Signaling pathways in brain ischemia: Mechanisms and therapeutic implications

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

“…Additionally, after the restoration of blood flow into the brain, the re-entry of oxygenated blood leads to the “oxygen paradox” phenomenon, accompanied by further ROS production, causing greater damage to neurons, astrocytes, oligodendrocytes, and microglia [ 8 ]. The entire IRI process, therefore, includes OS-mediated damage by enhancing inflammation and via endothelial dysfunction, leading to the disruption of the blood–brain barrier (BBB); microglial activation; lipid peroxidation; and direct cellular death through ferroptosis, pyroptosis, necroptosis, autophagy, and apoptosis, culminating in potential chronic damage, mainly due to glial scar formation, chronic inflammation, impaired axonal regeneration, impaired remyelination, and impaired neo-angiogenesis [ 9 , 10 , 11 , 12 ]. The main mechanisms and molecular pathways involved in brain damage due to IRI following stroke reperfusion are summarised in Figure 1 and Table 1 .…”

“…Activation of eNOS and nNOS are calcium-dependent, whereas activation of iNOS is calcium-independent. Following reperfusion, the nuclear factor kappa B (NF-κB) pathway upregulates iNOS, leading to excessive NO production, which promotes inflammation by increasing the release of proinflammatory factors and altering vascular permeability through the NO/caveolin-1/matrix metalloproteinase (MMP) pathway [ 12 ].…”

“…Tyrosine nitration of Keap1 promotes an alteration of the cellular antioxidant response by inducing the cytoplasmic nuclear shuttling of the Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) complex in endothelial cells. This prevents the cells from displaying an adequate Nrf2-mediated antioxidant response [ 12 ]. Additionally, tyrosine nitration of TIGAR leads to a jeopardised generation of NADPH, provoking endothelial tight junction damage and, thus, an alteration of the BBB.…”

“…Additionally, tyrosine nitration of TIGAR leads to a jeopardised generation of NADPH, provoking endothelial tight junction damage and, thus, an alteration of the BBB. This alteration is mediated through the downregulation of caveolin-1, further activation of the NOS [ 13 , 44 ], alteration of the E6-associated protein (E6AP)/Prx1 signalling pathways, and subsequent reduction in the antioxidant response, ultimately inducing mitochondrial dysfunction and apoptosis [ 12 ].…”

“…Metals can participate in the Fenton and Haber–Weiss reaction, promoting the overall production of ROS and RNS [ 43 , 45 ] and directly inducing lipid peroxidation and depletion of antioxidants, leading to membrane damage, loss of membrane fluidity, the formation of reactive by-products—such as malondialdehyde (MDA) or 4-hydroxynonenal—and the activation of inflammatory responses. Ultimately, these processes cause cell damage and death through several mechanisms, such as necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy [ 12 , 23 , 46 ].…”