Nesfatin‐1 Exerts a Neuroprotective Effect in Thioacetamide‐Induced Acute Hepatic Encephalopathy by Activating the PI3K /Akt/Nrf2/ HO ‐1 Pathway

ABSTRACT Introduction Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with liver failure. Nesfatin‐1 is a neuropeptide characterized by its antioxidant and anti‐inflammatory properties. Aim This study aimed to evaluate the neuroprotective and hepatoprotective effects of nesfatin‐1 in a thioacetamide (TAA)‐induced rat model of acute HE. Additionally, the study aimed to examine the underlying mechanisms, particularly the role of the PI3K/Akt/Nrf2/HO‐1 signaling pathway. Materials and Methods Male Sprague Dawley rats were divided into five groups: (1) untreated control, (2) nesfatin‐1‐treated control, (3) thioacetamide‐induced hepatic encephalopathy (HE), (4) HE + nesfatin‐1, and (5) HE + nesfatin‐1 + zinc protoporphyrin IX (ZnPP IX; HO‐1 inhibitor). Assessments included behavioral analysis, serum liver function biomarkers, oxidative stress and inflammatory markers, brain water content, mRNA expression of HO‐1 (Heme Oxygenase 1) and GFAP (Glial Fibrillary Acidic Protein), PI3K/Akt/Nrf2 protein levels, as well as histological and immunohistochemical evaluations. Results Nesfatin‐1 significantly improved psychomotor activity, reduced serum ALT, AST, total bilirubin, and ammonia levels, and increased albumin. It also lowered brain MDA, TNF‐α, IL‐6, and CRP levels, reduced brain water content, and upregulated the expression of HO‐1 and GFAP. Furthermore, nesfatin‐1 activated the PI3K/Akt/Nrf2 pathway and inhibited the expression of caspase‐3 and NF‐κB in liver and brain tissues. These protective effects were negated by HO‐1 inhibition using ZnppIX. Histological analysis demonstrated the structural integrity of liver and brain tissues in rats treated with nesfatin‐1. Conclusion Nesfatin‐1 exerts potent hepatoprotective and neuroprotective effects in TAA‐induced hepatic encephalopathy via antioxidative, anti‐inflammatory, and antiapoptotic mechanisms involving the PI3K/Akt/Nrf2/HO‐1 pathway.