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

• Published in: Neuropharmacology Vol. 135; pp. 139 - 150
• Main Authors: Motyl, Joanna, Przykaza, Łukasz, Boguszewski, Paweł M., Kosson, Piotr, Strosznajder, Joanna B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2018
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; bcl-Associated Death Protein - metabolism; Brain - metabolism; Fingolimod; Fingolimod Hydrochloride - pharmacology; Male; Mice; MPTP; MPTP Poisoning - metabolism; MPTP Poisoning - prevention & control; Neuroprotection - drug effects; Parkinson Disease - enzymology; Parkinson Disease - prevention & control; Parkinson's disease; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Pramipexole; Pramipexole - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rotarod Performance Test; Sphingosine kinase 1; Sphingosine-1-phosphate; Tyrosine 3-Monooxygenase - metabolism; Sphingosine kinase 1; Parkinson's disease; MPTP; Fingolimod; Pramipexole; Sphingosine-1-phosphate
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.02.023

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. AbbreviationsMPTP/MPP + - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpiridinum; PD - Parkinson's Disease; ROS - reactive oxygen species; SPHK1 - sphingosine kinase 1; S1P - sphingosine-1-phosphate; S1P1-5 - sphingosine-1-phosphate receptors; red arrows – the pro-apoptotic pathways; green arrows - the pro-survival pathways. [Display omitted] •Sphingosine kinase 1 (SPHK1) expression/activity are decreased in PD mouse model.•Pramipexole (PPX) reversed a reduction in SPHK1 activity in MPTP-lesioned mice.•Fingolimod (FTY720) exerts a neuroprotective effect in PD mouse model in Akt-dependent manner.•FTY720 and PPX improved locomotor activity in PD mice.