The scientists made their discovery after screening 6,766 clinically used drugs and pharmacologically active substances.
“We developed this assay and used it to test literally every single existing drug and a good selection of other biologically active compounds,” said UTMB professor Csaba Szabo, senior author of a paper on the research published online by Diabetes. “We were quite surprised when paroxetine came out as an active compound – a result, we later determined, of what seems to be a completely new effect unrelated to its antidepressant actions and not shared by any other known antidepressant drug.”
The initial screening process tested the ability of different compounds to protect the cells that make up the inner linings of blood vessels from the destructive effects of the high sugar levels produced by diabetes, known as hyperglycemia. In people with diabetes, hyperglycemia causes these endothelial cells to generate toxic molecules known as reactive oxygen species (ROS), which ravage blood-vessel linings and lead to diabetic endothelial dysfunction, the key factor in such destructive diabetic complications as heart attacks, strokes, retinopathy, nephropathy and neuropathy.
In subsequent test-tube studies, researchers found that paroxetine – which is sold as an antidepressant under the trade name “Paxil” – prevents hyperglycemia-initiated ROS damage to endothelial cells in two ways. First, it directly reduces concentrations of superoxide, a powerful ROS. Second, it suppresses superoxide production by mitochondria, tiny structures whose real job is making the energy-transfer molecules needed for most cellular processes. In a hyperglycemic environment, mitochondria are cells’ biggest source of superoxide. According to the researchers’ findings, paroxetine inhibits this activity without interfering with the mitochondria’s vital normal function.