The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

Abstract

Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague–Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-β) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.

Structure Modification Converts the Hepatotoxic Tacrine into Novel Hepatoprotective Analogs

“…To investigate whether the improvement of liver function and architecture induced by THQ derivative treatment was associated with antioxidant activity, we measured oxidative stress in the liver. We examined the level of reduced GSH and malondialdehyde (product of lipid peroxidation; MDA) as well as key biochemical markers, including the CYP2E1 metabolic enzyme . CCl 4 administration significantly elevated the level of CYP2E1 protein expression, a member of the cytochrome P450 mixed-function oxidase system that is implicated in a variety of pathological conditions .…”

“…We examined the level of reduced GSH and malondialdehyde (product of lipid peroxidation; MDA) as well as key biochemical markers, including the CYP2E1 metabolic enzyme. 28 CCl 4 administration significantly elevated the level of CYP2E1 protein expression, a member of the cytochrome P450 mixed-function oxidase system that is implicated in a variety of pathological conditions. 29 It is considered the major isozyme involved in carbon tetrachloride bioactivation, leading to the generation of toxic intermediates and excessive amounts of ROS.…”