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.

Keywords: CNS; antioxidant enzymes; inflammation; neurodegeneration; polymers; reactive oxygen species.

Figure 1

Schematic representing the effect of oxidative stress in neurodegenerative diseases. Imbalance in the level of ROS/RNS and antioxidants leads to an oxidative stress condition that causes damage to cellular biomolecules, i.e., lipids, proteins, and DNA. Mitochondrial dysfunction and accumulation of activated astrocytes and microglia release inflammatory cytokines and chemokines, promoting cellular apoptosis and tissue death.

Figure 2

ROS-mediated degenerative events during a stroke. Excessive production of ROS during I/R injury leads to mechanical damage to the brain due to breakdown of the BBB, hemorrhage and edema, causing a build-up of intracranial pressure (ICP). The biochemical changes lead to inflammation and progression of apoptosis. Therefore, excess ROS formed during I/R is considered a target to inhibit the progression of secondary brain damage.

Figure 3

Secondary injury cascade following spinal cord injury. Traumatic injury to the spinal cord leads to secondary injury progression that affects the lesion site and the entire spinal cord, including the cranial and caudal segments of the spinal cord. Following injury, excessive production of ROS is considered to trigger the secondary injury cascade of progressive degeneration that affects the entire spinal cord.

Figure 4

Natural and synthetic antioxidants: Classification of natural and synthetic antioxidants and the endogenous Nrf2 pathway, which regulates the activation of ARE genes. Kelch-like ECH-associated protein 1 (Keap1) represents a negative regulator of Nrf2. Under physiological conditions, Keap1 forms a ubiquitin E3 ligase complex with Cullin3 in the cytoplasm that targets Nrf2 for polyubiquitination and rapid proteasomal degradation. During oxidative stress, cysteines in Keap1 are modified and inactivated, and Nrf2 can quickly translocate into the nucleus, where it binds to small musculoaponeurotic fibrosarcoma oncogene homolog (sMaf) proteins, upregulates downstream ARE genes, and maintains redox homeostasis.

Figure 5

Antioxidant-based nanotherapy. Schematic depicting advantages of delivery of antioxidant-loaded nanoparticles to improve half-life of antioxidants and their ability to cross the BBB, improve bioavailability, and sustain the effect, thus effectively neutralizing oxidative stress in neurodegenerative diseases.

Figure 6

Antioxidant enzyme-based nanotherapy for spinal cord injury: Localization of nanoparticles at the lesion site following intravenous administration. Nanoparticles were injected 6 h post-injury, and spinal cords were analyzed for localization of the nanoparticles. Nanoparticles contained a near-infrared dye, and the spinal cords were analyzed 24 h after the injury using the Maestro Optical Imaging System site. Reproduced with permission from [350], copyright 2019 Elsevier. (A) Dose-dependent localization of nanoparticles at the lesion site. (B) Images of the spinal cord taken with Maestro Optical Imaging (Ba) Normal spinal cord without injury and nanoparticles. (Bb) Injured spinal cord from the animals that received dye-loaded nanoparticles intravenously. Efficacy of nano-SOD/CAT treatment (C)-treated animals show reduced mitochondrial ROS levels. (D) Mitochondrial isolated from the spinal cord of the treated animals show more ATP production capacity than those isolated from the spinal cords of untreated animals. * p < 0.05; *** p < 0.001 Reproduced with permission from [350], copyright 2019 Elsevier.