Oxidative Stress and Neuronal Death/Survival Signaling in Cerebral Ischemia

Abstract

It has been demonstrated by numerous studies that apoptotic cell death pathways are implicated in ischemic cerebral injury in ischemia models in vivo. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions and for mitochondrial oxidative phosphorylation to produce adenosine triphosphate. Oxygen radicals, the products of these biochemical and physiological reactions, are known to damage cellular lipids, proteins, and nucleic acids and to initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways could provide novel therapeutic strategies in clinical stroke.

Diabetes-Mediated Exacerbation of Neuronal Damage and Inflammation After Cerebral Ischemia in Rat: Protective Effects of Water-Soluble Extract from Culture Medium of Ganoderma lucidum Mycelia

“…Chronic oral treatment of MAK alleviated the exacerbation of cerebral injury and neurological deficits in the diabetic state, which could be attributed to its antioxidant activity and anti-inflammatory effects. ROS-induced oxidative stress is considered to be involved in the pathogenesis of transient cerebral ischemic injury (Fiskum et al, 2004;Saito et al, 2005;Niizuma et al, 2009). In particular, reperfusion after a long period of vessel occlusion triggers explosive generation of ROS, which causes cell death by peroxidative damage of lipids, proteins and nucleic acids (Warner et al, 2004;Anabela et al, 2006).…”

“…Additionally, a histochemical study revealed that generation of O 2 ⁻· and the occurrence of apoptosis in the ischemic penumbra were markedly increased in the brain of diabetic rats. A large amount of ROS locally generated by cerebral ischemia/reperfusion induces free radical chain reactions (Saito et al, 2005), which may be enhanced by increased oxidative stress in the diabetic state. Evidence is being accumulated that oxidative stress is enhanced by hyperglycemia in the diabetic state (Kusaka et al, 2004;Rizk et al, 2005;Tsuruta et al, 2010).…”

“…Additionally, they are more likely to have a poor prognosis and increased mortality after stroke (Biller et al, 1993;Vinik et al, 2002). Previous studies have demonstrated that the diabetic state increases oxidative stress in the brain and aggravates cerebral ischemic injury in both type I (Li et al, 2004;Saito et al, 2005;Rizk et al, 2005) and type II diabetic animal models (Anabela et al, 2006;Tureyen et al, 2011). In addition to neuronal damage attributed to hypoxia and ATP depletion caused by vascular obstruction in ischemic core region, cerebral injury caused by subsequent reperfusion is also involved in the pathophysiology of transient ischemia (Doyle et al, 2008;Nakka et al, 2008;Wang et al, 2010).…”

“…In addition to neuronal damage attributed to hypoxia and ATP depletion caused by vascular obstruction in ischemic core region, cerebral injury caused by subsequent reperfusion is also involved in the pathophysiology of transient ischemia (Doyle et al, 2008;Nakka et al, 2008;Wang et al, 2010). During reperfusion, the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is enhanced by abrupt re-oxygenation (Cuzzocrea et al, 2001;Saito et al, 2005). Besides direct injurious effects to the cell membrane, proteins and DNA by 217 reperfusion (MCAO/Re) in streptozotocin (STZ)-induced diabetic rats .…”

Apurinic/Apyrimidinic Endonuclease 1 Upregulation Reduces Oxidative DNA Damage and Protects Hippocampal Neurons from Ischemic Injury

“…This form of DNA damage is elicited by DNA endonucleases and involves double-strand DNA breaks during apoptosis. Passive DNA damage is also known as oxidative DNA damage and results from direct or indirect attacks by reactive oxygen species during reperfusion (15,38,55). Passive DNA damage can consist of DNA-protein crosslinks, apurinic/apyrimidinic (AP) sites, single-strand breaks, and 8-hydroxy-2¢-deoxyguanosine (8-OHdG) formation (15,17,38).…”