Mitochondria-Targeted Antioxidants, an Innovative Class of Antioxidant Compounds for Neurodegenerative Diseases: Perspectives and Limitations

Abstract

Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.

Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases

“…However, clinical trials using non-mitochondria-targeted antioxidants have shown that non-mitochondria-targeted antioxidant therapies are not effective in the treatment of aging and age-related diseases [ 154 , 155 ]. To complement these clinical findings, mitochondria-targeting antioxidants have recently been applied to various animal models, and there is growing evidence that mitochondria-targeting antioxidants have beneficial effects on aging and age-related diseases [ 156 , 157 ]. Therefore, research on how to effectively deliver genetic and pharmacological therapeutics targeting mitochondria will provide good therapeutic clues to break the vicious cycle leading to aging and age-related diseases.…”

Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer’s Disease

“…This may rely, at least partially, on the dual role of ROS, implying that in addition to their implication in neurodegeneration, some oxidant species, such as superoxide and hydrogen peroxide (O 2 2− and H 2 O 2 ) function as signaling molecules of essential redoxdependent signaling pathways [101]. Thus, antioxidants that directly target mitochondria seem to represent a more efficient approach to attenuating local ROS production, and some of these compounds have already led to promising results in clinical trials [102].…”

Cellular ROS and Antioxidants: Physiological and Pathological Role

“…A growing body of studies suggests that by neutralizing harmful free radicals, antioxidants prevent oxidative damage to cells and tissues, which are implicated in developing chronic diseases. Antioxidants play a crucial role in reducing the risk of chronic liver diseases [13], chronic heart failure [14], neurodegenerative diseases [15,16], and chronic kidney disease [17]. It has also been shown that antioxidants can reduce cardiotoxicity induced by anticancer therapy [18].…”