FTY720/fingolimod, an oral S1PR modulator, mitigates radiation induced cognitive deficits

Stessin, A.; Banu, Matei; Clausi, Mariano Guardia; Berry, Nicholas A.; Boockvar, John A.; Ryu, Samuel

doi:10.1016/j.neulet.2017.08.025

Cited by 15 publications

(7 citation statements)

References 19 publications

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“…Importantly, our in vivo results, showing an increased number of neuronal progenitor cells in neurogenic niches of the brain 4 weeks after 6 Gy X-ray exposure, indicate a neuroprotective effect of FTY720. These results are in line with a recent study, which demonstrated partial restauration of neurogenesis in the DG 7 weeks post-irradiation (Stessin et al, 2017). Since FTY720 pretreatment did not have significant effects on the DCX + cells and on proliferation in the first 24 h after irradiation, we conclude that neuroprotection by FTY720 mitigates delayed damage.…”

Section: Discussionsupporting

confidence: 93%

Fingolimod for Irradiation-Induced Neurodegeneration

et al. 2019

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Background Cranial irradiation is a common therapy for the treatment of brain tumors, but unfortunately patients suffer from side effects, particularly cognitive impairment, caused by neurodegenerative and neuroinflammatory mechanisms. Finding a therapeutic agent protecting hippocampal neurons would be beneficial. Fingolimod (FTY720), a sphingosine-1-phosphate receptor modulator approved for multiple sclerosis, is an immunosuppressant and known to enhance proliferation and differentiation of neuronal precursor cells (NPCs). Objectives To investigate whether pre-treatment with FTY720 protects NPCs in vitro and in vivo from irradiation-induced damage. Methods Neuronal precursor cells were isolated from E13 C57BL/6 wildtype mice, treated at day 0 of differentiation with FTY720 and irradiated on day 6 with 1 Gy. NPCs were analyzed for markers of cell death (PI, caspase-3), proliferation (Ki67), and differentiation (DCX, βIII-tubulin). Adult C57BL/6 wildtype mice were treated with FTY720 (1 mg/kg) and received a single dose of 6 Gy cranial irradiation at day 7. Using immunohistochemistry, we analyzed DCX and BrdU as markers of neurogenesis and Iba1, GFAP, and CD3 to visualize inflammation in the dentate gyrus (DG) and the subventricular zone (SVZ). B6(Cg)-Tyrc-2J/J DCX-luc reporter mice were used for bioluminescence imaging to evaluate the effect of FTY720 on neurogenesis in the DG and the spinal cord of naïve mice. Results FTY720 protected NPCs against irradiation induced cell death in vitro . Treatment with FTY720 dose-dependently reduced the number of PI + cells 24 and 96 h after irradiation without effecting proliferation or neuronal differentiation. In vivo treatment resulted in a significant survival of DCX + neurons in the DG and the SVZ 4 weeks after irradiation as well as a slight increase of proliferating cells. FTY720 inhibited microglia activation 24 h after X-ray exposure in the DG, while astrocyte activation was unaffected and no lymphocyte infiltrations were found. In naïve mice, FTY720 treatment for 4 weeks had no effect on neurogenesis. Conclusion FTY720 treatment of NPCs prior to X-ray exposure and of mice prior to cranial irradiation is neuroprotective. No effects on neurogenesis were found.

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Section: Discussionsupporting

confidence: 93%

Fingolimod for Irradiation-Induced Neurodegeneration

et al. 2019

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“…FTY720, a sphingosine analog, has also been shown to have PP2A-activating properties [134,135]. However, FTY720 functions primarily through immunosuppression by internalizing and activating the sphingosine 1 phosphate receptor (S1PR) [136]. FTY720 analogs, such as SH-RF-177, induce cell death in part through PP2A activation without the activation of S1PR, increasing the clinical significance of these compounds [137].…”

Section: Indirect Protein Phosphatase 2a (Pp2a) Activationmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

130

115

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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“…25 times above background levels (Figure 4). FTY720 has been shown to have beneficial effects on cognition in a number of animal models of CNS disorders, such as schizophrenia (Yu et al., 2023), multiple sclerosis (de Bruin et al., 2016; dos Santos et al., 2019), stroke (Nazari et al., 2016), Alzheimer's disease (Asle‐Rousta et al., 2013; Fagan et al., 2022; Fukumoto et al., 2014; Kartalou et al., 2020), Parkinson's disease (Vidal‐Martinez et al., 2019), Huntington's disease (Miguez et al., 2015), and even radiation‐induced cognitive deficits (Stessin et al., 2017). Here, however, we found no obvious effects of FTY720 on adolescent mouse behaviour in the Morris water maze spatial learning task.…”

Section: Discussionmentioning

confidence: 99%

The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

Magalhães,

Stewart,

Mampay

et al. 2024

Journal of Neurochemistry

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The small‐molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1‐phosphate (S1P) analogue currently used to treat relapsing–remitting multiple sclerosis in both adults and children. FTY720 can cross the blood–brain barrier (BBB) and, over time, accumulate in lipid‐rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor‐mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry‐based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy‐phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up‐regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down‐regulated. FTY720 also modulated anxiety‐like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system.

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FTY720/fingolimod, an oral S1PR modulator, mitigates radiation induced cognitive deficits

Cited by 15 publications

References 19 publications

Fingolimod for Irradiation-Induced Neurodegeneration

Fingolimod for Irradiation-Induced Neurodegeneration

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

The sphingosine 1‐phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus

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