Sphingosine-1-Phosphate Receptors Modulators Decrease Signs of Neuroinflammation and Prevent Parkinson's Disease Symptoms in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model

Abstract

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid mediator that acts as a natural ligand upon binding to five different receptors that are located in astrocytes, oligodendrocytes, microglial and neuronal cells. Recently, global activation of these receptors by FTY720 (fingolimod) has been suggested to provide neuroprotection in animal model of Parkinson's disease (PD). Among S1P receptors, the subtype 1 (S1P1R) has been linked to features of neuroprotection and, using the selective agonist SEW2871, the present investigation assessed potential benefits (and mechanisms) of this receptor subtype in an established animal model of PD. We demonstrated that oral treatments with SEW2871 are able to provide protection to the same levels as FTY720 against loss of dopaminergic neurons and motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg, i.p., 5 days) mouse model of PD. At the molecular level, we observed that the beneficial effects of both S1PR agonists were not associated with alterations in ERK and Akt levels, two markers of molecular adaptations in the striatum neurons. However, these compounds have the capacity to prevent signs of neuroinflammation such as the activation of astrocytes and glial cells, as well as MPTP-induced reduction of BDNF levels in key regions of the brain implicated in motor functions. These findings suggest that selective S1P1R modulation has the ability to provide neuroprotection in response to MPTP neurotoxicity. Targeting S1P1R in PD therapy may represent a prominent candidate for treatment of this neurodegenerative conditions.

Keywords: FTY720; MPTP; S1P receptors; SEW2871; neuroinflammation; neuroprotection.