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

Abstract

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.

Ischemic Brain Injury: Involvement of Lipids in the Pathophysiology of Stroke and Therapeutic Strategies

“…The brain is particularly vulnerable to ROS and RNS compared with other organs because of high oxygen consumption, low neuronal antioxidant activity, high levels of peroxidizable lipids, and high concentrations of iron [ 37 , 38 ]. Ischemia–reperfusion injury triggers the excessive production of ROS, including superoxide anions (O 2 − ), hydroxyl radicals (OH − ), and hydrogen peroxide (H 2 O 2 ), primarily through the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, and mitochondrial dysfunction [ 39 ]. In physiological conditions, antioxidant defenses (enzymatic or non-enzymatic) protect brain tissues against oxidative stress cytotoxicity [ 40 , 41 ].…”