Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

Abstract

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

“…Of the protective agents investigated in MS models, citicoline best matches the fit of cuprizone. Sphingolipids have a role in the development of neurodegenerative diseases via the promotion of ceramide-induced apoptosis [24]. Fingolimod, a sphingosine-1-phosphate receptor modulator, shares template fitting-points with its analogue sphingosine.…”

“…The research literature identifies many apoptosis-modulating compounds rele-vant to neuron degeneration in Parkinson's, motor neurone disease (MND), demyelinating diseases and the peripheral neuropathy of diabetes. Apoptosis and disease-inducing compounds investigated in animal models and cell culture: palmitic acid [3], dexamethasone [5], ceramide [24], glucose [25], tolbutamide [25],…”

“…Compounds providing protection against apoptosis and motor neurone degeneration: sphingosine-1-phosphate [24], metformin [31], thymoquinone [44], citicoline [45], nitrovinyl benzoic acid (4-[(1E)-2-nitrovinyl] benzoic acid) [46], ambroxol [47], isofagomine [47], fingolimod [47], fasudil [48], Y-27632 [48], acerogenin [49]. Xanomeline [16], telmisartan [37], orientin [50], geniposide [51], licochalcone A [52], taraxasterol [53], acetylcarnitine [54], atorvastatin [55], riluzole [56] and sulforaphane [57] protect neurons against oxygen-glucose deprivation/reperfusion.…”

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

“…In particular, they have been shown to modulate several viral processes (e.g., inflammation and infection), including those related to SARS-CoV-2. In this context, Cer and S1P play opposite roles since Cer mainly controls cell growth arrest, death, and senescence, whereas S1P regulates cell proliferation and survival [41]. Indeed, researchers demonstrated that the infection of cultured epithelial cells with the SARS-CoV-2 S protein activated the ASM, thus catalyzing the conversion of SMs into Cers [42].…”

The Role of Sphingolipids and Sphingosine-1-phosphate—Sphingosine-1-phosphate-receptor Signaling in Psoriasis

“…Sphingolipids are one of the major lipid components of cell membranes and are involved in various physiological functions, such as the nervous, immune, and cardiovascular systems [6][7][8][9]. The sphingolipid metabolites ceramide, ceramide-1-phosphate (C1P), sphingosine, and sphingosine-1-phosphate (S1P) have been well studied in terms of regulating stress tolerance, proliferation, differentiation, and maturation in nervous system cells [10][11][12]. Therefore, it has been reported that sphingolipids are significantly involved in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis [13][14][15].…”