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2 Acta Neurobiologiae Experimentalis

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Sphingosine-1-phosphate and its receptors signaling in neurodegeneration/neuroprotection

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Strosznajder J. B. , Motyl J. , Czubowicz K. , Strosznajder R.

Acta Neurobiologiae Experimentalis

2015

tom 75

nr Supl.

Sphingosine -1-phosphate (S1P) is synthesized by sphingosine kinases (SphK1/2E.C. 2.7.1.91) and exerts its function as intracellular messenger or acts in an autocrine or paracrine fashion through specific G protein operated receptors (S1P1-S1P5). Depending on SphK type and its localization S1P may influence different cell functions. S1P synthesized by SphK1 is involved in cell survival while produced by SphK2 may activate death signaling. S1P is degraded by phosphohydrolyses and irreversibly by S1P lyase (SPL, E.C.4.1.2.27) which appears to be very important in sphingolipid homeostasis. The alterations of sphingolipid rheostat is suggested to be crucial in pathogenesis/pathomechanism of neurodegenerative disorders. In our study we have evaluated the SphKs and SPL expression/activity as well as the role of S1P in different types of oxidative stress involved in neurodegenerative disorders. Moreover, the implications of SphK/S1P in the cell models of Alzheimer’s disease induced by amyloid peptides (AB) and alfa synuclein (ASN) were determined. Oxidative stress alters SphKs and SPL expression, activity and cells viability. In AD model significant decrease of SphK expression and activity/lower S1P synthesis leads to series of the following consecutive events: oxidative stress, down regulation of antiapoptotic protein Bcl-2, up-regulation of pro-apoptotic BAX and HrK and finally to cell’s death. Exogenous S1P and the agonist(s) of S1P1 or S1P3 receptors exert cytoprotective effects which are mediated by PI3/ Akt signaling pathway and by regulation of Bcl2 proteins. Summarizing, our data suggest that S1P, its receptor(s) agonists and inhibitors of SPL should be considered in therapy of neurodegenerative disorders. Supported by NCN grant 5870/P01/2011/40

Ceramide/sphingosine-1-phosphate in cellls survival and death: implication in Alzheimer’s disease

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Strosznajder R. P. , Czubowicz K. , Gassowska M. , Cieslik M.

tom 73

nr Suppl.1

Ceramide and sphingosine-1-phosphate (S1P) are very active sphingolipid messengers which play a crucial role in regulation of neuronal cells survival and death. Alternation of ceramide/S1P rheostat is related to several pathological disorders including Alzheimer’s disease. Ceramides are involved in cells proliferation, differentiation and apoptotic death, while S1P enhances cell proliferation and antagonizes apoptosis. S1P regulates cellular processes by binding to five specific G protein coupled-receptors (S1PR1-5). The aim of the study was to investigate the molecular processes of neuronal death evoked by ceramide and the role of S1P in neuroprotection. Our study indicated that ceramide enhanced significantly the level of free radicals and decreased neuronal cells (SHSY5Y) viability through inhibition of PI3-K/Akt pathway. Ceramide also decreased anti-apoptotic (Bcl-2) and increased pro-apoptotic (Bax, Hrk) gene expression. Exogenously added S1P increased the viability of cells through S1PR (1-3) receptors-dependent mechanism. S1P also increased Bcl-2 gene expression and decreased the gene expression of Hrk protein. Summarizing, our study indicated that the action of ceramide and S1P on mitochondria may control neuronal fate and may play a crucial role in neurodegeneration and neuroprotection.