Effects of Ibuprofen on Mice Liver Proteasome

Abstract

Abstract Nonsteroidal anti-inflammatory drugs like Advil (Ibuprofen) works via the inhibition of prostaglandin G/H synthases, commonly known as cyclooxygenases (COX-1 and COX-2). The long-term and chronic use of NSAIDs such as Ibuprofen has been shown to increase the risk of developing stroke and cardiovascular diseases (CVDs). Ibuprofen are derived from isobutylphenylpropanoic acid and they are generally used to relieve pain, headaches, muscle aches, fever, and inflammation. It can also be used to treat juvenile idiopathic arthritis, rheumatoid arthritis, patent ductus arteriosus, and pericarditis. The NSAID-mediated precise molecular mechanism that leads to thrombotic risk which eventually results in stroke and CVDs remains largely unknown. In our present study, we investigated the effects of Ibuprofen on protein homeostasis in liver using both male and female mice. We observed that Ibuprofen reduces proteasome activity in the Beta-1 (caspase-like) and Beta-2 (trypsin-like) subunits and enhances the aggregation of ubiquitinated abnormal proteins. We observed that Ibuprofen causes proteasome dysfunction in liver cells by increasing the production of reactive oxygen species (ROS). The experimental data also suggests that proteasome dysfunction in livers from Ibuprofen treated mice differs in male and female mice. Since Vitamin C (ascorbic acid) has been shown to aid in detoxification of free radicals such as ROS, we thereby postulated that Ibuprofen treated mice that were cotreated with Vitamin C should restore proteasome function. We observed an increase in the proteasome activity in the Beta-5 subunit (chymotrypsin-like) with both male and female mice that were cotreated with Ibuprofen and Vitamin C, suggesting that Vitamin C partly restores proteasome function.