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1

Effects of myriocin and FTY720 on gene expression of sphingolipid metabolism enzymes in animal model of Alzheimer’s disease

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Jesko H., Wencel P. L., Strosznajder R. P.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
|
nr Suppl.1
INTRODUCTION: Sphingolipid imbalance has been observed in Alzheimer’s disease (AD) (accumulation of the pro-apoptotic ceramide, and loss of the protective sphingosine-1-phosphate – S1P) being correlated with the progress of neurodegeneration. Deregulated sphingolipid homeostasis may lead to neuronal death. Therefore enzymes regulating sphingolipid metabolism gain attention as highly promising targets in AD research/therapy. AIM(S): We examined the influence of myriocin and FTY720 on gene expression of enzymes metabolizing ceramide/sphingosine-1-phosphate in a mouse transgenic AD model. METHOD(S): mRNAs were measured with real-time PCR in the cerebral cortex of 6-months old FVB mice overexpressing human Aβ precursor protein (APP) treated with myriocin, a ceramide biosynthesis inhibitor, and FTY720 a sphingosine analog and sphingosine-1-phosphate receptor modulator. RESULTS: Myriocin has increased the expression of ceramidases ACER2 and -3, ceramide kinase (CERK), sphingosine kinase 2 (SPHK2) and S1P receptors (S1PR1 and -5) in APP mice. These results suggest a metabolic shift from ceramide towards the survival-promoting ceramide-1-phosphate and S1P. However, both Bcl-2 and Bax were increased, leaving the question open. The mock-transfected animals seemed to respond to treatment with a shift towards ceramide accumulation and dephosphorylation of S1P into sphingosine. FTY720 treatment of APP animals increased mRNA levels of ceramide synthases (CERS2 and 6), SPHK1 and 2, and proteins from Bcl-2 family. CONCLUSIONS: Our results suggest that myriocin and FTY720 treatment may lead to widespread modification of gene expression in the sphingolipid rheostat and signaling pathways, which requires further research to fully understand their mechanisms of action. FINANCIAL SUPPORT: Supported by the National Science Center grant no NCN/15/B/NZ3/01049.
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Sphingosine kinase-1, the new target in the neuroprotective effect of fingolimod and pramipexole in Parkinson’s disease animal model

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Motyl J., Wencel P. L., Przykaza L., Kosson P., Boguszewski P. M., Strosznajder J. B.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Sphingosine kinase (Sphk1) synthetizing sphingosine-1-phoshate (S1P) is a key enzyme responsible for the regulation of cell fate. Sphk1/S1P could be the attractive target in Parkinson’s disease (PD) neuroprotective therapy. Our previous data showed inhibition of Sphk1 expression/activity in PD in vitro model and indicated neuroprotective effect of S1P analog phospho‑fingolimod (FTY720-P). AIM(S): The aim of current research was to investigate the effect of FTY720 and dopamine D2/D3 receptors agonist – pramipexole (PPX) on Sphk1 dependent molecular pathway(s) in selected parts of the brain and on locomotor activity in PD animal model. METHOD(S): Neurotoxin 1-methyl-4-phenyl-1,2,3,6- -tetrahydropyridine (MPTP, 40 mg/kg) was administrated i.p. to adult C57BL/6 mice. FTY720 (1 mg/kg) or PPX (1 mg/kg) were injected i.p. during 10 days. Behavioral tests (open field, rota-rod) were performed. Midbrain and striatum were separated. The immunochemical, spectrofluorometrical, and QPCR methods were applied. RESULTS: Our data indicated that PD mice exhibited significant loss of dopaminergic nerve terminals within striatum, evaluated by reduced tyrosine hydroxylase immunoreactivity level (TH-IR). Moreover we found the lower level of mRNA/ immunoreactivity and activity of Sphk1 in the midbrain of PD mice. Both FTY720 and PPX significantly increased TH-IR in MPTP mice striatum. FTY720 and PPX protected against MPTP-evoked Sphk1 alterations and significantly elevated pro-survival Akt kinase phosphorylation, which indicated its activation. Subsequently, FTY720 increased BAD protein phosphorylation in MPTP mice midbrain, which may protect cells against BAD-mediated death. Then it was observed that FTY-720 and PPX improved locomotor impairment in PD mice. CONCLUSIONS: Our data indicated the new neuroprotective mechanism of PPX and FTY720 action connected with sphingolipid signaling and demonstrated beneficial properties of these compounds on movement alterations in PD animal model. FINANCIAL SUPPORT: This abstract is financially supported by The National Science Centre grant 2013/09/N/ NZ4/02045.
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