Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Increasing evidence suggests it can disturb the physiology of sickle red blood cell (RBC) membranes and perturb intracellular processes. Therefore, it is hypothesized that antioxidant therapies might add value as secondary treatments in SCD.

Here, we will briefly discuss how oxidative stress arises in sickle RBCs and whether antioxidant agents might help counterbalance the resultant oxidative damage.

Origins of Oxidative Damage in Sickle RBCs

Reactive oxidizing species (ROS) can be generated not only by sickle RBCs but also by activated leukocytes, platelets, endothelial cells, and plasma enzymes.

For instance, a recent study conducted by researchers from the University of Pittsburgh and the Children’s Hospital of Pittsburgh in Pennsylvania demonstrated a relationship between increased platelet mitochondrial ROS and propensity for thrombosis—an important contributor to the high morbidity and mortality of SCD—in an SCD mouse model. Moreover, they showed that treatment with mitochondrial ROS scavengers decreased the levels of ROS and attenuated the propensity for thrombus formation.

“These data demonstrate that [mitochondrial ROS] significantly contribute to the mechanism of hemolysis-induced thrombosis in vivo and suggest a potential role for mitochondrially targeted antioxidant therapy in hemolysis and SCD-related thrombosis,” the study’s authors said.

Learn about SCD etiology

Multiple mechanisms contribute to the generation of ROS and reactive nitrogen species (RNS) in patients with SCD. They include increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and endothelial xanthine oxidase, abnormal sickle hemoglobin autoxidation, heme and iron release, increased asymmetric dimethylarginine, and uncoupling of nitric oxide synthase activity and decreased nitric oxide bioavailability.

These mechanisms, which were discussed in detail by Vona et al in a review article published in the journal Antioxidants, ultimately disrupt the balance between oxidative stress and antioxidants in sickle RBCs, leading to cellular damage.

In addition, several studies have reported decreased levels of antioxidants in RBCs, mononuclear cells, and platelets of people with SCD. Among the deficient substances are glutathione, vitamins E and C, β-carotene, and plasma retinol. Antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, also seem to be downregulated. These aspects further push the balance towards oxidative damage, which is deleterious to RBCs.

Antioxidants for SCD: Where Do We Stand?

As explained by Vona et al, to identify suitable antioxidant agents for SCD, researchers look for compounds able to reduce hemoglobin-dependent oxidative reactions and ROS levels and repair the eventual oxidative damage. Among the most promising candidates are L-glutamine, N-acetylcysteine, zinc supplementation, nitric oxide, L-arginine, α-lipoic acid, and acetyl-L-carnitine.

From those, only L-glutamine has received approval by the US Food and Drug Administration (FDA) for the prevention of acute complications in SCD. Almost all of the others are currently undergoing clinical trials: N-acetylcysteine (NCT01800526 and NCT01849016), nitric oxide (NCT00094887), L-arginine (NCT02447874), α-lipoic acid and acetyl-L-carnitine (NCT01054768). The administration of gum arabic and vitamin E to SCD patients are also being evaluated in clinical settings (NCT04191213 and NCT03903133, respectively).

Learn about SCD treatment

In addition to these compounds, several research groups have been dedicated to identifying new potential antioxidants for use in RBC treatment. For instance, researchers from Brazil have recently identified a glucal-triazol-derived molecule, named 11m, with antioxidant and anti-sickling activity. “By in silico pharmacokinetics analysis, we could see that 11m has appropriated proprieties for druggability and the probable mechanism of action is the binding to peroxiredoxin-5, an antioxidant enzyme that reduces the hydrogen peroxide levels, verified after molecular docking assays,” the study’s authors explained.

Overall, studies suggest that antioxidant agents can be used either alone or in combination with hydroxyurea to enhance antioxidant defense sources in patients with SCD.

For Vona et al, “Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, ie, by decreasing the oxidant formation or repairing the induced damage.”

Reference

Vona R, Sposi NM, Mattia L, Gambardella L, Straface E, Pietraforte D. Sickle cell disease: role of oxidative stress and antioxidant therapy. Antioxidants. 2021;10(2). doi:10.3390/antiox10020296

Annarapu GK, Nolfi-Donegan D, Reynolds M, Wang Y, Shiva S. Mitochondrial reactive oxygen species scavenging attenuates thrombus formation in a murine model of sickle cell disease. J Thromb Haemost. 2021;19(9):2256-2262. doi:10.1111/jth.15298

Vieira Veloso R, Shamim A, Lamarrey Y, Stefani HA, Mozer Sciani J. Antioxidant and anti-sickling activity of glucal-based triazoles compounds – an in vitro and in silico study. Bioorg Chem. 2021;109:104709. doi:10.1016/j.bioorg.2021.104709

Antioxidant therapy to reduce inflammation in sickle cell disease. ClinicalTrials.gov. January 22, 2010. Updated August 3, 2021. Accessed January 12, 2022.

A pilot study of N-acetylcysteine in patients with sickle cell disease (NACinSCD). ClinicalTrials.gov. February 23, 2013. Updated July 9, 2020. Accessed January 12, 2022.

N-acetylcysteine in patients with sickle cell disease (NAC). ClinicalTrials.gov. May 8, 2013. Updated July 4, 2016. Accessed January 12, 2022.

Nitric oxide inhalation to treat sickle cell pain crises. ClinicalTrials.gov. October 28, 2004. Updated February 5, 2020. Accessed January 12, 2022.

Arginine therapy for the treatment of pain in children with sickle cell disease (R34 pK/PD). ClinicalTrials.gov. May 19, 2015. Updated March 16, 2021. Accessed January 12, 2022.

Antioxidant therapy to reduce inflammation in sickle cell disease. ClinicalTrials.gov. January 22, 2010. Updated August 3, 2021. Accessed January 12, 2022.

Gum arabic as anti-oxidant, anti-inflammatory and fetal hemoglobin inducing agent in sickle cell anemia patients (GA&SCA). ClinicalTrials.gov. December 9, 2019. Updated January 28, 2020. Accessed January 12, 2022.

Endothelial monocyte-activating polypeptide-II in Egyptian sickle patients. ClinicalTrials.gov. April 4, 2019. Updated April 16, 2020. Accessed January 12, 2022.