Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation

Abstract

Free radicals are formed as a part of normal metabolic activities but are neutralized by the endogenous antioxidants present in cells/tissue, thus maintaining the redox balance. This redox balance is disrupted in certain neuropathophysiological conditions, causing oxidative stress, which is implicated in several progressive neurodegenerative diseases. Following neuronal injury, secondary injury progression is also caused by excessive production of free radicals. Highly reactive free radicals, mainly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), damage the cell membrane, proteins, and DNA, which triggers a self-propagating inflammatory cascade of degenerative events. Dysfunctional mitochondria under oxidative stress conditions are considered a key mediator in progressive neurodegeneration. Exogenous delivery of antioxidants holds promise to alleviate oxidative stress to regain the redox balance. In this regard, natural and synthetic antioxidants have been evaluated. Despite promising results in preclinical studies, clinical translation of antioxidants as a therapy to treat neurodegenerative diseases remains elusive. The issues could be their low bioavailability, instability, limited transport to the target tissue, and/or poor antioxidant capacity, requiring repeated and high dosing, which cannot be administered to humans because of dose-limiting toxicity. Our laboratory is investigating nanoparticle-mediated delivery of antioxidant enzymes to address some of the above issues. Apart from being endogenous, the main advantage of antioxidant enzymes is their catalytic mechanism of action; hence, they are significantly more effective at lower doses in detoxifying the deleterious effects of free radicals than nonenzymatic antioxidants. This review provides a comprehensive analysis of the potential of antioxidant therapy, challenges in their clinical translation, and the role nanoparticles/drug delivery systems could play in addressing these challenges.

The Preparation, the Physicochemical Assessment, and the Antimicrobial Action of Nanocurcumin‐Loaded Dental Temporary Restorative Material

“…Both metallic restorative compounds and nanoparticles may show numerous types of toxicities [37,38]. One of the main toxicity mechanisms is oxidative damage, and since curcumin (with confirmed antioxidant capacity [39], also in nanoformulation [40]), has been employed in this study, it appears reasonable to potentiate the beneficial role of curcumin in the prevention of those adverse effects.…”

Oxidative Stress as a Potential Mechanism Underlying Membrane Hyperexcitability in Neurodegenerative Diseases

“…Under oxidative stress conditions, dysfunctional mitochondria are unable to produce the high energy levels required by neuronal cells to perform their normal biochemical and physiological functions. This mitochondrial impairment makes them vulnerable to rapid cell death [ 41 ]. Under physiological concentrations ROS play a crucial role as regulators of various cellular functions such as growth, proliferation, differentiation and survival; they participate in cognitive function and in the maintenance of antioxidant mechanisms [ 42 , 43 ].…”

“…Mitochondrial dysfunction in AD involves impaired mitochondrial complexes that control ATP generation, producing 4-hidroxinonenal (4-HNE) and leading to Aβ accumulation. In addition, increased ROS levels drive to tau aggregates, tau hyperphosphorylation and cell death [ 38 , 41 ]. The imbalance of bioactive metals has also been proposed as one of the mechanisms by which oxidative stress influences AD.…”

“…This results in protein misfolding and aggregation, increased ROS production, and redox system disequilibrium, which ultimately leads to nerve cell loss [ 67 ]. In sporadic form of ALS, the overexpression of the cystine/glutamate antiporter causes increased levels of ROS and RNS and extracellular glutamate accumulation, which translates into an increase of neuron excitability [ 41 , 67 ].…”

The Impact of General Anesthesia on Redox Stability and Epigenetic Inflammation Pathways: Crosstalk on Perioperative Antioxidant Therapy

“…Numerous studies in the preceding decades have focused on reducing the pro-oxidative profile in surgical patients [ 202 ]. Different antioxidant therapies have been proposed, targeting either the inhibition of biological processes responsible for the production of certain molecules or the neutralization of the redox activity of free radicals by complexing them in molecular formulas with no chemical activity [ 203 , 204 , 205 ]. One such widely studied molecule is hydrogen sulfide (H 2 S), which due to its structural properties can easily diffuse through cell membranes and through the membranes of organelles.…”