Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

Abstract

Fingolimod is a well-tolerated, highly effective disease-modifying therapy successfully utilized in the management of multiple sclerosis. The active metabolite, fingolimod-phosphate, acts on sphingosine-1-phosphate receptors (S1PRs) to bring about an array of pharmacological effects. While being initially recognized as a novel agent that can profoundly reduce T-cell numbers in circulation and the CNS, thereby suppressing inflammation and MS, there is now rapidly increasing knowledge on its previously unrecognized molecular and potential therapeutic effects in diverse pathological conditions. In addition to exerting inhibitory effects on sphingolipid pathway enzymes, fingolimod also inhibits histone deacetylases, transient receptor potential cation channel subfamily M member 7 (TRMP7), cytosolic phospholipase A2α (cPLA2α), reduces lysophosphatidic acid (LPA) plasma levels, and activates protein phosphatase 2A (PP2A). Furthermore, fingolimod induces apoptosis, autophagy, cell cycle arrest, epigenetic regulations, macrophages M1/M2 shift and enhances BDNF expression. According to recent evidence, fingolimod modulates a range of other molecular pathways deeply rooted in disease initiation or progression. Experimental reports have firmly associated the drug with potentially beneficial therapeutic effects in immunomodulatory diseases, CNS injuries, and diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and even cancer. Attractive pharmacological effects, relative safety, favorable pharmacokinetics, and positive experimental data have collectively led to its testing in clinical trials. Based on the recent reports, fingolimod may soon find its way as an adjunct therapy in various disparate pathological conditions. This review summarizes the up-to-date knowledge about molecular pharmacology and potential therapeutic uses of fingolimod.

Fingolimod effects on the brain are mediated through biochemical modulation of bioenergetics, autophagy, and neuroinflammatory networks

“…The mechanisms by which PPAR signaling promotes remyelination in MS may be through downregulation of NF‐κB/β‐catenin and upregulation of PI3K/Akt pathways [ 72 , 73 ]. Neuroprotective effects of fingolimod following traumatic brain injury (TBI) and other neurodegenerative disease has also been shown to be correlated with activation of the PI3K/Akt pathway [ 74 , 75 ]. Lysosome associated protein networks were also differentially affected in each brain region, while it was upregulated in CB, its downregulation was evident in FC.…”

Forskolin, an Adenylcyclase/cAMP/CREB Signaling Activator Restoring Myelin-Associated Oligodendrocyte Destruction in Experimental Ethidium Bromide Model of Multiple Sclerosis

“…Our study uses a combination of drugs (FNG, DON, MEM, and SIM) used in the MS condition. It directly shows correlation with phosphorylation of CREB [ 11 , 24 ]. FNG plays a part in preventing demyelination by increasing the number of oligodendrocytes cells [ 25 ].…”

“…FNG is the first orally approved drug with high disease modifying efficacy used for the treatment of multiple sclerosis (MS) because it works as a sphingosine-1-phosphate (S1P) modulator [ 23 ]. The Akt and ERK pathways, which are directly involved in the phosphorylation of CREB, are activated as a result of FNG [ 11 , 24 ]. It also improves myelination and remyelination, neuron survival, proliferation, differentiation, and migration and reduces apoptosis by increasing OPC [ 25 ].…”

Repurposing drugs against Alzheimer’s disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

“…Several studies reported neuroprotective effects of fingolimod on Aβ pathology, APP metabolism, AD-related memory deficits, BDNF elevation, and neuro-inflammation and were nicely summarized in recent reviews (compare Angelopoulou et al 2019;Bascunana et al 2020;Pournajaf et al 2022). There is strong evidence that fingolimod may contribute to the inhibition of Aβ accumulation by reducing the Aβ load in the brain (Aytan et al 2016;Carreras et al 2019;Kartalou et al 2020;McManus et al 2017;Takasugi et al 2013).…”

“…Fingolimod has emerged recently as a promising neuroprotective agent in a wide range of CNS diseases, including Alzheimer's disease (AD; reviewed, e.g., in Angelopoulou and Piperi 2019;Bascunana et al 2020;Pournajaf et al 2022). Importantly, fingolimod tackles those immunological and neuro-inflammatory processes that are triggered by amyloid-β and tau fibrillary tangle pathology (Aytan et al 2016;Baloni et al 2022;Bascunana et al 2023;Fagan et al 2022;Kartalou et al 2020).…”