Modulation of the Liver-Brain Axis by Ondansetron in Thio-Acetamide-Induced Acute Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a severe neurological complication of liver failure characterized by hyperammonemia, oxidative stress, neuroinflammation, and progressive neuronal dysfunction. Ondansetron (OND), a selective 5-hydroxytryptamine-3 (5-HT₃) receptor antagonist, has reported anti-inflammatory and neuroactive properties, but its effects in HE remain poorly defined. This study evaluated OND in a thioacetamide (TAA)-induced acute HE model in female Sprague-Dawley rats. Animals were assigned to Control, TAA, OND, TAA+OND (0.5 mg/kg), and TAA+OND (1 mg/kg) groups. Serum and cerebral glutamine, oxidative and antioxidant parameters, histopathological alterations, and TLR2, NF-κB, IL-1β, GFAP, NLRP3, and caspase-1 immunoreactivity were assessed in liver and brain tissues. TAA increased glutamine accumulation, produced tissue injury, altered redox parameters, and increased several inflammation-related markers. OND significantly reduced cerebral glutamine and attenuated selected biochemical, histopathological, and immunohistochemical alterations, with generally more pronounced effects at 0.5 mg/kg. These findings indicate that OND administration is associated with partial modulation of metabolic, oxidative, inflammatory, and structural alterations in TAA-treated rats, warranting further receptor-specific and functional studies to clarify its mechanisms and therapeutic relevance.