FTY720 (Fingolimod) Attenuates Beta-amyloid Peptide (Aβ42)-Induced Impairment of Spatial Learning and Memory in Rats

Abstract

Imbalanced lipid metabolism and increase in the ceramide-to-S1P ratio in the brain have been postulated to play a role in amyloidogenesis, neuroinflammatory reactions, and neuronal apoptosis in Alzheimer's disease (AD) pathology. FTY720, the immunomodulatory sphingosine 1-phosphate (S1P) analog, has recently gained interest because of its CNS-directed effects. In addition to its immunomodulatory functions in multiple sclerosis, FTY720 possesses anti-inflammatory and neuroprotective roles in different cerebral ischemia models. In the present study, we examined the effects of FTY720 in a rat model of AD. Memory deficit was induced by bilateral intrahippocampus injection of beta-amyloid peptide (Aβ(42)) and examined through the Morris water maze test. The extent of histological injury in the hippocampus and the activation of caspase-3 were determined respectively by Nissl staining and Western blotting. Chronic daily administration of FTY720 (1 mg/kg, i.p., 14 days) significantly attenuated the Aβ(42)-induced learning and memory impairment and prevented the hippocampus neuronal damage as well as caspase-3 activation. These data show for the first time that FTY720 has a beneficial effect in restoring memory loss in Aβ(42)-induced neurotoxicity and also suggest that S1P receptors and signaling pathways may provide a potential target for the treatment of AD.

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

“…FTY720 is also reported to modulate sphingolipid metabolism, which is thought to promote disease progression in NOD EAE and MS (3,19,23,69,70). Indeed, we showed that inhibitors of B4GALT6 and lactosyl ceramide production suppress disease progression in NOD EAE by arresting local CNS-innate immunity and neurodegeneration (3).…”

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…This phenomenon is exploited in its therapeutic applications thus far, but makes interpretation of the results of its experimental administration much more difficult. Chronic, peripheral FTY720 treatment has been shown to attenuate histological damage and reduce behavioral deficits in the hippocampal CA1 field of Aβ 42 -injected rats [64]; in vitro FTY720 is able to reduce Aβ production by primary mouse neurons, although with some increase of the Aβ 42 /Aβ 40 ratio [65]. The mechanism of fingolimod's action may include effects on apoptotic signaling (as an S1P analog, it may counteract the effects of ceramide), or on AβPP/Aβ metabolism.…”

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…S1PRs have also been shown to limit events of demyelination and promote remyelination, which are probably mediated by the dampening of pro-inflammatory cytokine levels (Miron et al, 2010;Sheridan and Dev, 2012). Overall, therefore, S1PRs represent an important drug target that can be exploited for use in neuroinflammatory, demyelinating and neurodegenerative diseases, as documented by a growing body of literature (Asle-Rousta et al, 2013;Deogracias et al, 2012). Here we investigate whether regulation of S1P signalling alters psychosine-induced astrocyte dysfunction, pro-inflammatory cytokine release and demyelination.…”