Fisetin ameliorates neurobehavioral deficits in bile duct ligated rat model by restoring spine density and memory...

Chronic liver damage is characterized by cognitive impairments primarily due to metabolic imbalance notably hyperammonemia, termed as hepatic encephalopathy (HE). The present study investigated the neuroprotective potential of fisetin, a bioactive flavonoid, in bile duct-ligated (BDL) rat model that mimics HE. BDL rats exhibited significant liver morphological alterations, driven by inflammation and fibrosis causing metabolic imbalance and persistent chronic liver damage. These rats further demonstrated deficits in spatial memory, learning, and object recognition, as observed through various behavioral paradigms including morris water maze, barnes maze, Y-maze, and novel object recognition test. These cognitive deficits were accompanied by neurodegeneration, reduced spine density, disrupted expression of synaptic markers, and altered brain metabolite levels. Fisetin supplementation (25 mg/kg, p.o. for 28 d post-BDL surgery) to BDL rats significantly improved cognitive performance in the behavioural tests. Additionally, fisetin restored spine density and clustering patterns, upregulated key memory-associated genes (PSD95, synaptophysin, synaptotagmin-1), and reduced brain levels of ammonia, glutamate, and glutamine, which correlated with enhanced neurobehavioral outcomes. Histological assessments showed significantly reduced neuronal degeneration in BDL rats supplemented with fisetin, suggesting its ability to ameliorate HE-associated neurodegeneration. These findings collectively underscore fisetin's neuroprotective potential in BDL rats by mitigating neurodegeneration, preserving synaptic integrity, and enhancing cognitive function.