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Neuropharmacology. 2018 Jun;135:139-150. doi: 10.1016/j.neuropharm.2018.02.023. Epub 2018 Feb 23.

Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase.

Author information

1
Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland. Electronic address: jmotyl@ibib.waw.pl.
2
Laboratory of Experimental Neurosurgery, Department of Neurosurgery, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland. Electronic address: lprzykaza@imdik.pan.pl.
3
Laboratory of Animal Models, Neurobiology Centre, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland. Electronic address: pmbogusz@gmail.com.
4
Toxicology Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland. Electronic address: pkosson@imdik.pan.pl.
5
Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland. Electronic address: jstrosznajder@imdik.pan.pl.

Abstract

Parkinson's disease (PD) is one of the most severe neurodegenerative diseases with unknown pathogenesis and currently unsuccessful therapies. Recently, neuroprotection via sphingosine-1-phosphate (S1P)-dependent signalling has become a promising target for the treatment of neurodegenerative disorders. Our previous study demonstrated down-regulation and inhibition of the S1P-synthesizing enzyme sphingosine kinase 1 (SPHK1) in a PD cellular model. Moreover, we have previously identified a neuroprotective effect of fingolimod (FTY720), a first S1P receptor modulator utilized in the clinic. This study focused on the effects of FTY720 and the dopamine D2/D3 receptor agonist pramipexole (PPX) in a PD mouse model, induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of FTY720, similar to PPX, abolished an observed loss of tyrosine hydroxylase (TH) immunoreactivity in MPTP-lesioned brain regions. Moreover, significant changes in SPHK1 expression/activity in MPTP-lesioned mouse midbrain were identified. PPX, but not FTY720 treatment, significantly protected against these alterations. Both drugs activate another pro-survival enzyme, Akt kinase, which is a crucial protein downstream of S1PR(s). FTY720 increased BAD protein phosphorylation and in this way may protect mitochondria against the BAD-induced apoptotic signalling pathway. Both FTY720 and PPX enhanced the locomotor activity of PD mice in the rotarod tests. Our data suggest a neuroprotective role for FTY720 related to the S1PR/Akt kinase signalling pathways as a beneficial treatment target in planning new PD therapeutic options. Moreover, our findings have shed new light on a neuroprotective mechanism of PPX action associated with SPHK1 activation, which provides an opportunity for evaluating multi-target (SPHK1/S1P/S1PR) effects in the context of PD.

KEYWORDS:

Fingolimod; MPTP; Parkinson's disease; Pramipexole; Sphingosine kinase 1; Sphingosine-1-phosphate

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