Sodium Phenylbutyrate Attenuates Hippocampal Redox Imbalance, Neuroinflammation, and Recognition Memory Impairment in Rats with CCl4-Induced Hyperammonemia

Chronic hyperammonemia (HA) secondary to liver dysfunction is associated with cognitive impairment, oxidative stress, and neuroinflammation, particularly in hippocampal regions involved in learning and memory. This exploratory study evaluated the effects of sodium phenylbutyrate (PBA) on behavior and on biochemical and molecular changes in a rat model of CCl4-induced HA. Male Wistar rats were randomly distributed into five groups: CTRL (control), COV (corn oil vehicle) + SSI (isotonic saline solution), HA + SSI, COV + PBA, and HA + PBA. At the end of the administration periods, locomotor activity and recognition memory were evaluated with the Open-Field Test (OFT) and Novel-Object Recognition Test (NORt). HA induced significant increases in plasma and hippocampal ammonia and glutamine levels, accompanied by hepatic dysfunction. These alterations were associated with elevated lipid peroxidation, nitrite levels, disruption of antioxidant defenses, and increased proinflammatory cytokines in the hippocampus. In addition, HA + SSI animals showed reduced BDNF (Brain-Derived Neurotrophic Factor) and NT-3 (Neurotrophin-3) levels and impaired behavioral performance. PBA administration reduced ammonia accumulation, improved redox balance (pro- and antioxidant levels), attenuated the hippocampal proinflammatory cytokine profile, and restored neurotrophin levels. These effects were accompanied by improvement in locomotor and cognitive performance. In conclusion, our results indicate that PBA attenuates systemic and hippocampal alterations induced by chronic HA.