FTY720 (fingolimod) attenuates beta-amyloid peptide (Aβ42)-induced impairment of spatial learning and memory in rats

J Mol Neurosci. 2013 Jul;50(3):524-32. doi: 10.1007/s12031-013-9979-6. Epub 2013 Feb 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Apoptosis / drug effects
  • Fingolimod Hydrochloride
  • Hippocampus / pathology
  • Male
  • Maze Learning / drug effects*
  • Memory / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / drug therapy*
  • Peptide Fragments / toxicity*
  • Propylene Glycols / pharmacology*
  • Propylene Glycols / therapeutic use
  • Rats
  • Rats, Wistar
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Sphingosine / therapeutic use

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Propylene Glycols
  • amyloid beta-protein (1-42)
  • Fingolimod Hydrochloride
  • Sphingosine