The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells

Abstract

Background: Major role of oxidative stress in the pathogenesis of neurodegenerative diseases have been suggested, being mitochondria one of the main sources of ROS. Aim: In the present work, we have studied the antioxidant effect of fingolimod phosphate (FP) on neuronal mitochondrial function and morphology using a model of mitochondrial oxidative damage induced by menadione (Vitk3). Methods: SN4741 neuronal cells were grown (70-80% confluence) and used as control (nontreated cells) or treated cells with Vitk3 15 µM alone or in presence of FP 50 nM during 4 hours. Mitochondrial membrane potential (MMP), cytochrome c oxidase (COX) activity, mitochondrial oxygen consumption rate (OCR), mitochondrial distribution (MTG) and morphology (EM) were analysed. Statistical differences were determined using one-way ANOVA. Results: Vitk3 incubation produces a dramatical decrease in MMP compared to control (43.7 %); this can be almost totally reverted by the co-incubation of Vitk3 in presence of FP (p<0.05). A 20.7 % decrease in COX activity has been found after Vitk3 incubation, again this effect was counteracted when Vitk3 and FP are combined, restoring COX activity to control levels (p<0.05). Vitk3 incubation triggers initially an increase in OCR, decreasing dramatically (61%) after 4 hours. In experiments co-incubating Vitk3 in presence of FP, the OCR decrease found was reduced to only 17% (p<0.05). In experiments with MitoTracker™ Green, we found a change in the network pattern distribution after Vitk3 administration that partially disappears when co-incubated in presence of FP. Almost all the mitochondria treated with Vitk3 show ultrastructural alterations at the electron microscopy level while normal mitochondria can be found when Vitk3 and FP are combined. Conclusion: FP protects against the mitochondrial damage induced by Vitk3, as seen by the results obtained in mitochondrial functional markers, distribution and morphology.

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…It has been suggested that high levels of ROS can induce the activation of sphingomyelinase (SMase) and shift the ''sphingolipid rheostat'' towards ceramide accumulation, thus triggering cell apoptosis (Petrache and Berdyshev, 2016). Meanwhile, temperate oxidative stress can activate SphK1 and lead to the upregulation of S1P, thereby promoting cell survival (Martín-Montañez et al, 2019). The protective role of S1P against oxidative stress-induced cellular damage has been validated, as proven by Pyszko and Strosznajder that S1P treatment can reverse MPP+ mediated free radical production and cellular apoptosis (Pyszko and Strosznajder, 2014).…”

Sphingosine 1-phosphate protects against radiation-induced ovarian injury in female rats—impact on mitochondrial-related genes

“…A study by Zelinski Mary B et al showed that female macaques' ovaries rapidly failed after 15 Gy radiation, while with S1P or its analogue, fingolimod (FTY720) pretreatment, macaques would quickly resume menstruation and fertility was restored after radiation, and their offspring developed normally without genomic instability [17]. Currently, the active metabolite fingolimod-phosphate (FP), one of the oral drugs for the treatment of multiple sclerosis (MS), seems to increase the stability of mitochondria in neurons, regulate mitochondrial oxidative stress, and restore mitochondrial kinetics under oxidative stress [10]. These characteristics of S1P and its analogues make it one of the most promising protective agents for radiation-induced ovary damage in the future.…”

“…S1P plays an important role in ovarian physiology, participating as an essential stimulator of follicular development in both the preantral and antral phases, as well as in ovulation and corpus luteum development [7]. The protective effect of S1P on the ovaries has been confirmed in several previous studies [8,9], and other studies have shown that analogues of S1P can regulate mitochondrial oxidative stress [10]; however, the radioprotective mechanism of S1P and the role of mitochondria in ovarian protection are still unclear.…”

Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

“…Taking all of this into consideration, the positive outcomes of fingolimod in cuprizone-induced demyelination can lead to propose a new mechanism of action. A recent in vitro study on mouse neuronal cells demonstrated that the oxidative damage induced by menadione is counteracted by the incubation with fingolimod (50 nM) [ 131 ]. The compound decreased the level of ROS and enhanced the expression and activity of protective factors, such as nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1(HO-1), and NAD(P)H: Quinone acceptor oxidoreductases-1 (NQO1) [ 131 ].…”

“…A recent in vitro study on mouse neuronal cells demonstrated that the oxidative damage induced by menadione is counteracted by the incubation with fingolimod (50 nM) [ 131 ]. The compound decreased the level of ROS and enhanced the expression and activity of protective factors, such as nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase-1(HO-1), and NAD(P)H: Quinone acceptor oxidoreductases-1 (NQO1) [ 131 ]. Consistently, increased expression of Nrf2 was observed in human iPSC-derived astrocytes treated with 100 nM of S1PR modulators, fingolimod, and siponimod [ 132 ].…”