Reactive oxygen species (ROS) are generated in a number of physiological reactions in our body. They are responsible for a number of diseases, such as cancer, inflammatory, autoimmune and neurodegenerative disorders.
Currently, an effective antioxidant therapy is not available. Therefore, an in-depth knowledge of the mechanisms responsible for the production of ROS and their role in the inflammation pathways is critical for the development of new drugs.
Recent publications have demonstrated that the ROS derived from mitochondria (mtROS) were responsible for the up-regulation of cytokines through a number of signal transduction pathways. Hypertension is a condition that is co-related with an increased level of mtROS in different organs.
Ang II, the hormone associated with hypertension, has been shown to increase the ROS production. Many studies have targeted mtROS for the treatment of hypertension. Mice transgenics for the mitochondrial antioxidant enzyme Trx2 were shown to resist Ang II-induced hypertension. Moreover, hypertension was also relieved by overexpressing a mitochondrial enzyme (SOD2) or treatment with mitoTEMPO.
These studies demonstrated that hypertension could be relieved by targeting mtROS. Many in vivo experiments revealed that an excess level of mtROS could lead to the development of atherosclerosis.
Mice models deficient in the mitochondrial antioxidant enzyme SOD2 easily developed atherosclerosis. Overexpression of SOD2 and other mitochondrial enzymes, such as Trx2, reduced atherosclerosis in the mice models by reducing oxidative stress.
Further studies about the role of mtROS in human atherosclerosis are underway. In addition to atherosclerosis, mtROS have been known to play a major role in many inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, cancer, thyroiditis and Type 1 diabetes.
A number of antioxidant enzymes are present in mammalian systems to fight with mtROS. They include superoxide dismutase, glutathione peroxidase and catalase. Although the natural antioxidants play a role in decreasing the concentration of mtROS, they are not effective in treatment, because they are not able to cross the blood-brain barrier and cannot get accumulated within mitochondria.
Drugs that particularly target mtROS have been developed to address these problems. Mito Vit-E was the first targeted scavenger that was developed for mtROS, and it was generated by covalently attaching the triphenylphosphonium cation to Vit-E. It has been shown to decrease the ROS production and apoptosis in the endothelial cells. However, Mito Vit-E was not effective against hypoxic-ischemic striatal injuries in rat models.
MitoQ10 was the second scavenger developed for mtROS. It was generated by covalently attaching the lipophilic triphenylphosphonium cation to a ubiquinone derivative through an aliphatic linker. MitoQ10 has been shown to decrease ROS in mitochondria, and its effectiveness has been proven in the rodent models of cardiac ischemia and reperfusion injury.
SkQ1 is an alternate compound for MitoQ10. SkQ1 has been shown to reduce ischemia-induced arrhythmia and infarct size in rats, when used at a concentration 1 million-fold lower than that of the MitoQ. Clinical studies for SkQ1 are still ongoing.
In summary, oxidative stress could lead to a number of diseases. Antioxidants have been extensively studied for the prevention and treatment of these diseases, but many clinical trials have failed to explain the therapeutic potential of antioxidants.
One possibility might be that only small proportions of antioxidants are actually located inside the mitochondria. Since the mtROS play a key role in inducing cytokine production, targeting mtROS might be a novel therapy for the treatment of many inflammatory diseases. Further characterization of mtROS and their role in inflammatory diseases needs to be performed for the development of novel, effective drugs.
