Modulation of sphingosine-1-phosphate receptor by FTY720 contributes in improvement of hepatic encephalopathy induced by bile duct ligation

Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder, which is associated with memory loss and behavioral abnormalities. The cellular and molecular mechanisms that led to hippocampal dysfunction in bile duct ligation (BDL)-induced HE and neuroprotective mechanisms of FTY720 administration were evaluated using whole-cell patch clamp, field-potential recording, western blot, stereology and behavioral experiments. The animals were divided into 4 groups of control (n = 24), sham (n = 21), BDL + V (n = 21) and BDL + FTY720 (n = 20), each having three subgroups. The first subgroup was used for field potential, western blot and stereology experiments. The second and third subgroups were used for behavioral experiments and whole cell patch clamp recording, respectively. The BDL led to considerable loss of hippocampal neurons and apoptosis, along with large impairments in their intrinsic electrophysiological properties, including decrease of firing frequency and increases of first spike latency (FSL), AHP amplitude, irregularity of firing, and half-width, as well as impaired long-term synaptic plasticity and memory. Importantly, FTY720 decreased AHP amplitude probably by direct inhibition of Ca2+ channels and/or KCa2+ currents and improved the FSL and firing irregularity and frequency possibly by decreasing A-type K+ currents in the BDL + FTY720 group. FTY720 administration in the BDL rats also decreased the release probability, which was evident by the increased paired-pulse ratio, but the increased number of readily releasable pool (RRP) of neurotransmitter. Moreover, the AHP improvement and RRP increment most likely led to recovery of LTP and memory performance. In total, FTY720 ameliorated brain disorders in the BDL rats via its direct neuroprotective and/or indirect anti-inflammatory effects.