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

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 CCl 4 dose, daily, orally, for 14 days, then sacrificed. Group II: received CCl 4 , 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 CCl 4 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 CCl 4 . 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 CCl 4 , through antioxidant and anti-inflammatory activities.