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

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…S1P may also regulate assembly of complex IV of respiratory chain by interaction with mitochondrial protein prohibitin 2 (PHB2) [87]. Pathogenic ASN and S1P inhibit and activate, respectively, the Akt kinase (serine/threonine protein kinase B)/brain-derived neurotrophic factor (BDNF) signaling pathway [81,83,88,89] (regular green). S1P inhibits histone deacetylase 1 and 2 (HDAC1 and HDAC2), thus enhancing histone acetylation [90], while ASN hinders access of histone acetyltransferases (HATs) by interacting with histone H3 [28] (dark green).…”

Sphingosine‐1‐Phosphate, Motor Severity, and Progression in Parkinson's Disease (MARK‐PD)

“…In this study, we show that (1) serum S1P concentrations are lower in PD patients when compared to non-PD S1P agonists protect dopaminergic neurons from MPP-induced cell death, and S1P signaling elicits neuroprotective effects in PD mouse models. 3,4 Besides PD, S1P signaling also confers beneficial effects in other neurological diseases. In the central nervous system, S1P receptor agonists improve neurovascular microcirculation, strengthen brain endothelial barrier function thereby limiting plasma and leukocyte extravasation, and support cell survival.…”

“…2 All these processes can be attenuated by sphingosine-1-phosphate (S1P) mimics in PD mouse models. 3,4 In cell culture experiments, S1P protected dopaminergic neurons from 1-methyl-4-phenyl-4-propion (MPP) induced cell death by activation of S1P receptor 1 (S1PR1) signaling and enhancing mitochondrial biogenesis. 5 In addition to in vitro experiments, the S1P receptor modulator fingolimod reduced α-synuclein aggregation, increased brain-derived neurotrophic factor (BDNF), diminished dopaminergic neurodegeneration, attenuated the decrease of striatal dopamine levels, and eventually decreased motor deficits in different pharmacologically induced PD mouse models.…”

Editorial: Oxidative Stress: How Has It Been Considered in the Design of New Drug Candidates for Neurodegenerative Diseases?

“…One example is the agonist S1P receptor fingolimod, approved by FDA in 2010 as the first oral treatment for multiple sclerosis, but that also demonstrated ability to promote neuroprotection in animal models of PD. Stimulated by these previous results, Pépin et al (2020) investigated the profile of compound SEW2871, a selective agonist of S1P receptors in animal models of PD. The obtained results clearly indicated that SEW2871 presented a neuroprotective activity similar to that displayed by fingolimod in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, being a promising candidate for treatment of this ND.…”

“…Abundant literature data suggest that OS may induce not only cellular and membrane damage, but also DNA repair system breakdown or mitochondrial disfunction, contributing to a complex network of events related to energy supply, neurodegeneration and aging, a phenomena observed in AD or PD, for example ( Schieber and Chandel, 2014 ). Increased reactive oxygen species (ROS) levels is a prompt consequence of OS and it is usually related to down-regulation in several defense systems including antioxidant enzymes or endogenous small-molecule antioxidants ( Sayre et al, 2001 ).…”