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Oxidative Stress: How has it been Considered in the Design of New Drug Candidates for Neurodegenerative Diseases?

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Background: Oxidative stress is considered as one of the key players in the aetiology and progression of various neurodegenerative disorders (NDs). These pathologies include common and debilitating disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic ...

Background: Oxidative stress is considered as one of the key players in the aetiology and progression of various neurodegenerative disorders (NDs). These pathologies include common and debilitating disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Although the clinical and neuropathological aspects of these disorders are distinct and most have their onset attributted to abnormal protein deposits as a crucial factor, all have a common and characteristic pattern of neuronal degeneration in anatomically or functionally related regions. To date, no cure is available for these diseases and the available therapies are symptomatic, being unable to change the course or progression of the underlying disease.

In recent years, we have observed a significant increase of interest to investigate antioxidative and anti-inflammatory effects of diverse classes of natural and synthetic compounds as promising drug candidates for the treatment of NDs. This interest is supported by many pathological conditions associated with overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as superoxide anion, hydroxyl radicals, hydrogen peroxide, lipid peroxyl radicals, nitric oxide and peroxynitrite. These species are commonly generated in many cellular systems, through enzymatic and nonenzymatic reactions, but in excess these species can attack key proteins, lipids and DNA, affect signal transduction pathways, destroy membranes and subcellular organelles, and cause subsequent apoptosis and cell death. Abundant literature data suggest that oxidative stress (OS) may induce not only cellular and membrane damage, but also DNA repair system breakdown or mitochondrial disfunction, contributing to a complex network of events related to energy supply, neurodegeneration and aging, a phenomena observed in AD or PD, for example. Increased ROS levels is a crucial and prompt consequence of oxidative stress and it is related to down-regulated by several defence systems including antioxidant enzymes or endogenous small-molecule antioxidants (e.g. superoxide dismutase, glutathione peroxidase, catalase, peroxiredoxins, tri-peptide glutathione, vitamins E and C). Conversely, decline in ROS levels has been evidenced in many other physiological processes like cellular signalling, pro-survival pathways or activation of transcription factors regulating cellular response to ROS. In this context, a number of hypotheses have been proposed recently to explain the complexity and multifactorial pathogenesis of AD, including oxidative stress as a pivotal player and, maybe, one of the major causative factors of NDs, unifying a number of other sequential or individual pathophysiological events. By this consensus, oxidative damage in the brain of patients is a result of excessive production of free radicals induced by insoluble and/or overproduced protein fragments, such as Aβ, α-synuclein, tau and hungtintin, with functional alteration in mitochondria, inadequacy in energy supply, production of inflammatory mediators, and alteration of antioxidante defenses. Thus, modulation of cellular oxidative process should lead to a novel concept in drug design and possibly a novel way for searching more effective disease modifying chemical entities, reinforcing the hope for, at least, a real clinical relief, if the cure still remains not possible. 
 
Details for authors: The scope of this Research Topic is the most recent contributions in the field of medicinal chemistry and pharmacology for the discovery and/or development of new drug candidates or prototypes for neurodegenerative diseases, including the design, synthesis, evaluation, computational studies, pharmacological models and results from molecular biology taking oxidative stress as target for disease-modifying therapeutical  strategies.


Keywords: neurodegenerative diseases, oxidative stress, antioxidant, free radicals, neuronal death


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