Volume 59, Issue 332, August 2023

Prevention of the NMDA glutamate receptor antagonist ketamine-induced oxidative stress, brain neuronal degeneration and liver injury by methylene blue

Omar ME Abdel-Salam^1♦, Amany A Sleem², Eman R Youness³, Enayat A Omara⁴

¹Toxicology and Narcotics Department, Medical Research and Clinical Studies, Institute National Research Centre, Cairo, 12622, Egypt
²Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, 12622, Egypt
³Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, 12622, Egypt
⁴Pathology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, 12622, Egypt

^♦Corresponding author
Toxicology and Narcotics Department, Medical Research and Clinical Studies, Institute National Research Centre, Cairo, 12622, Egypt

ABSTRACT

Methylene blue (MethyB) was shown to possess potential neuro- and liver protective properties. The aim of this study was to investigate the effect of MethyB on brain neurodegeneration and liver injury induced by ketamine. Rats were treated with single intraperitoneal (i.p.) injection of ketamine (35 mg/kg) either alone or combined with MethyB at doses of 20 or 40 mg/kg and euthanized 4h later. The determination of biomarkers of oxidative stress including malondialdehyde, nitric oxide and reduced glutathione as well as paraoxonase-1 (PON-1) was carried out in brain and liver tissue. In addition, the concentrations of acetylcholinesterase (AChE) and Aβ-peptide were determined in brain tissue and histological studies were done using haematoxylin and eosin staining. Results indicated that compared to the saline control, ketamine-treated rats exhibited significantly elevated malondialdehyde, decreased nitric oxide levels, as well as depletion of reduced glutathione and decreased PON-1 activity in brain and liver. There were also significant decrements in brain Aβ-peptide, AChE levels by ketamine treatment. The presence of dark shrunken cortical neurons with deeply stained pyknotic nuclei and shrunken degenerated hippocampus pyramidal cells having dark eosinophilic cytoplasm with pyknotic nuclei was detected in brain after ketamine injection. The liver of these animals exhibited severe degeneration of hepatocytes and perivascular infiltrations of inflammatory cells with dilated sinusoids. In ketamine-treated rats, the administration of MethyB resulted in significant inhibition of lipid peroxidation, increased reduced glutathione levels and PON-1 activity, while it decreased nitric oxide in brain and liver. It had no effect on AChE but caused further decrease in Aβ-peptide in brain of ketamine-treated rats. MethyB conferred dose-dependent protection against the ketamine-induced histological changes in brain and liver with the higher dose bringing about almost normalization of these tissues. It is concluded that MethyB exerts a neuro- and hepato-protective effects against ketamine toxicity and these may involve anti-oxidative actions as a potential mechanism.

Keywords: Methylene blue, ketamine, neurotoxicity, hepatotoxicity, nitric oxide, amyloid Aβ-peptide, acetylcholinesterase

Discovery, 2023, 59, e106d1312

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Published: August 2023