCs into both neurons and oligodendrocytes; therefore, FTY720 may be a promising drug for the manipulation of NSC pool used in stem cells graft therapies, promoting their survival, proliferation and oriented differentiation, as well as integration [17, 18]. The active form of FTY720 is considered the phosphorylated one; however, a growing literature demonstrates the effectiveness of the non-phosphorylated form of FTY720 not only in vivo, where FTY720 can be phosphorylated by endogenous sphingosine kinase 2, but also in vitro [17, 18, 20, 32, 56–58] . In our NSC cultures, we cannot exclude that the effect observed with FTY720 is due to phosphorylation FTY720-P by sphingosine kinases eventually present in the cultures, as reported elsewhere [17, 58].…”

Section: Discussionmentioning

confidence: 99%

“…FTY720 shows positive effects on survival, proliferation, migration and differentiation of NSCs in vitro [18–21]. In addition, in vivo chronic treatment with FTY720 increases proliferation, survival and formation of new neurons in healthy mouse hippocampus [19, 20], improving contextual fear memory [19] and enhanced learning and memory ability [20].…”

Section: Introductionmentioning

confidence: 99%

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Effects of FTY720 on brain neurogenic niches in vitro and after kainic acid-induced injury

Cipriani

Chara

Rodríguez‐Antigüedad

et al. 2017

J Neuroinflammation

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BackgroundFTY720 (fingolimod, Gilenya™) is an oral, blood-brain barrier (BBB)-passing drug approved as immunomodulatory treatment for relapsing-remitting form of the multiple sclerosis (MS). In addition, FTY720 exerts several effects in the central nervous system (CNS), ranging from neuroprotection to reduction of neuroinflammation. However, the neurogenic and oligodendrogenic potential of FTY720 has been poorly investigated. In this study, we assessed the effect of FTY720 on the production of new neurons and oligodendrocytes from neural stem/precursor cells both in vitro and in vivo.MethodsNeural stem cells (NSCs) derived from the young rat subventricular zone (SVZ) were exposed to FTY720 (10, 100 nM), and their differentiation into neurons and oligodendrocytes was measured using immunofluorescence for anti-β-III tubulin or CNPase (2′,3′-cyclic nucleotide 3′-phosphodiesterase) as markers of mature neurons or oligodendrocytes, respectively. In addition, intracerebroventricular (icv) administration of kainic acid (KA; 0.5 μg/2 μl) in Sprague-Dawley rats was used as an in vivo model of neuronal death and inflammation. FTY720 was applied icv (1 μg/2 μl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 8 days after KA injection. To visualize cell proliferation in the hippocampus and in white matter regions, rats were administered 5-bromo-2-deoxyuridine (BrdU) 100 mg/kg, ip injected every 2 days. Immunohistochemical analyses were performed on rat brain slices to measure the production of new neuronal precursors (doublecortin/DCX+ cells) and new oligodendrocytes precursors (proteoglycan/NG2+ cells).ResultsIn this study, we observed that FTY720 increased postnatal NSCs differentiation into both neurons and oligodendrocytes in vitro. In turn, in adult animals, FTY720 enhanced the percentage of BrdU+ cells coexpressing DCX marker, both in basal (FTY720 alone) and in neurodegenerative (FTY720 + KA) conditions. However, FTY720 had only a partial effect on proliferation and differentiation of oligodendrocyte progenitor cell (OPC) population in vivo.ConclusionsFTY720 promotes neurogenesis and oligodendrogenesis in vitro under basal conditions. In addition, it increases the generation of neuroblasts and oligodendrocytes after excitotoxic brain injury. This suggests that FTY720 has the potential to activate the neurogenic niche and thus favour tissue repair after lesion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0922-6) contains supplementary material, which is available to authorized users.

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“…Studies have shown that FTY720 increases the viability and neurogenic potential of irradiated NSCs of the hippocampus [23, 24]. For example, Stessin et al reported more neuronal (NeuN positive) differentiation in the presence of 10 nM FTY720 in the irradiated brain, which counteracted the radiation-induced suppression of NSCs neurogenic potential.…”

Section: Discussionmentioning

confidence: 99%

Effects of FTY720 (Fingolimod) on Proliferation, Differentiation, and Migration of Brain‐Derived Neural Stem Cells

Tan

Luo

Yan

et al. 2016

Stem Cells International

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Insufficient proliferation, differentiation, and migration are the main pitfalls of neural stem cells (NSCs) in reparative therapeutics for the central nervous system (CNS) diseases. The potent lipid mediator sphingosine-1-phosphate (S1P) regulates cells' biological behavior broadly in the CNS. However, the effects of activating S1P on NSCs are not quite clear. In the current study, FTY720 (Fingolimod), an analog of S1P, was employed to induce the proliferation, differentiation, and migration of cultured brain-derived NSCs. The results indicated that proliferation and migration ability of NSCs were promoted by FTY720. Though we observed no obvious neuron prefers differentiation of NSCs, there were more protoplasmic astrocytes developed in the presence of certain concentration of FTY720. This work gives more comprehensive understanding of how FTY720 affects NSCs.

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FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells

Cited by 29 publications

References 46 publications

Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets

Innate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets

Effects of FTY720 on brain neurogenic niches in vitro and after kainic acid-induced injury

Effects of FTY720 (Fingolimod) on Proliferation, Differentiation, and Migration of Brain‐Derived Neural Stem Cells

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