FTY720 Attenuates 6-OHDA-Associated Dopaminergic Degeneration in Cellular and Mouse Parkinsonian Models

Abstract

FTY720 (fingolimod) is the first oral drug approved for treating relapsing-remitting forms of multiple sclerosis. It is also protective in other neurological models including ischemia, Alzheimer's disease, Huntington disease and Rett syndrome. However, whether it might protect in a 6-hydroxydopamine (6-OHDA) mouse model associated with the dopaminergic pathology of Parkinson's disease (PD), has not been explored. Therefore, in the present study, we investigated the effects of FTY720 on 6-OHDA-induced neurotoxicity in cell cultures and mice. Here we show that FTY720 protected against 6-OHDA cytotoxicity and apoptosis in SH-SY5Y cells. We also show that prior administration of FTY720 to 6-OHDA lesioned mice ameliorated both motor deficits and nigral dopaminergic neurotoxicity, while also reducing 6-OHDA-associated inflammation. The protective effects of FTY720 were associated with activation of AKT and ERK1/2 pro-survival pathways and an increase in brain derived neurotrophic factor (BDNF) expression in vitro and in vivo. These findings suggest that FTY720 holds promise as a PD therapeutic acting, at least in part, through AKT/ERK1/2/P-CREB-associated BDNF expression.

A Pilot Microbiota Study in Parkinson’s Disease Patients versus Control Subjects, and Effects of FTY720 and FTY720-Mitoxy Therapies in Parkinsonian and Multiple System Atrophy Mouse Models

“…Additional work should test this possibility as well as evaluate identified shared microbial markers that correlated with disease in our PD and MSA mouse models. Our results suggest that mice may be useful surrogates for evaluating therapeutic effects on gut function and/or pathology, as we did with FTY720 in parkinsonian A53T Tg mice [22,26,28]. Although here we saw little impact of FTY720 on mouse microbiota, desirable microbial effects were noted in response to FTY720-Mitoxy, supporting further evaluation of this anti-synucleinopathy, neurotrophic-factorenhancing, brain penetrating compound [32,33].…”

“…Previously we and others have studied protection by FTY720, an approved oral immunosuppressive drug for multiple sclerosis, that when phosphorylated acts on sphingosine-1-phosphate receptors (S1P-Rs) [25]. FTY720 causes immunosuppression but also enhances expression of brain derived trophic factor in multiple cell and animal models [26][27][28][29][30]. We showed that FTY720 improves GI physiology/function and reduces GI aSyn pathology in A53T Tg parkinsonian mice [22].…”

Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson's disease and does not lead to a sustainable increase of brain‐derived neurotrophic factor

“…Fingolimod protected dopaminergic markers against the toxicity of 6‐OHDA, rotenone and an acute regimen of MPTP that causes necrotic death of dopaminergic neurons (Ren et al . ; Zhao et al . ; Motyl et al .…”

“…Our findings are unexpected given three studies published during preparation of this manuscript that found beneficial effects of fingolimod in other toxin-based models of PD. Fingolimod protected dopaminergic markers against the toxicity of 6-OHDA, rotenone and an acute regimen of MPTP that causes necrotic death of dopaminergic neurons (Ren et al 2017;Zhao et al 2017;Motyl et al 2018). In addition, fingolimod reduced a-synuclein pathology in a transgenic mouse model (Vidal-Mart ınez et al, 2016).…”

Targets and Mechanisms in Prevention of Parkinson's Disease through Immunomodulatory Treatments

“…However, recently, many other animal studies have emerged applying novel oral substances. Ren et al [59] showed that prior administration of fingolimod (FTY720) to 6OHDA-lesioned mice ameliorated motor deficits, dopaminergic neurotoxicity and decreased inflammation. Signalling pathway inhibitors have also been tried.…”