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

Neuropharmacology
Joanna MotylJoanna B Strosznajder

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). ...Continue Reading

Citations

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Jan 7, 2019·Molecular Neurobiology·Kinga CzubowiczRobert P Strosznajder
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Jul 3, 2021·International Journal of Molecular Sciences·Joanna A MotylRobert P Strosznajder
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