MODULATION OF SPHINGOSINE-1-PHOSPHATE SIGNALING BY FINGOLIMOD COUNTERACTS SCOPOLAMINE-INDUCED MEMORY DEFICITS

Neurolipid receptors have been implicated in neuroprotective mechanisms that may counteract cognitive deficits. In this context, we assessed whether the modulation of sphingosine-1-phosphate (S1P) signalling pathway using fingolimod (FTY720) could exert a neuroprotective effect due to biochemical modifications that can reverse scopolamine-induced spatial memory loss.
Spatial memory was tested in the Barnes Maze with Sprague Dawley rats treated with a daily intraperitoneal fingolimod (0.5, 1 and 3 mg/kg) for 5 days and a single scopolamine dose (2 mg/kg) before the fifth day probe. Acquisition speed, latency, and distance were measured for each quadrant. The collected brain samples were analyzed by Western blot (WB) to determine S1P1 receptor expression levels in the cortex, hippocampus, and cerebellum, as well as the phosphorylation cascades of enzymes involved in S1P synthesis and degradation.
Scopolamine treated group (SCOP) spent less time in the target quadrant compared to vehicle group (VEH) (51.03±3.21 s, n=14 vs 88.64±6.79 s, n=12, ****p≤0.0001), confirming memory impairment. This deficit was counteracted by fingolimod at 3 mg/kg (FTY3mg/kg) (82.02±6.20 s, n=12, ***p≤0.001). Unlike SCOP animals, fingolimod-treated groups showed a preference for the target quadrant, with SCOP+FTY3mg/kg group displaying the most significant effect (p≤0.0001). This cognitive improvement closely correlated with neurochemical modulation of S1P1 receptor expression observed by WB analysis.
Thus, fingolimod mitigated scopolamine-induced spatial memory deficits through modulation of S1P pathway, probably by enhancing the muscarinic cholinergic neurotransmission. Further studies will investigate the possible involvement of additional S1P receptor subtypes and modulation of cerebral lipid species.