Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

Roggeri, Alessandra; Schepers, Melissa; Tiane, Assia; Rombaut, Ben; Veggel, Lieve van; Hellings, Niels; Prickaerts, Jos; Pittaluga, Anna; Vanmierlo, Tim

doi:10.3390/ijms21207537

Cited by 28 publications

(27 citation statements)

References 160 publications

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“…The affinity of fingolimod-P for the S1P receptor1 (S1PR1) is high ( Brinkmann et al, 2002 ), which is the first identified and the most studied S1P receptor ( Roggeri et al, 2020 ). It is the only S1PR that couples exclusively to Gαi/o ( Lee et al, 1998 ).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

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%

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

et al. 2022

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“…Myelination by oligodendrocytes is an ongoing process between infancy and adulthood, and abnormal neural tracts result from abnormalities of the myelinating oligodendrocytes. A pool of undifferentiated oligodendrocyte precursor cells (OPC) remains in the parenchyma of the adult CNS, and they can differentiate into pre-myelinating and myelinating, mature oligodendrocytes [ 1 ]. Abnormal forms are detectable in SCZ: Vikhreva et al reported that 21 patients with SCX had degenerative changes in oligodendrocytes that included swelling, vacuolation, paucity of ribosomes, reduction in volume and number of mitochondria, and an increase in lipofuscin granules [ 2 ].…”

Section: Introduction: General Overview Abnormal Oligodendrocytes In ...mentioning

confidence: 99%

Abnormal oligodendrocyte function in schizophrenia explains the long latent interval in some patients

Fessel

2022

Transl Psychiatry

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A puzzling feature of schizophrenia, is the long latency between the beginning of neuropathological changes and the clinical presentation that may be two decades later. Abnormalities in oligodendrocyte function may explain this latency, because mature oligodendrocytes produce myelination, and if myelination were abnormal from the outset, it would cause the synaptic dysfunction and abnormal neural tracts that are underpinning features of schizophrenia. The hypothesis is that latency is caused by events that occur in some patients as early as in-utero or infancy, because clones of abnormal, myelinating oligodendrocytes may arise at that time; their number doubles every ~2 years, so their geometric increase between birth and age twenty, when clinical presentation occurs, is about 1000-fold plus the effect of compounding. For those patients in particular, the long latency is because of a small but ongoing increase in volume of the resulting, abnormally myelinated neural tracts until, after a long latent interval, a critical mass is reached that allows the full clinical features of schizophrenia. During latency, there may be behavioral aberrancies because of abnormally myelinated neural tracts but they are insufficiently numerous for the clinical syndrome. The occurrence of behavioral symptoms during the long latent period, substantiates the hypothesis that abnormal oligodendrocytes explain the latency in some patients. Treatment with fingolimod or siponimod benefits both oligodendrocytes and neural tracts. Clinical trial would validate their potential benefit in appropriate patients with schizophrenia and, concurrently, would validate the hypothesis.

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“…As cause for such dysregulated gene expression in OLGs, recent evidence points to the actions of extrinsic factors rather than intrinsic OLG defects (Golan et al, 2021; Kirby et al, 2019; Mozafari et al, 2020; Saraswat et al, 2021; Starost et al, 2020). Thus, targeting druggable signaling pathways with the capacity to modulate gene expression profiles associated with OLG maturation has emerged as a promising approach toward promoting repair of the myelin sheath in MS (Angelini et al, 2021; Gaesser & Fyffe‐Maricich, 2016; Göttle et al, 2019; Green et al, 2017; Jeffries et al, 2016, 2021; Lecca et al, 2020; Mausner‐Fainberg et al, 2021; Mierzwa et al, 2013; Petersen et al, 2021; Rajendran et al, 2021; Roggeri et al, 2020; Skinner & Lane, 2020; Thümmler et al, 2019; Wang et al, 2020; Welliver et al, 2018). Despite an increasing number of potential pathways with promyelinating characteristics, however, clinical translation has, up until now, been below expectation (Abu‐Rub & Miller, 2018; Lubetzki et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

Spencer

Suárez-Pozos

Soto-Verdugo

et al. 2022

Journal of Neurochemistry

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The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G proteincoupled receptor LPA 6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, the cell surface accessibility of LPA 6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA 6 and LPA 6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA 6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA 6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA 6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA 6 protein levels appear | 479 SPENCER et al.

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Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

Cited by 28 publications

References 160 publications

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Abnormal oligodendrocyte function in schizophrenia explains the long latent interval in some patients

Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation

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Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

Cited by 28 publications

References 160 publications

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Abnormal oligodendrocyte function in schizophrenia explains the long latent interval in some patients

Lysophosphatidic acid signaling via LPA6: A negative modulator of developmental oligodendrocyte maturation

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Lysophosphatidic acid signaling via LPA₆: A negative modulator of developmental oligodendrocyte maturation