New pathways driving the experimental hepatoprotective action of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) against acute hepatotoxicity

• Published in: Biomedicine & pharmacotherapy Vol. 79; pp. 215 - 221
• Main Authors: Abdel-Hamid, N.M, Wahid, Ahmed, Mohamed, E.M, Abdel-Aziz, M.A, Mohafez, O.M, Bakar, Sally
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2016
• Subjects: Acute Disease; Animals; Carbon Tetrachloride; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Catalase - metabolism; Cyclic N-Oxides - pharmacology; Cyclic N-Oxides - therapeutic use; Gene Expression Regulation - drug effects; Glutathione - metabolism; Internal Medicine; IRE-1; Liver - drug effects; Liver - enzymology; Liver - pathology; Liver Diseases - drug therapy; Liver Diseases - pathology; Liver injury; Male; Medical Education; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Piperidines - pharmacology; Piperidines - therapeutic use; Protective Agents - pharmacology; Protective Agents - therapeutic use; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Spin Labels; Tempol; Thiobarbituric Acid Reactive Substances - metabolism; TNF-α; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tempol; IRE-1; TNF-α; Caspase-3; Carbon tetrachloride; Liver injury
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2016.02.016

Abstract Purpose In absence of liver protective drugs, a large number of hepatopathies may arise during drug administration. This study was executed to investigate the possible new pathways underlying the hepatoprotective effect of Tempol (4-hydroxy-2,2,6,6- tetramethylpiperidine-1-oxyl), following oral administration of carbon tetrachloride in mice. Methods and results Thirty albino mice were randomized into 3 equal groups. The duration of study was 28 days. The groups were classified as follows: Group I (healthy control): received saline, in the same volume of CCl4 dose, daily, orally, for 14 days, then sacrificed. Group II: received CCl4 , as a single oral dose only, of 1 ml/kg body weight, dissolved in olive oil (1:1 v/v), the animals of this group were sacrificed 14 days after CCl4 single dose intoxication. Group III (protective Tempol treated): received a single dose of Tempol, 20 mg/kg, orally, daily for 14 days. Two hours after the last Tempol dose, animals of group III received a single oral dose of CCl4 . Fourteen days later, animals were scarified to collect blood and liver tissues for analysis. Tempol pretreatment significantly captured elevated levels of ALT and AST activities, lipid peroxidation, total bilirubin and increased total thiol and catalase contents. Notably, it significantly reduced the expression of tumor necrosis factor-alpha (TNF-α), Caspase-3 and endoplasmic reticulum (ER) inositol-requiring enzyme 1(IRE1) mRNAs, which is an ER trans membrane sensor that activates the unfolded protein response (UPR) to maintain the ER and cellular function. Conclusion Pretreatment with Tempol has potential hepatoprotective effects against acute liver injury, induced by CCl4 , through antioxidant and anti-inflammatory activities.