FTY720 in CNS injuries: Molecular mechanisms and therapeutic potential

Zhang, Li; Wang, Handong

doi:10.1016/j.brainresbull.2020.08.013

Cited by 23 publications

(12 citation statements)

References 107 publications

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“…Caspase-6 activation was responsible for apoptosis induction by fingolimod in these cells ( Sonoda et al, 2001 ). Both intrinsic (caspase and mitochondrial-dependent) and extrinsic apoptotic pathways are involved in the apoptotic death triggered by fingolimod ( Fujino et al, 2002 ; Zhang and Wang, 2020 ). Apoptotic activation of caspase cascade in fingolimod-treated Jurkat cells may be initiated by activation of mitochondria ( Fujino et al, 2001 ).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…It has been reported that phosphorylated fingolimod acts through S1PR3 to inhibit the TLR2/4-PI3K-NFκB signaling pathway ( Dong et al, 2018 ). Affecting PTEN as PI3K/Akt regulator is another proposed mechanism ( Zhang and Wang, 2020 ), yet further investigations have to be performed to unravel the exact mechanism. The promising results of fingolimod in different models of brain injury led to its use in clinical trials.…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

“…Affecting PTEN as PI3K/Akt regulator is another proposed mechanism (Zhang and Wang, 2020), yet further investigations have to be performed to unravel the exact mechanism. The promising results of fingolimod in different models of brain injury led to its use in clinical trials.…”

Section: Cns Injuriesmentioning

confidence: 99%

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Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

et al. 2022

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Fingolimod is a well-tolerated, highly effective disease-modifying therapy successfully utilized in the management of multiple sclerosis. The active metabolite, fingolimod-phosphate, acts on sphingosine-1-phosphate receptors (S1PRs) to bring about an array of pharmacological effects. While being initially recognized as a novel agent that can profoundly reduce T-cell numbers in circulation and the CNS, thereby suppressing inflammation and MS, there is now rapidly increasing knowledge on its previously unrecognized molecular and potential therapeutic effects in diverse pathological conditions. In addition to exerting inhibitory effects on sphingolipid pathway enzymes, fingolimod also inhibits histone deacetylases, transient receptor potential cation channel subfamily M member 7 (TRMP7), cytosolic phospholipase A2α (cPLA2α), reduces lysophosphatidic acid (LPA) plasma levels, and activates protein phosphatase 2A (PP2A). Furthermore, fingolimod induces apoptosis, autophagy, cell cycle arrest, epigenetic regulations, macrophages M1/M2 shift and enhances BDNF expression. According to recent evidence, fingolimod modulates a range of other molecular pathways deeply rooted in disease initiation or progression. Experimental reports have firmly associated the drug with potentially beneficial therapeutic effects in immunomodulatory diseases, CNS injuries, and diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and even cancer. Attractive pharmacological effects, relative safety, favorable pharmacokinetics, and positive experimental data have collectively led to its testing in clinical trials. Based on the recent reports, fingolimod may soon find its way as an adjunct therapy in various disparate pathological conditions. This review summarizes the up-to-date knowledge about molecular pharmacology and potential therapeutic uses of fingolimod.

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Section: Mechanisms Of Actionmentioning

confidence: 99%

Section: Therapeutic Applicationsmentioning

confidence: 99%

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Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

et al. 2022

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“…It has been demonstrated that activation of pro-survival Akt/Erk pathways protects neurons in degenerative conditions, 19 and previously fingolimod treatments were shown to induce Akt/Erk phosphorylation through S1PR1. 45 We, therefore, investigated the effect of siponimod treatments and neuronal deletion of S1PR1 on Akt/Erk activations in 8 weeks of high IOPexposed mice retinas. The western blot analysis of retinal lysates revealed a significant decrease (p < .05 for Akt and p < .01 for Erk) in Akt/Erk phosphorylation levels in high IOP retinas (Figure 4A).…”

Section: Siponimod-induced Akt/erk1/2 Activationmentioning

confidence: 99%

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

et al. 2022

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Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1‐phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1/2 activation and attenuated the apoptotic signaling via suppression of c‐Jun/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt/Erk1/2 activation, c‐Jun/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c‐Jun/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.

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“…In conclusion, studies of the molecular effects of sphingolipids on membrane fusion and related processes increase our understanding of the physiological regulation of neurosecretion and provide a promise to conceive new therapeutic approaches against neurological syndromes [67][68][69][70][71][72][73][74][75][76]90], and cancer [77][78][79][80][81][82][83]91].…”

Section: Discussionmentioning

confidence: 99%

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

Villanueva

Giménez-Molina

Davletov

et al. 2022

IJMS

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The fusion of membranes is a central part of the physiological processes involving the intracellular transport and maturation of vesicles and the final release of their contents, such as neurotransmitters and hormones, by exocytosis. Traditionally, in this process, proteins, such SNAREs have been considered the essential components of the fusion molecular machinery, while lipids have been seen as merely structural elements. Nevertheless, sphingosine, an intracellular signalling lipid, greatly increases the release of neurotransmitters in neuronal and neuroendocrine cells, affecting the exocytotic fusion mode through the direct interaction with SNAREs. Moreover, recent studies suggest that FTY-720 (Fingolimod), a sphingosine structural analogue used in the treatment of multiple sclerosis, simulates sphingosine in the promotion of exocytosis. Furthermore, this drug also induces the intracellular fusion of organelles such as dense vesicles and mitochondria causing cell death in neuroendocrine cells. Therefore, the effect of sphingosine and synthetic derivatives on the heterologous and homologous fusion of organelles can be considered as a new mechanism of action of sphingolipids influencing important physiological processes, which could underlie therapeutic uses of sphingosine derived lipids in the treatment of neurodegenerative disorders and cancers of neuronal origin such neuroblastoma.

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FTY720 in CNS injuries: Molecular mechanisms and therapeutic potential

Cited by 23 publications

References 107 publications

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

S1PR1 signaling attenuates apoptosis of retinal ganglion cells via modulation of cJun /Bim cascade and Bad phosphorylation in a mouse model of glaucoma

Vesicle Fusion as a Target Process for the Action of Sphingosine and Its Derived Drugs

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