Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells

Vargas-Medrano, Javier; Krishnamachari, Sesha; Villanueva, Ernesto; Godfrey, Wesley H.; Lou, Haiyan; Ramesh, Chinnasamy; Arterburn, Jeffrey B.; Perez, Ruth G.

doi:10.1021/ml500128g

Cited by 31 publications

(40 citation statements)

References 30 publications

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“…These indings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREBassociated BDNF expression. [7,8]. Together, these data strongly suggest that FTY720 is highly protective in vivo.…”

Section: Introductionmentioning

confidence: 75%

“…Previous studies have shown that FTY720 can increase BDNF expression in dopaminergic MN9D cells [7]. In order to assess whether it also increased BDNF expression in another dopaminergic cell line, we next treated SH-SY5Y cells with 2 μM of FTY720 at various time points (4, 8 and 24 h) then measured BDNF protein levels.…”

Section: Fty720 Promotes Phosphorylation Of Pro-survival Molecules Amentioning

confidence: 99%

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FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models

et al. 2016

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FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.

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Section: Introductionmentioning

confidence: 75%

Section: Fty720 Promotes Phosphorylation Of Pro-survival Molecules Amentioning

confidence: 99%

FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models

et al. 2016

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“…Previously we and others have studied protection by FTY720, an approved oral immunosuppressive drug for multiple sclerosis, that when phosphorylated acts on sphingosine-1-phosphate receptors (S1P-Rs) [25]. FTY720 causes immunosuppression but also enhances expression of brain derived trophic factor in multiple cell and animal models [26][27][28][29][30]. We showed that FTY720 improves GI physiology/function and reduces GI aSyn pathology in A53T Tg parkinsonian mice [22].…”

Section: Introductionmentioning

confidence: 99%

A Pilot Microbiota Study in Parkinson’s Disease Patients versus Control Subjects, and Effects of FTY720 and FTY720-Mitoxy Therapies in Parkinsonian and Multiple System Atrophy Mouse Models

Vidal-Martinez

Chin

Camarillo

et al. 2020

JPD

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Background: Parkinson's disease (PD) and multiple system atrophy (MSA) patients often suffer from gastrointestinal (GI) dysfunction and GI dysbiosis (microbial imbalance). GI dysfunction also occurs in mouse models of PD and MSA. Objectives: To assess gut dysfunction and dysbiosis in PD subjects as compared to controls, identify potential shared microbial taxa in humans and mouse models of PD and MSA, and to assess the effects of potential therapies on mouse GI microbiota. Methods: In this human pilot study, GI function was assessed by fecal consistency/frequency measured using the Bristol Stool Form Scale and GI transit time assessed using Sitzmarks pills and abdominal radiology. Human and mouse microbiota were analyzed by extracting fecal genomic DNA followed by 16S rRNA sequencing. Results: In our PD patients genera Akkermansia significantly increased while a trend toward increased Bifidobacterium and decreased Prevotella was observed. Families Bacteroidaceae and Lachnospiraceae and genera Prevotella and Bacteroides were detected in both humans and PD mice, suggesting potential shared biomarkers. In mice treated with the approved multiple sclerosis drug, FTY720, or with our FTY720-Mitoxy-derivative, we saw that FTY720 had little effect while FTY720-Mitoxy increased beneficial Ruminococcus and decreased Rickenellaceae family. Conclusion: Akkermansia and Prevotellaceae data reported by others were replicated in our human pilot study suggesting the use of those taxa as potential biomarkers for PD diagnosis. The effect of FTY720-Mitoxy on taxa Rikenellaceae and Ruminococcus and the relevance of S24-7 await further evaluation. It also remains to be determined if mouse microbiota have predictive power for human subjects.

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“…More recently, evidence has been obtained showing that the therapeutic effect of FTY‐720 in RRMS is due to its ability to affect both the immune system and CNS (Zhang et al, ). Many researches have proposed that FTY‐720 can exert a neuroprotective effect in several CNS disorders, such as stroke, Alzheimer's disease and Parkinson's disease (Hemmati et al, ; Vargas‐Medrano et al, ).…”

Section: Introductionmentioning

confidence: 99%

The sphingosine‐1‐phosphate analogue, FTY‐720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice

Sun

Hong

Zhang

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEFingolimod (FTY-720) is the first oral therapeutic drug approved for the relapsing-remitting forms of multiple sclerosis. Neural stem cells (NSCs) are capable of continuous self-renewal and differentiation. The dentate gyrus of the hippocampus in the adult mammalian brain contains a population of NSCs and is one of the regions where neurogenesis takes place. FTY-720 has been shown to have neuroprotective effects in several model systems, so we investigated the direct effects of FTY-720 on NSCs and adult neurogenesis. EXPERIMENTAL APPROACHESWe assessed the effects of FTY-720 on the proliferation and differentiation of cultured embryonic hippocampal NSCs using the 5-bromo-2-deoxyuridine incorporation assay, the neurosphere formation assay and western blot analysis. Receptor selective agonists and antagonists were used to identify the mechanisms involved. Neurogenesis in the hippocampus of C57BL/6 mice was also assessed by immunohistochemistry. The Morris water maze and fear conditioning tests were used to detect the learning and memory abilities of mice. KEY RESULTSFTY-720 promoted the proliferation of embryonic hippocampal NSCs probably via the activation of ERK signalling, G i/o proteins and S1P 1 receptors. However, FTY-720 did not affect the differentiation of cultured hippocampal NSCs. In vivo, chronic treatment with FTY-720 promoted hippocampal neurogenesis in adult C57BL/6 mice and enhanced their learning and memory abilities. CONCLUSIONS AND IMPLICATIONSOur results suggest a new target for the activation of NSCs and provide an insight into the therapeutic effects of FTY-720 in neuropsychiatric disorders, neurodegenerative diseases and age-related cognitive decline where hippocampal neurogenesis is compromised.Abbreviations FC, fear conditioning; MWM, Morris water maze; NSCs, neural stem cells; S1P, sphingosine-1-phosphate

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Novel FTY720-Based Compounds Stimulate Neurotrophin Expression and Phosphatase Activity in Dopaminergic Cells

Cited by 31 publications

References 30 publications

FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models

FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models

A Pilot Microbiota Study in Parkinson’s Disease Patients versus Control Subjects, and Effects of FTY720 and FTY720-Mitoxy Therapies in Parkinsonian and Multiple System Atrophy Mouse Models

The sphingosine‐1‐phosphate analogue, FTY‐720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice

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