Ligustrazine attenuates high-fat diet-induced neurobehavioral deficits and hepatic dysfunction via modulation of the HO-1/Nrf-2/SIRT-1/PPAR-α axis.

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disorder that not only progresses to severe hepatic complications but is increasingly associated with neurological dysfunction, including cognitive impairment, anxiety, depression, and motor deficits. The present study investigated the neuroprotective and hepatoprotective potential of ligustrazine (LTZ) in a high-fat diet (HFD)-induced NAFLD-associated neurological dysfunction model in adult Wistar rats, with a mechanistic focus on SIRT-1, HO-1, Nrf-2, and PPAR-α signaling pathways. Molecular docking analyses demonstrated favorable binding of LTZ with SIRT-1, HO-1, Nrf-2, and PPAR-α receptors, suggesting its potential to modulate these targets. NAFLD and associated neurobehavioral deficits were induced by HFD administration for 35 days, followed by oral treatment with LTZ (80, 160, and 240 mg/kg) or pioglitazone (5 mg/kg) for an additional 35 days. LTZ treatment dose-dependently improved locomotor activity, motor coordination, depressive-like behavior, learning, and memory as assessed by open field, rotarod, forced swim, and Morris water maze tests. Biochemical and molecular analyses revealed that LTZ significantly restored antioxidant defenses, normalized lipid and liver enzyme profiles, reduced systemic and neuroinflammation, attenuated neuronal apoptosis, and corrected neurotransmitter imbalances in multiple brain regions. Furthermore, LTZ markedly upregulated SIRT-1, HO-1, Nrf-2, and PPAR-α levels in both liver and brain tissues, accompanied by histopathological and complete blood count profile improvement. Collectively, these findings demonstrate that ligustrazine effectively mitigates HFD-induced NAFLD-associated neurological dysfunction through multi-target modulation of oxidative stress, inflammation, apoptosis, and metabolic signaling pathways, highlighting its potential as a promising therapeutic strategy for NAFLD-related hepatic and neurobehavioral complications.