Sphingosine kinase-1, the new target in the neuroprotective effect of fingolimod and pramipexole in Parkinson’s disease animal model

• Autorzy: Motyl J. , Wencel P.L. , Przykaza L. , Kosson P. , Boguszewski P.M. , Strosznajder J.B.
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.62

Twórcy

autor

Motyl J.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Wencel P.L.

• Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Przykaza L.

• Laboratory of Experimental Neurosurgery, Department of Neurosurgery, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Kosson P.

• Laboratory for Genetically Modified Animals, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Boguszewski P.M.

• Laboratory of Limbic System, Department of Neurophysiology, Nencki Institute of Experimental Biology Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder J.B.

• Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland