New phthalimide analog ameliorates CCl4 induced hepatic injury in mice via reducing ROS formation, inflammation, and apoptosis.

Bishoy El-Aarag,Alshaimaa Attia,Ali Younes,Ehab Tousson,Magdy Zahran

doi:10.1016/j.sjbs.2021.07.014

Abstract

The present study aimed, for the first time, to examine the biochemical effects of new phthalimide analog, 2-[2-(2-Bromo-1-ethyl-1H-indol-3-yl) ethyl]-1H-isoindole-1,3(2H)-dione, compared to thalidomide drug against liver injury induced in mice. Carbon tetrachloride was intraperitoneal injected in mice for 6 consecutive weeks at a dose of 0.4mL/kg twice a week for liver injury induction. Histopathological examination, levels of malondialdehyde, nitric oxide, and antioxidant enzymes were determined. Additionally, the protein levels of vascular endothelial growth factor, proliferating cell nuclear protein, tumor necrosis factor-alfa, nuclear factor kappa B-p65, B-cell lymphoma-2, and cysteine-aspartic acid protease-3 were determined. Results revealed that the treatment with phthalimide analog improved the detected liver damage and presented an obvious antioxidant activity through decreasing malondialdehyde and nitric oxide levels accompanied by increasing the levels of the antioxidant enzymes. Furthermore, the analog exhibited an effective inhibitory activity towards the studied protein expressions in liver tissues. Moreover, the B-cell lymphoma-2 protein level was increased while the cysteine-aspartic acid protease-3 level was suppressed after the treatment with phthalimide analog. Together, these results propose that phthalimide analog can ameliorate carbon tetrachloride-induced liver injury in mice through its potent inhibition mediating effect in oxidative stress, inflammation, and apoptosis mechanisms.

Highlights

The alteration in cellular oxidation–reduction balance and the high level of reactive oxygen species (ROS) production initiates oxidative stress
The protein expressions of vascular endothelial growth factor (VEGF), PCNA, tumor necrosis factor-alpha (TNF-a), and NFkB-p65 in liver tissues of normal mice and in that treated with phthalimide analog and thalidomide were detected
The results revealed that both PCNA and VEGF levels were elevated in the liver tissues of mice injected with CCl4 compared to normal mice

Summary

Introduction

The alteration in cellular oxidation–reduction balance and the high level of reactive oxygen species (ROS) production initiates oxidative stress. It is believed to be a crucial risk factor in the development of liver disease (Uchida et al, 2020). A common experimental liver injury model was established via intoxication with carbon tetrachloride (CCl4). Cytochrome P450 catalyzed the conversion of CCl4 to a trichloromethyl radical (∙CCl3). In the presence of molecular oxygen, ∙CCl3 transformed to trichloromethyl peroxy free radicals (CCl3OO∙) which interferes with microsomal. Production and hosting by Elsevier membranes leading to lipid peroxidation, membrane impairment and hepatocellular injury (Jeong et al, 2020). Antioxidative enzymes are scavengers to ∙CCl3 and lipid peroxy radicals in CCl4-induced oxidative stress in hepatocytes (Li et al, 2015). Superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) are complicated in the protection towards ROS (He et al, 2017)

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Results

Discussion

Conclusion