Guanosine Attenuates Astrocyte-Associated Glutamatergic Dysregulation and Improves Survival in Acute Liver Failure-Induced Hepatic Encephalopathy

Background/Objectives: Acute liver failure (ALF) rapidly induces hepatic encephalopathy (HE), a severe neurological syndrome associated with astrocytic dysfunction and glutamatergic dysregulation. Guanosine (GUO), an endogenous guanine-based nucleoside, has neuroprotective properties, but its effects on astrocyte-associated glutamate regulation in ALF-induced HE remain incompletely understood. This study tested whether GUO attenuates neurological deterioration and glutamatergic dysfunction in an experimental model of ALF-induced HE. Methods: Male Wistar rats underwent 92% subtotal hepatectomy and received intraperitoneal GUO (7.5 mg/kg) or saline at prespecified time points after surgery. Neurological severity and survival were monitored for 72 h. Astrocytic morphology was assessed by GFAP immunofluorescence. Cerebrospinal fluid (CSF) albumin, glutamate, and glutamine levels, cortical Na+-dependent glutamate uptake, GLAST immunocontent, and the 67 kDa GLT-1 monomer immunocontent were evaluated. Results: Subtotal hepatectomy induced progressive neurological impairment, high mortality, GFAP-associated astrocytic remodeling, increased CSF albumin, glutamate, and glutamine levels, and reduced cortical glutamate uptake. GUO attenuated neurological deterioration and increased 72 h survival from 10.5% to 39.0% (log-rank p = 0.03). GUO also reduced CSF albumin, glutamate, and glutamine concentrations and improved cortical Na+-dependent glutamate uptake without altering GLAST or GLT-1 monomer immunocontent. Conclusions: GUO attenuated astrocyte-associated glutamatergic dysregulation and improved survival in ALF-induced HE. These findings support further mechanistic and translational investigation of GUO as an experimental modulator of astrocyte-associated glutamate handling in ALF-induced HE.