Novel Multi-Antioxidant Approach for Ischemic Stroke Therapy Targeting the Role of Oxidative Stress.

Stroke is a major contributor to global mortality and disability. While reperfusion is essential for preventing neuronal death in the penumbra, it also triggers cerebral ischemia-reperfusion injury, a paradoxical injury primarily caused by oxidative stress, inflammation, and blood-brain barrier disruption. An oxidative burst inflicts marked cellular damage, ranging from alterations in mitochondrial function to lipid peroxidation and the activation of intricate signalling pathways that can even lead to cell death. Thus, given the pivotal role of oxidative stress in the mechanisms of cerebral ischemia-reperfusion injury, the reinforcement of the antioxidant defence system has been proposed as a protective approach. Although this strategy has proven to be successful in experimental models, its translation into clinical practice has yielded inconsistent results. However, it should be considered that the availability of numerous antioxidant molecules with a wide range of chemical properties can affect the extent of injury; several groups of antioxidant molecules, including polyphenols, carotenoids, and vitamins, among other antioxidant compounds, can mitigate this damage by intervening in multiple signalling pathways at various stages. Multiple clinical trials have previously been conducted to evaluate these properties using melatonin, acetyl-L-carnitine, chrysanthemum extract, edaravone dexborneol, saffron, coenzyme Q10, and oleoylethanolamide, among other treatments. Therefore, multi-antioxidant therapy emerges as a promising novel therapeutic option due to the potential synergistic effect provided by the simultaneous roles of the individual compounds.

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

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.

Improvement of a Novel Proposal for Antioxidant Treatment Against Brain Damage Occurring in Ischemic Stroke Patients.

The underlying mechanism of cerebral injury occurring in patients with acute ischemic stroke involves a key pathophysiological role of oxidative stress. Thus, reactive oxygen species are related to the development of brain edema, calcium overload, mitochondrial dysfunction, excitotoxicity, iron release and inflammation. Nevertheless, although experimental studies have tested the use of antioxidants as an adjuvant therapy in this setting, clinical data and randomized trials are still lacking. Current approved pharmacological therapy is aimed at reperfusion strategies; however, the therapeutic window is limited and also challenged by the injury known to result from the reperfusion. We have recently defined a time-course occurrence of pathological events triggered by reperfusion-dependent increased reactive oxygen species, thus suggesting the beneficial role of the pertinent use of antioxidants. The present study was aimed to support the hypothesis that an enhanced antioxidant neuroprotection could be achieved by the use of two or more antioxidants opportunely provided to ischemic stroke patients focused against the specific mechanism occurring throughout the pathophysiological process. From this paradigm, using an underexplored therapeutic principle, it could be suggested that antioxidant-based therapy is a novel, promising, safe, available and cost-effective strategy against the deleterious effects of ischemic stroke that needs to be further studied in clinical protocols.

Pathophysiology of Ischemic Stroke: Role of Oxidative Stress.

Stroke is the second leading cause of mortality and the major cause of adult physical disability worldwide. The currently available treatment to recanalize the blood flow in acute ischemic stroke is intravenous administration of tissue plasminogen activator (t-PA) and endovascular treatment. Nevertheless, those treatments have the disadvantage that reperfusion leads to a highly harmful reactive oxygen species (ROS) production, generating oxidative stress (OS), which is responsible for most of the ischemia-reperfusion injury and thus causing brain tissue damage. In addition, OS can lead brain cells to apoptosis, autophagy and necrosis. The aims of this review are to provide an updated overview of the role of OS in brain IRI, providing some bases for therapeutic interventions based on counteracting the OS-related mechanism of injury and thus suggesting novel possible strategies in the prevention of IRI after stroke.