Neuroprotective and neurogenic effects of fingolimod/FTY720

ABSTRACT

FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1Rs).
However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. Several effects of FTY720 in the central nervous system (CNS) have been described, ranging from neuroprotective to anti-inflammatory effects; on the other hand, the neurogenic and oligodendrogenic potential of FTY720 has been poorly investigated.

In our study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death, and we examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection.

We showed that FTY720 was able to reduce excitotoxicity in vitro, protecting both cortical neuronal and organotypic cerebrocortical cultures from NMDA-induced neuronal death. Moreover, in vivo repeated FTY720 administration attenuated neurodegeneration and microgliosis induced by intracerebroventricular administration of kainic acid (KA) in adult rats. Given the anti-inflammatory effect of the drug observed in vivo, we analyzed how microglia cells responded to FTY720. FTY720 negatively modulated p38 MAPK in LPS-activated microglia, whereas it had no effect on JNK1/2 activation. These data support a role for FTY720 as a neuroprotective agent against excitotoxin-induced neuronal death and as a negative modulator of neuroinflammation by targeting the p38 MAPK stress signalling pathway in microglia.
In a second part of the study, we focused on the neurogenic potential of FTY720, and we assessed the effect of FTY720 on the production of new neurons and oligodendrocytes from neural stem cells (NSCs) both in vitro and in vivo. We observed that FTY720 increased NSCs differentiation into both neurons and oligodendrocytes in vitro. In turn, FTY720 enhanced the percentage of proliferating cells coexpressing the neuroblast marker doublecortin, both in basal (FTY720 alone) and in neurodegenerative (FTY720 + KA) conditions. However, FTY720 had no effects on proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) population in vivo.

We can conclude that FTY720 promotes neurogenesis and oligodendrogenesis in vitro under basal conditions. In addition, it increases the generation of neuroblasts but not of oligodendrocytes after excitotoxic brain injury. This suggests that FTY720 has the potential to activate the neurogenic niche and thus favour tissue repair after lesion.