NADPH Oxidase-2: Linking Glucose, Acidosis, and Excitotoxicity in Stroke

Abstract

Significance: Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke. Recent Advances: Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase f/d, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury. Critical Issues: Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria. Future Directions: It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade. Antioxid. Redox Signal. 22,[161][162][163][164][165][166][167][168][169][170][171][172][173][174]

Genetically encoded cell-death indicators (GEDI) to detect an early irreversible commitment to neurodegeneration

“…Furthermore, with the increased time resolution of death possible using GEDI, subpopulations of death-resistant neurons and the spread of neuronal death can now be imaged. For instance, reports of subpopulations of neurons displaying resistance to glutamate have been described in culture and in vivo [80][81][82][83] , yet each report has relied on dyes to characterize death at static time points, limiting the ability to resolve the time coarse and cell-to-cell transmission of excitotoxic injury on a single cell level now possible with GEDI (Figure 2A-D).…”

Combination therapy of normobaric oxygen with hypothermia or ethanol modulates pyruvate dehydrogenase complex in thromboembolic cerebral ischemia

“…Oxidative stress by disruption of mitochondrial activity is known to play an important role in the pathogenesis of stroke (Pradeep et al, ). Non‐mitochondrial sources of superoxide may also contribute to oxidative stress during ischemia and reperfusion (Suh et al, ; Reeve et al, ; Brennan‐Minnella et al, ). Given the importance of ROS production mediating PDH activity, roles of mitochondrial or non‐mitochondrial sources in the oxidative stress in ischemia–reperfusion injury remain to be determined further.…”

Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

“…The ensuing spontaneous depolarization causes an increase in intracellular calcium, and dysregulated release of neurotransmitters. Particularly devastating is spontaneous glutamate release, which eventually culminates in excitotoxic cell death [71, 72]. Despite the low levels of metabolism associated with hypoxic/ischemic events, the high levels of intracellular cations and ADP increase mitochondrial ROS production (Figure 4).…”