Fingolimod as a Treatment in Neurologic Disorders Beyond Multiple Sclerosis

Abstract

Fingolimod is an approved treatment for relapsing–remitting multiple sclerosis (MS), and its properties in different pathways have raised interest in therapy research for other neurodegenerative diseases. Fingolimod is an agonist of sphingosine-1-phosphate (S1P) receptors. Its main pharmacologic effect is immunomodulation by lymphocyte homing, thereby reducing the numbers of T and B cells in circulation. Because of the ubiquitous expression of S1P receptors, other effects have also been described. Here, we review preclinical experiments evaluating the effects of treatment with fingolimod in neurodegenerative diseases other than MS, such as Alzheimer’s disease or epilepsy. Fingolimod has shown neuroprotective effects in different animal models of neurodegenerative diseases, summarized here, correlating with increased brain-derived neurotrophic factor and improved disease phenotype (cognition and/or motor abilities). As expected, treatment also induced reductions in different neuroinflammatory markers because of not only inhibition of lymphocytes but also direct effects on astrocytes and microglia. Furthermore, fingolimod treatment exhibited additional effects for specific neurodegenerative disorders, such as reduction of amyloid-β production, and antiepileptogenic properties. The neuroprotective effects exerted by fingolimod in these preclinical studies are reviewed and support the translation of fingolimod into clinical trials as treatment in neurodegenerative diseases beyond neuroinflammatory conditions (MS).

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

“…ASN may impair S1P1 signaling [80]. Fingolimod (FTY720) targets both the peripheral immune system [170] as well as exerts a direct neuroprotectiv effect [189], including synucleinopathy reduction in gut-brain axis [64] and also improves the blood brain barrier (BBB) function [190]. The effects of the FTY720 are shown in blue rectangles.…”

“…Besides its well-known mechanisms, which operate by sequestration of autoreactive lymphocytes within the lymph nodes and limiting of their migration into the CNS, FTY720 exerts a direct effect on the S1P receptors expressed on neuronal and glial cells [189]. FTY720 has also been reported to enhance the properties of the blood-nerve barrier [190,191].…”

Age-Related Transcriptional Deregulation of Genes Coding Synaptic Proteins in Alzheimer's Disease Murine Model: Potential Neuroprotective Effect of Fingolimod

“…FTY720 also reduces the numbers of activated microglia and astrocytes in the brain of rodent AD models, normalizing cytokines, synaptic morphology, plasticity, and learning performance (Hemmati et al, 2013;Aytan et al, 2016). Anti-inflammatory effects of FTY720 have also been shown in other diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), neuronal ceroid lipofuscinoses, and neonatal hyperoxia (Bascuñana et al, 2020). Although feedback S1PR internalization upon ligation has been considered the main mechanism of the anti-inflammatory action of FTY720, the atypical dose-response characteristics suggest that agonistic action on S1PRs may also be important in this case, possibly involving two different mechanisms depending on compound concentration (Aytan et al, 2016).…”

The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer’s Disease

“…Taken together, this shows that Fingolimod is a promising new therapeutic approach for AD. Moreover, other neurodegenerative or neuro-inflammatory diseases such as Parkinson’s disease, Huntington’s disease, and epilepsy also explore the use of Fingolimod as possible treatment because of its diverse anti-inflammatory and neuroprotective effects ( 146 ). However, although different animal models show promising results upon treatment with Fingolimod, further experiments, as well as clinical studies, should elucidate if patients indeed benefit from Fingolimod as medication.…”