The effects of the histone deacetylase inhibitor sodium butyrate were evaluated in ketamine-induced neurotoxicity and liver injury in the rat. Ketamine was intraperitoneally (i.p.) administered in a single dose of 35 mg/kg, and rats were treated at the same time with either saline or sodium butyrate at 100 or 200 mg/kg. Rats were euthanized 4h later. Biochemical markers of oxidative stress: nitric oxide, reduced glutathione, malondialdehyde, as well as paraoxonase 1 activity were estimated in the brain and liver. In addition, brain amyloid beta (Aβ)-peptide and acetylcholinesterase (AChE) concentrations were determined. Histological examination of brain and liver sections was also performed. A significant increase in malondialdehyde and a significant decrease in reduced glutathione and paraoxonase 1 were found in the brain and liver after injection of ketamine, whereas a significant decrease in nitric oxide was observed in the brain tissue. Moreover, ketamine-treated rats exhibited significantly lower levels of Aβ-peptide and AChE compared to the saline control. Sodium butyrate treatment significantly reduced malondialdehyde levels, and increased both reduced glutathione, and paraoxonase 1 in brain and liver, but had no significant effects on nitric oxide levels. Furthermore, sodium butyrate treatment caused further decrease in Aβ-peptide concentrations and restored AChE concentrations in brain compared to ketamine controls. Ketamine induced diffuse degeneration in cerebral cortex and severely degenerated hepatocytes. Sodium butyrate resulted in marked alleviation of the histologic damages. These results suggest the potential use of sodium butyrate in the treatment of neurotoxicity associated with ketamine abuse and possibly in other neurodegenerative states