Potential Role of Natural Antioxidants in Countering Reperfusion Injury in Acute Myocardial Infarction and Ischemic Stroke

Abstract

Stroke and acute myocardial infarction are leading causes of mortality worldwide. The latter accounts for approximately 9 million deaths annually. In turn, ischemic stroke is a significant contributor to adult physical disability globally. While reperfusion is crucial for tissue recovery, it can paradoxically exacerbate damage through oxidative stress (OS), inflammation, and cell death. Therefore, it is imperative to explore diverse approaches aimed at minimizing ischemia/reperfusion injury to enhance clinical outcomes. OS primarily arises from an excessive generation of reactive oxygen species (ROS) and/or decreased endogenous antioxidant potential. Natural antioxidant compounds can counteract the injury mechanisms linked to ROS. While promising preclinical results, based on monotherapies, account for protective effects against tissue injury by ROS, translating these models into human applications has yielded controversial evidence. However, since the wide spectrum of antioxidants having diverse chemical characteristics offers varied biological actions on cell signaling pathways, multitherapy has emerged as a valuable therapeutic resource. Moreover, the combination of antioxidants in multitherapy holds significant potential for synergistic effects. This study was designed with the aim of providing an updated overview of natural antioxidants suitable for preventing myocardial and cerebral ischemia/reperfusion injuries.

Keywords: acute myocardial infarction; antioxidants; ischemic stroke; oxidative stress; reperfusion injury.

Figure 1

Role of oxidative stress in myocardial damage caused by ischemia followed by reperfusion. The increase in cytosolic calcium is associated with the activation of XO, which is an enzyme with pro-oxidant properties. The increase in calcium inside the mitochondria and the increase in pH during reperfusion lead to the opening of the mPTP, which causes the decrease in the mitochondrial transmembrane potential linked to ROS generation. These reactive oxygen molecules activate the transcription factor NF-κB, promoting inflammation and neutrophil migration to the injured region as well as increasing ROS production by NADPH oxidase. Also, ROS originates from uncoupled eNOS, oxidizing lipids, proteins, and DNA, triggering cell death. In addition, apoptosis is induced by the release of cytochrome c via mPTP, whereas ferroptosis is inducted by reduced GSH and GPX4 activity, leading to the accumulation of lipid peroxidation products. Furthermore, miR-132 directly targets SIRT1 and negatively regulates its expression, leading to a decrease in Nrf2 transcription, which in turn results in diminished antioxidant capacity; Ca²⁺: calcium; DNA: deoxy-ribonucleic acid; NF-κB: nuclear factor kappa B; eNOS: endothelial nitric oxide synthase; O2•−: superoxide anion; NOX: NADPH oxidases; TNFα: tumor necrosis factor-alpha; IL-6: interleukin 6; IL-1: interleukin 1; miR-132: microRNA-132; SIRT1: sirtuin 1; Nrf2: nuclear factor erythroid 2-related factor 2.

Figure 2

Role of oxidative stress in brain damage caused by ischemia followed by reperfusion. ATP: adenosine triphosphate; Na⁺: sodium; K⁺: potassium; Ca²⁺: calcium; ROS: reactive oxygen species; ADS: antioxidant defense system; BBB: blood–brain barrier; NF-κB: nuclear factor kappa B.

Figure 3

Antioxidant protective pathways involved in counteracting reperfusion injury. Nrf2: nuclear factor erythroid 2-related factor 2; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; ARE: antioxidant response elements; SIRT1: sirtuin 1; CAT: catalase; factor-alpha; NF-κB: nuclear factor kappaB; Ca²⁺: calcium; eNOS: endothelial nitric oxide synthase; iNOS: inducible nitric oxide synthase; NADPH oxidase: nicotinamide adenine dinucleotide phosphate oxidase; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumor necrosis factor alpha; GPX: glutathione peroxidase; HMT1: type 1 arginine methyltransferase; TfR1: transferrin receptor protein 1.