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.
Highlights
With a strong rationale that oxidative stress is a key component of neurodegenerative diseases, antioxidants of different types, either alone or in combination, natural and synthetic have been tested in neurodegenerative disease models
We demonstrated aggravation of the blood-brain barrier (BBB) permeability when tissue plasminogen activator (t-PA) alone was administered via the carotid artery in the same thromboembolic rat stroke model [348]
Substantial evidence supports the hypothesis that oxidative stress plays a key role in disease progression; antioxidant treatment could provide a potential solution
Summary
Free radicals are generated during pivotal biological processes such as metabolic reactions, cell signaling, and gene transcription [1] Cellular organelles such as mitochondria, peroxisomes, lysosomes, microsomes, endoplasmic reticulum, plasma membrane, and phagocytic cells are the source of free radical production [2,3]. Pro-oxidants or free radicals are usually those atoms or molecules that contain an unpaired electron in their outermost orbit and can be formed when oxygen interacts with certain molecules [18] These free radicals are very unstable but highly reactive and, when they interact with other molecules, create additional free radicals, initiating a self-propagating chain reaction of free radical formation [18]. The OH radical, produced from H2 O2 in the metal-catalyzed (free Fe and Cu) redox reactions such as Fenton reaction, is unstable and reacts rapidly and nonspecifically with most biological molecules [3]
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