Efeitos do tratamento com ácido gálico sobre parâmetros oxidativos, moleculares e comportamentais induzidos por cetamina em ratos

Abstract

Ketamine is a dissociative anesthetic drug, which blocks NMDA glutamatergic receptors for restricted clinical use due to its high addictive potential. Studies have shown neurotoxicity and memory impairments development after acute- and chronic-KET exposure. Gallic acid (AG) is a natural antioxidant, whose activity has shown benefits over memory. The current study was designed to evaluate possible beneficial actions of GA on the harmful consequences of acute and sub-chronic ketamine administration in male adolescent rats. Forty-five Wistar rats were assigned to two experimental protocols (UFSM/8629131218): In the protocol 1 (acute/binge exposure; Binge-KET group), animals received five doses of KET (ketamine) (10 mg/kg, ip) every three hours for the first 12 hours of the day, receiving three doses of GA (13.5 mg/ kg, po) or vehicle in the following 12 hours; In protocol 2 (sub-chronic exposure to KET; SbChro-KET group), animals received a daily dose of KET (10 mg/kg, ip) for 10 days and they were sequentially treated with one dose of GA (13.5 mg/kg, po) or vehicle daily for three consecutive days. In protocol I, KET impaired the working memory of the animals by reducing the percentage of alternation in the Y labyrinth test. Biochemical analyzes showed that these animals showed increased levels of plasma creatinine, lipoperoxidation (LP) in the kidney and hippocampus, in addition to increased catalase (CAT) activity in the liver and hippocampus, which was reduced in the kidney. Acute exposure to KET also changed molecular parameters, increasing hippocampal immunoreactivity of pro BDNF and TrkB. Treatment with AG did not reverse the impaired memory by acute KET, but it completely reversed the levels of creatinine (plasma), CAT activity (liver and hippocampus) and LP (kidney), in addition to reversing the immunocontent of pre BDNF and TrKB. In protocol II, animals subchronically exposed to KET showed impaired memory, increased levels of AST and ALT in plasma, LP in the liver, kidney and hippocampus, in addition to increased CAT activity in the liver and kidney. At the molecular level, such exposure to KET increased the pro-BDNF immunoreactivity and reduced the levels of BDNF and TrkB in the hippocampus. The AG recovered working memory, previously impaired by the drug in the acute protocol, fully recovered the levels of AST and ALT in plasma, and also of LP in the kidney, liver and hippocampus in addition to CAT activity in the liver and kidney. All hippocampal molecular changes (pro BDNF, BDNF and TrkB) induced by subchronic KET exposure were reversed by AG. Interestingly, BDNF levels showed a negative correlation with LP levels in the hippocampus and positive with the percentage of alternation in the Y labyrinth, while the latter showed a negative correlation with the hippocampal levels of LP. Given these outcomes, it is possible to suggest that, following clinical studies, GA may be considered a natural antioxidant agent of promising usefulness for reversing damages induced by both acute and subchronic-KET abuse.