SIRT1 activator resveratrol improves the ALF-induced cognitive and motor function deficits in rats via modulating glutamate-NMDAR-NOS-cGMP pathway.

Acute liver failure (ALF) is a life-threatening condition often leading to acute hepatic encephalopathy (acute HE), a neuropsychiatric disorder characterized by cognitive deficits and motor dysfunction due to elevated ammonia levels and neuroinflammation. This study investigates the therapeutic potential of resveratrol (RSV), a SIRT1 activator, in mitigating the cognitive and motor impairments associated with ALF-induced acute HE. SIRT1 is an NAD + -dependent class III histone deacetylase and mammalian ortholog of yeast Sir2, linking longevity, caloric restriction, neuroprotection, metabolism, inflammation, and oxidative stress regulation. It deacetylates PGC-1α and represses PPARγ, thereby enhancing mitochondrial function, insulin sensitivity, fat oxidation, gluconeogenesis, and DNA repair via p53. Using an ALF rat model induced by thioacetamide (TAA), the study demonstrates that RSV pretreatment significantly reduces ammonia levels and restores neurotransmitter balance in the brain. Specifically, RSV modulates the glutamate-NMDAR-NOS-cGMP pathway, reducing excitotoxicity by downregulating NR2B and upregulating NR2A receptor subunits. Additionally, in the downstream pathway, RSV ameliorates oxidative stress and neuroinflammation by normalizing iNOS and nNOS expression, reducing nitric oxide (NO) production, and restoring cGMP levels, thus improving spatial memory and motor coordination. Further, the neurobehavioral tests, including T-maze, rotarod, and traction control, confirm RSV's protective role in acute HE by mitigating the neurobehavioral deficits. These findings suggest that targeting SIRT1 with resveratrol may offer a promising therapeutic approach for acute HE management during ALF by providing neuroprotection and improving cognitive and motor function.