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Subjects:
Cardiac & Cardiovascular Systems
Natural antioxidants are present in low concentrations within cells. They reduce free radicals to provide a protection system against vascular diseases. They have a strong potential to inhibit OS, lipid peroxidation and the oxidation of breakdown products. Natural antioxidants can function either individually or synergistically to remove free radicals generated during oxidative metabolism, thus maintaining the redox balance.
- oxidative stress
- reperfusion injury
- antioxidants
- ischemic stroke
- acute myocardial infarction
1. Introduction
Acute ischemic diseases, such as acute myocardial infarction (AMI) and ischemic stroke (IS), stand as major causes of death and disability worldwide [1]. Both conditions result from the occlusion of a vascular structure [2,3]. The acute management for them is the prompt restoration of blood flow to the tissue [4,5], thereby reducing the time of hypoperfusion to preserve organ function [6]. Paradoxically, the restoration of blood flow induces an important additional damage [7,8], which is a phenomenon known as ischemia–reperfusion injury (IRI). This phenomenon was first described by Jennings et al. [9], in relation to the myocardium in 1960, and by Ames et al. [10], in relation to the brain, in 1968. While cardiac ischemia/reperfusion is associated with necrosis, cardiomyocyte apoptosis, contractile dysfunction, and life-threatening ventricular arrhythmias, cerebral IRI induces an increase in trans-endothelial permeability and blood–brain barrier (BBB) damage [11]. While essential for restoring aerobic ATP production, the re-entry of oxygenated blood into ischemic tissue leads to elevated reactive oxygen species (ROS) production. This effect can induce oxidative modifications in nearly all types of biomolecules within cells, ultimately resulting in cell dysfunction. This phenomenon has been labeled the ‘oxygen paradox’ [12], wherein oxidative stress-mediated injury and ischemia reperfusion damage play pivotal roles. However, the pathophysiology of IRI involves a complex interplay of mechanisms, including oxidative stress (OS), endoplasmic reticulum stress, calcium overload, inflammatory response, disturbances in energy metabolism, apoptosis, and various forms of programmed cell death (e.g., necroptosis, autophagy, pyroptosis, patanatos, and ferroptosis) [1].
IRI also comprises other mechanisms, such as microvascular vasoconstriction, whereas endothelin in the vascular wall can increase in OS, contributing to the reduction in NO bioavailability and consequently leading to vascular dysfunction [13]. Also, IRI is characterized by tissue necrosis and leukocyte infiltration, especially neutrophils that are recruited to the ischemic site following reperfusion and, prior to extravasation, adhere to the endothelium.
Hypoxia-inducible factor-1α (HIF-1α), an oxygen-sensitive transcription factor that mediates adaptive metabolic responses to hypoxia, is activated in IRI by improving mitochondrial function and decreasing OS, thus accounting for protective cellular mechanisms [15]. HIF-1α activates the transcription of other genes which play an important role in a cell’s adaptive responses to hypoxia, such as vascular endothelial growth factor (VEGF), erythropoietin (EPO) and glucose transporter-1. Among them, VEGF is the most important angiogenetic factor in all steps of angiogenesis [16]. During ischemia reperfusion, VEGF activity decreases due to the increase in its antagonist soluble fms-like tyrosine kinase-1 (sFlt-1), which is a truncated form of the VEGF receptor fms-like tyrosine kinase-1 (Flt-1) lacking the transmembrane and cytoplasmic domains. Therefore, increased sFlt-1 results in a harmful effect on the heart following MI, and it has been positively related to the severity and mortality of these patients [17].
Also, microRNAs (miRs) have been shown to be involved in the regulation and pathogenesis of ischemia [18] and IRI in the heart [19] as well as in the central nervous system [20]. They are tissue-specific [21] and are capable of silencing target genes, and thus, among other functions, miRs regulate OS by targeting ROS producers, ROS pathways and antioxidant effectors. Their functionality varies across contexts; some miRs exhibit pro-oxidant effects, while others concurrently target genes with opposite redox regulatory functions [22].
The cellular oxidative status is determined by the equilibrium between ROS formation and the activity of various antioxidant systems [23]. The mechanisms of damage are mainly mediated by ROS-induced transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). During ischemia followed by reperfusion, ROS mediate NF-κB activation by phosphorylating the IκB (NF-κB inhibitor proteins family) subunit, thereby provoking its proteolytic digestion. Then, NF-κB is translocated into the nucleus, leading to the transcription of genes causing inflammation and apoptosis [24]. Also, ischemia reperfusion leads to c-Jun N-terminal kinase (JNK) phosphorylation, which is translocated into the nucleus, inducing the expression of inflammation and apoptosis-related genes and AP-1 activation.
The antioxidant defense system (ADS) is regulated by transcriptions factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2), which is a critical regulator of the cellular stress response. It controls cellular defense responses against OS by modulating the expression of antioxidant enzymes at the transcriptional, post-transcriptional and post-translational levels [26]. The ADS operates through both enzymatic and non-enzymatic molecules. Key enzymes include superoxide dismutases (SODs), catalase (CAT), peroxiredoxins, thioredoxins, glutaredoxins, and glutathione peroxidases (GPXs). Non-enzymatic molecules can be classified as endogenous, such as reduced glutathione, and exogenous, including vitamin C, vitamin E, carotenoids, flavonoids, and polyphenols, among others [24,27,28]. It is noteworthy that natural antioxidants constitute a diverse group of exogenous molecules that can be considered as pharmacological resources due to their safety, availability, and potential pleiotropic benefits against oxidative challenges.
2. Natural Antioxidant Bioactive Molecules against Myocardial Infarction and Ischemic Stroke Injury
2.1. Phenolic Compounds
2.1.1. Polyphenols
Resveratrol
Resveratrol, also known as 3,5,4′-trihydroxy-trans-stilbene, is a phytoalexin produced in various plants in response to injury caused by pathogens or physical damage. This compound can scavenge ROS and prevent lipid peroxidation in various OS related diseases. Foods such as grape skins, blackberries, raspberries, blueberries and peanuts contain resveratrol, being also one of the main components of red wine [92].
Resveratrol exists in either cis- or trans-resveratrol isoforms, the trans-isomer being more active as an antioxidant than the diastereomeric mixture [93]. This compound is also characterized by a good absorption capacity and rapid metabolization in the body, mainly through the formation of sulfoxide and glucuronide conjugates, which are mainly eliminated in the urine. In general, resveratrol has been found to be well tolerated, and no significant toxic effects associated with its consumption have been reported [94].
Resveratrol has been the subject of numerous preclinical and clinical studies due to its beneficial effects on various diseases, demonstrating its ability to reduce both OS and inflammation in different OS-dependent pathologies, both in animal models and in humans. Resveratrol has been shown to have neuroprotective effects in both animal models and clinical studies of IS. This happens through a variety of mechanisms, mainly because of its antioxidant and anti-inflammatory capacities [95], among other mechanisms, some of them not fully elucidated. Resveratrol has been shown to promote neurogenesis while reducing neurotoxicity by modulating glial activity and signaling [96].
To understand its protective effect in brain IRI, it is relevant to consider the Nrf2 and antioxidant response elements (ARE) signaling pathway. Normally, Nrf2 is found interacting with Kelch-like ECH-associated protein 1 (Keap1), forming the Keap1–Nrf2 complex, which limits Nrf2-mediated gene expression [100].
This is precisely where resveratrol plays an important role, as it has been shown to ameliorate brain injury caused by OS due to brain ischemia reperfusion by regulating the expression of Nrf2 and HO-1. By activating the Nrf2/ARE pathway, resveratrol promotes intracellular antioxidant defense, reducing levels of OS and providing protection against brain damage in the context of ischemia reperfusion [101].
There is a variety of preclinical and clinical evidence regarding the beneficial effect of resveratrol following IS. In a study conducted in rodents, resveratrol demonstrated a remarkable ability to significantly decrease neurological deficit scores, reduce brain infarct size, mitigate neuronal injury and myeloperoxidase activity [102]. In the context of cerebral ischemia, increased expression levels of toll-like receptor 4 (TLR4), NF-κB p65, cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 beta (IL-1β) were observed, but resveratrol was able to attenuate the activity of all these factors [102]. Thus, resveratrol exerts a beneficial effect by reducing inflammation, preserving the integrity of the BBB and protecting against brain damage in rats subjected to focal cerebral ischemia.
Interestingly, a study has highlighted the role of resveratrol preconditioning in providing a long-term window of tolerance to cerebral ischemia, extending up to 2 weeks in mice [103]. This preconditioning process has been shown to have a significant impact on bioenergetic efficiency through its effect on cellular pathways such as enhanced glycolysis, mitochondrial respiration efficiency, and increased energy production (increased tricarboxylic acid cycle) as well as regulated oxidative phosphorylation and pyruvate uptake [103].
In summary, resveratrol shows significant antioxidant action by activating SOD and downregulating MDA in brain IRI. Furthermore, its ability to regulate the Nrf2/ARE signaling pathway and increase the expression of antioxidant enzymes such as HO-1 and SOD translates into a neuroprotective effect that helps mitigate the damage caused by OS in the brain subjected to ischemia and subsequent reperfusion. These findings highlight the therapeutic potential of resveratrol in the treatment of OS and ischemia reperfusion-related brain conditions.
Regarding cardiac protection, resveratrol acts directly and indirectly on molecular pathways [105]. Decades ago, resveratrol was shown to be able to suppress low-density lipoprotein (LDL) oxidation in humans [106] as well as to reduce lipid peroxidation [107]. Since then, several studies have expanded the evidence supporting the potential of resveratrol to combat cardiovascular diseases, mainly by acting on OS and inflammation.
In relation to its involvement in OS, resveratrol plays a crucial role as a component of the ADS not only by acting as a free radical scavenger but also by increasing the activity of antioxidant enzymes and regulating genes related to redox balance, nitric oxide (NO) availability and mitochondrial functionality [108]. The stimulation of endothelial NO production is achieved by the upregulation of eNOS expression [109].
Furthermore, several studies have shown that resveratrol exerts certain effects through modifications in sphingolipids, a category of biological lipids with multiple cellular functions, including apoptosis, cell proliferation, OS, and inflammation. These lipids have attracted considerable interest as critical emerging determinants in the risk and development of cardiometabolic diseases. The resveratrol-mediated modulation of sphingolipid metabolism and signaling may represent an essential mechanism by which the compound exerts its effects, including the maintenance of oxidative balance [110].
Quercetin
Quercetin is a flavonoid that is widely found in commonly consumed foods such as fruit, vegetables, tea, and red wine. It is safe for human consumption, even in high doses [114,115]. This compound has a number of biological properties, including antioxidant, anti-inflammatory, anti-aggregating and anti-aging [116].
Quercetin has been extensively investigated for its effect on ameliorating OS. This compound has been found to have the ability to scavenge free radicals [117] and to induce the expression of the antioxidant enzyme HO-1, which in turn helps to reduce OS caused by the enzyme NOX [118]. In addition, it has been observed that quercetin can suppress the expression of NOX2, which is an isoform of the NOX system that plays an important role in the production of ROS, such as H2O2 [119]. The overproduction of NOX has been shown to contribute to neurotoxicity and cerebrovascular disease, and it has been implicated as a major source of ROS in the brain [120].
Regarding evidence in IS, a recent systematic review and meta-analysis aimed at evaluating the efficacy and possible mechanisms of quercetin in the treatment of focal cerebral ischemia showed that compared to the control group, the quercetin-administered groups exhibited a marked improvement in neurological function score and a significant effect on reducing infarct volume. In addition, it was shown that quercetin could alleviate BBB permeability and brain water content [123]. The mechanisms involved in quercetin’s action against focal cerebral ischemia are diverse and involve antioxidation, anti-apoptosis, anti-inflammation and a reduction in calcium overload [123].
One of the limitations of using quercetin in patients undergoing IS is that its effectiveness varies substantially depending on the type of source plant, the dose and the chemical properties after processing [126]. In humans, quercetin has low bioavailability, and it is noteworthy that it poorly crosses the BBB [127]. For this reason, studies have been conducted that aim to increase the bioavailability of quercetin in the brain, such as the use of nano-encapsulation and enzymatic modification, among other strategies.
This compound has also been shown to reverse myocardial remodeling after myocardial ischemia. Studies in animal models have shown that quercetin can reduce ischemic–reperfusion injury in the heart and improve myocardial function. It has also been shown to inhibit myocardial fibrosis, increase mitochondrial energy metabolism, reduce inflammatory response and attenuate OS in the heart [129,130].
Curcumin
Turmeric species, in particular Curcuma longa L., have been extensively studied and found to possess a wide range of pharmacological properties, including anti-inflammatory, anti-diabetic, anti-cancer, antiproliferative, antithrombotic, antioxidant, hypotensive, hypocholesterolemic, antirheumatic and antiviral effects, among many others [132,133]. The active compound in turmeric extract is curcumin, which is a lipophilic polyphenol with proven safety and good tolerance at high oral doses [134].
Curcumin has demonstrated synergistic therapeutic effects, enhancing the efficacy of other drugs and compounds, such as antibiotics, anti-inflammatories and polyphenols. Regarding myocardial IRI, curcumin has been shown to protect white matter after IS by inhibiting microglia/macrophage pyroptosis through the suppression of NF-κB and inhibition of the nucleotide-binding domain and leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) inflammasome, thus reducing injury and improving functional outcomes in mice [135].
Furthermore, curcumin has been reported to decrease the expression of light chain 3 phosphatidylethanolamine conjugate (LC3-II) and HIF-1α while increasing P62 levels in an in vitro model of IRI [137]. LC3-II is a widely used marker to assess autophagy, which is a cellular process that plays a crucial role in the degradation and recycling of damaged or unneeded cellular components. On the other hand, HIF-1α is a transcription factor that is activated under conditions of hypoxia (low oxygen availability) and plays a role in the cellular response to oxygen deprivation. The reduced expression of LC3-II and HIF-1α, together with increased P62, results in decreased cell death and apoptosis.
Curcumin also contributes to the protection of the cardiomyocytes through several mechanisms. It improves cardiac function after IRI by inhibiting extracellular matrix degradation and collagen synthesis through the transforming growth factor beta (TGFβ)/ mothers against decapentaplegic (Smad) signaling pathway. In addition, curcumin mitigates oxidative damage and reduces cardiomyocyte apoptosis through activation of the janus kinase (JAK) 2/signal transducers and activator of transcription (STAT) 3 pathway, thereby alleviating myocardial IRI.
5.1.2. Phenolic Acids
Phenolic acids are compounds that have a carboxylic acid group and are present in a wide variety of foods of plant origin, such as the skin of fruits, grape seeds, tea, honey, peach, red wine, and the leaves of vegetables. They are usually found as amides, esters, or glycosides, and they are rarely in free form [144]. Phenolic acids are mainly divided into two subgroups: hydroxybenzoic acid and hydroxycinnamic acid [145]. These compounds are of interest since they possess considerable antioxidant activity.
An in vivo study shows that treatment with Macrotyloma uniflorum seed extract, which is rich in phenolic acids such as p-coumaric acid and ferulic acid, exerts a significant cardioprotective effect in rats exposed to isoproterenol, probably due to the potent antioxidant activity of phenolic acids, which protect the myocardium from the harmful effects of isoproterenol [146].
5.2. Carotenoids
Carotenoids are lipophilic compounds that are found in a wide range of fruits, vegetables, and other natural sources. They serve important functions in plants, protecting chlorophyll and mitochondria, while in animals, they act as potent antioxidants and support various aspects of health [150,151]. Once consumed, carotenoids are absorbed in the intestines and transported to various tissues in the body through lipoproteins. One of the best-known carotenoids is beta-carotene, which is abundant in carrots, sweet potatoes, and green leafy vegetables. Beta-carotene is a precursor of vitamin A, which is a nutrient essential for vision, immune function and cell growth [151].
In humans, carotenoids play a crucial role as antioxidants, helping to neutralize harmful free radicals and protecting cells from oxidative damage. The consumption of carotenoid-rich foods has been associated with various health benefits, including a reduced risk of chronic diseases, such as cardiovascular disease, certain cancers, and age-related macular degeneration [152]. In conjunction with their antioxidant function, carotenoids have also been studied for their potential anti-inflammatory and immunomodulatory effects [152].
Carotenoids present in natural plant products have been shown to provide neuroprotection through a variety of mechanisms. Some of the main mechanisms by which carotenoids exert their neuroprotective effect include the following.
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Inhibition of neuroinflammation: Carotenoids have shown the ability to reduce inflammation in the central nervous system by inhibiting the production of pro-inflammatory cytokines and inflammatory cell activation.
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Regulation of microglial activation: Carotenoids can modulate the activity of microglial cells, which are immune cells in the central nervous system, helping to limit excessive inflammatory response.
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Protection against the excitotoxic pathway: Carotenoids may act as neuroprotective agents by preventing neuronal damage caused by excitotoxicity, which is a process that occurs when there is excessive overstimulation of glutamate receptors on neurons.
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Modulation of autophagy: Carotenoids can influence autophagy, which is a cellular process that plays a crucial role in the removal of damaged cellular components, thus helping to maintain the integrity of neurons.
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Reducing oxidative damage: Carotenoids are known for their potent antioxidant activity, enabling them to neutralize ROS and reduce cell damage caused by OS.
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Activation of defensive antioxidant enzymes: Carotenoids can also stimulate the activity of endogenous antioxidant enzymes in the brain, thereby enhancing the nervous system’s ability to counteract the effects of OS.
These various mechanisms of action work together to protect and preserve neuronal health, suggesting that carotenoids could be a promising option for the development of therapeutic or preventive strategies in neurodegenerative diseases and other neurological disorders. However, there is controversial evidence regarding the benefits of carotenoid supplementation [156]. Thus, it is important to note that more research is needed to fully understand the effects and benefits of carotenoids in neuroprotection and their potential clinical application.
Additionally, the protective role of crocin (present in Crocus sativus) in reperfusion injury after AMI has been investigated. Crocin was found to exert protective effects through the Akt/eNOS/GSK-3β axis not only toward isoproterenol-induced cardiotoxicity but also counteracting norepinephrine-induced myocardial hypertrophy [162]. Evidence shows that this extract has a cardioprotective effect by upregulating Nrf2 expression [162].
The role of oleanolic acid (derived from terpenes) as a cardioprotective agent against reperfusion injury after myocardial infarction in isolated rat hearts has also been investigated. Pretreatment with oleanolic acid was found to enhance the mitochondrial antioxidant mechanism through increased reduced glutathione and alpha-tocopherol, thus providing a cardioprotective effect [163].
Regarding the mechanism of action, in vivo studies support that the protective effects of astaxanthin on the myocardium work through the Keap1–Nrf2 signaling pathway and mitochondria-mediated apoptosis [165]. Similarly, another in vivo study showed that this compound suppresses OS via activating the Nrf2/HO-1 pathway, thereby ameliorating cardiomyocyte apoptosis and cardiac dysfunction in rats [166]. Its mechanism of action also appears to be linked to inhibition of the TLR4/NF-κB signaling pathway, thus suppressing the release of inflammatory cytokines, which can cause myocardial cell death [167].
5.3. Vitamins
5.3.1. Vitamin C
Ascorbic acid, also recognized under the epithet of vitamin C, represents a fundamental pleiotropic antioxidant that performs various functions in multiple cellular compartments, acting on water-soluble elements [172]. The mechanisms whereby vitamin C exerts its beneficial influences have been the subject of much research, and part of this process is based on its ability to directly decrease ROS [173]. In addition to its ability to behave as an ROS scavenger, ascorbic acid intricately downregulates several enzymes related to ROS production, endothelial dysfunction, platelet coagulation, and smooth muscle cell tension.
The major mechanisms by which ascorbate is able to modulate endothelial function include the upregulation of antioxidant enzymes, eNOS and phospholipase A2, together with a direct reduction in the activity of NOX, which is the major source of O2•− in the cardiovascular system [174,175]. Although the underlying rationale for these effects has not been completely unraveled, it has been reported that ascorbate may be involved in the regulation of NOX synthesis [176] as well as in its regulation at both the transcriptional and post-transcriptional levels [176,177].
One other aspect of relevance that deserves to be highlighted in relation to the ascorbate effect consists in the fact that in addition to its direct interventions in aqueous environments, this compound is capable of regenerating α-tocopherol in cell membranes by means of achieving the reduction in the α-tocopheroxyl radical to its original α-tocopherol form [179].
In relation to the clinical evaluation of the efficacy of ascorbate in cardiovascular conditions, several studies have been performed in recent decades that have yielded remarkable results. For example, in a cross-sectional analysis of 2383 individuals, low serum vitamin C levels were found to be associated with inflammation and the severity of peripheral arterial disease in smokers [183].
5.3.2. Vitamin E
Alpha-tocopherol, commonly known as vitamin E, is a lipid-soluble vitamin with antioxidant properties that has several potential benefits for the human health. Indeed, vitamin E encompasses a group of tocopherols and tocotrienols which have been identified as possible anti-inflammatory, neuroprotective, anticarcinogenic, antihypertensive, atherogenesis inhibitor, antiallergic, antidiabetic, and telomerase activity modulators, in addition to being preventive against cardiovascular diseases, among other positive effects. It is present in several plant sources, especially in nuts such as walnuts and vegetable oils. It can also be found in foods that are part of the regular diet, such as vegetables, fruits, eggs, seafood and cheese [194].
It is recognized that this vitamin plays an essential role in safeguarding lipids against peroxidation [195], which in turn prevents this crucial event in the development and progression of atherosclerosis [196,197]. Therefore, it has been postulated that alpha-tocopherol could attenuate the atherosclerotic process and reduce the risk of cardiovascular disease. The main action of this compound is based on its ability to inhibit NOX and lipid peroxidation, which justifies its contribution to the reversal of endothelial dysfunction [176].
Recently, a systematic review has been carried out that provided evidence for the positive effects of tocotrienols in models of brain injury and myocardial IRI. Tocotrienols were found to lead to significant improvements in structural, functional, and biochemical aspects in these models. Additionally, a marked reduction in OS, inflammation and apoptosis was observed because of tocotrienol treatment. These findings hint that tocotrienols may have therapeutic potential to counteract the adverse effects of IRI in both the brain and myocardium [201].
5.3.3. Vitamin D
Vitamin D is a secosterol known to regulate calcium and phosphate metabolism. It can be obtained from food and endogenously produced in the skin through sun exposure. There are two main dietary sources of vitamin D: cholecalciferol or vitamin D3, which can be found in foods such as oily fish or egg yolks and vitamin ergosterol or vitamin D2, which can be found in fungi and yeast [207]. Once in the bloodstream, vitamin D is transformed in the liver to 25-hydroxyvitamin D3, which in turn is further converted to the active form 1,25-dihydroxyvitamin D3 in the kidneys, being thus able to bind to its nuclear receptor to exert its physiologic functions [208].
Regarding its effects on OS and IRI, in vitro studies show that vitamin D3 exerts cardioprotective effects against myocardial IRI by protecting mitochondrial structural and functional integrity and reducing mitophagy [209]. When applied to a mouse model, vitamin D3 treatment mitigated mitochondrial fission, apoptosis, mitophagy, and myocardial structural abnormalities [209].
5.3.4. Folic Acid
Folic acid, a type of B vitamin essential in the regular human diet, is strongly associated with neuroinflammation [210]. It is also key for the development and function of the nervous system [86] and has been shown to have an antioxidant and a neuroprotective role [211]. A recent study assessed its potential role on synaptic structure and function, using an oxygen-glucose deprivation and reperfusion cell model, as well as a brain ischemia–reperfusion model. In this model, it was found that folic acid can effectively improve cognitive impairment and reduce neuronal death after cerebral ischemia, probably through improving synaptic dysfunction, concomitant with upregulated known markers of synaptic plasticity and downregulated N-methyl-D-aspartate receptor (NMDAR) expressions. Therefore, it could be suggested that folic acid may be a potential treatment to improve ischemic injury-induced cognitive decline [86].
5.4. Trace Elements
5.4.1. Selenium
It has been suggested that Se has a great potential to ameliorate cerebral IRI. This process includes the Se-induced upregulation of mitofusin-1 expression, thus alleviating OS and ferroptosis, and the mechanism operates through the promotion of mitochondrial fusion both in vivo and in vitro [213].
The ability of the selenium compounds to increase GPX expression and activity has been related to their effectiveness in protecting against neuronal damage caused by cerebral ischemia–reperfusion in a murine model. From these studies, it was suggested that pretreatment with Se compounds provides neuronal protection in vivo against ischemia–reperfusion damage.
5.4.2. Copper
Based on the occurrence of copper-induced Fenton reaction, this trace element provides a link toward pathophysiological cascades leading to OS and inflammation, playing a pathogenic role in stroke and ischemia–reperfusion myocardial damages. However, on the other hand, clinical data have suggested that plasma copper was significantly associated with a higher risk of IS [217], which was consistent with a previous study reporting the occurrence of significantly lower serum copper levels in patients with acute hemorrhagic stroke than in healthy control ones [218].
5.4.3. Zinc
Zinc is a micronutrient essential to numerous biochemical pathways in human cells. In addition, salts of zinc have been used due to their protective effects against gastric, renal, hepatic, muscle, myocardial, or neuronal ischemic injury. With regard to target OS, Zn supplementation increased antioxidant parameters such as SOD, CAT, GPX, and GSH among others as well as Nrf2 expression and decreased mPTP opening, MDA and miRs-(122 and 34a), apoptotic factors, and histopathological changes [221].
The brain is an organ highly enriched in Zn content, the latter acting as a critical mediator of neuronal death during ischemia. An important mechanism of neuronal cell death in ischemic penumbra may be provided through the activation of endoplasmic reticulum stress by excessive Zn [222]. Studies of brain cerebral IRI by zinc accumulation in a murine model have reported that excessive zinc causes specific neuronal apoptosis induced by inflammation [223]. On the other hand, it has been suggested that Zn homeostasis plays a role in myocardial IRI, establishing an association between Zn deficiency and the development of cardiovascular diseases, which is supported by numerous studies.
5.4.4. Manganese
Manganese is needed for the activity of manganese superoxide dismutase (MnSOD) or SOD2, which is one of the main antioxidant enzymes that protects the heart against IRI. This enzyme is a major mitochondrial antioxidant that scavenges O2•−. During ischemia followed by reperfusion, numerous studies have found a loss of SOD2 activity within the heart. Is important to note that the toxicity levels of Mn causing manganese stress, evoking increased ROS production and OS, are not well-defined. It was hypothesized that the affected energy metabolism is the primal cause of manganese toxicity. Manganese stress depletes cellular iron, affecting energy metabolism. In addition, impairment in the biogenesis of electron transport chain complexes causes ROS production [226].
5.5. Other Antioxidants
5.5.1. Ginsenosides
The general structure of ginsenosides is a hydrophobic tetracyclic steroid skeleton, which is connected with sugar molecules and responsible for the hydrophilicity of the molecule [227]. Panax ginseng Meyer is a traditional Chinese herbal medicine in China whose pharmacological activities, such as anti-inflammatory, anti-oxidative, platelet aggregation-inhibiting, and neuronal apoptosis-suppressing effects [228], are mainly attributed to saponins, known as ginsenosides; and to other bioactive monomers like fatty acids, polysaccharides, and mineral oils [229]. In the following paragraphs, a more detailed description of ginsenoside Rg1 (G-Rg1) and ginsenoside Rb1 (G-Rb1) is made, due to their potential use in preventing ischemia after reperfusion in the brain [87] and heart [89,90], respectively. G-Rg1 exerts neurotrophic and neuroprotective pharmacological effects on the central nervous system [228].
5.5.2. Erythropoietin
Several other protective pathways mediated by EPO have been reported including SIRT1 and JAK2/STAT pathways. The EPO-mediated activation of SIRT1 resulted in deacetylation and enhanced peroxisome proliferator-activated receptor gamma co-activator 1 alpha transcriptional activity which, in turn, promoted mitochondrial function and biogenesis in cardiomyocytes [233]. In fact, EPO pretreatment was demonstrated to decrease myocardial IRI [234]. Also, EPO decreases the cerebral ischemic area and the number of apoptotic cells in the ischemic penumbra in a rat model. These effects may be achieved via the EPO-mediated protection of cells against apoptosis [235].
5.5.3. Estrogen
Estrogen deficiency is an important factor leading to cardiovascular diseases. 16α-hydroxyestrone, an estrogen-active component, could prevent cell death in myocardial tissue by regulating autophagy through the AMPK/mTOR pathway [236]. Also, a combined estrogen and progesterone treatment after ischemia could protect against glutamate neurotoxicity through modulating glutamate transporter expression, which in consequence induces glutamate re-uptake from extracellular space and prevents neurotoxicity [237].
This entry is adapted from the peer-reviewed paper 10.3390/antiox12091760
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