Reversal of Postischemic Hypoperfusion by Tempol: Endothelial Signal Transduction Mechanism

Okada, Tomoaki; Teranishi, Kohsuke; Chen, Ye; Tomori, Toshiki; Strasser, Alois; Lenz, Frederick A.; McCarron, Richard M.; Spatz, Maria

doi:10.1007/s11064-011-0595-y

Cited by 5 publications

(7 citation statements)

References 45 publications

(69 reference statements)

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“…66 Okada reported in transient global ischemia that CBF changes at the induction of ischemia and also at reperfusion within 1 min. 67 Westermaier et al saw local cortical blood flow drop in 1 min while pO 2 dropped in 2−3 min in a subarachnoid hemorrhage model. 68 Prunell determined, also in a subarachnoid hemorrhage model, that CBF dropped in 40 s while pO 2 reached a minimum in 1.5−2 min.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

“…More quantitatively, Peters et al found changes in cortical CBF within 5 min (the shortest time measured) after induction of focal ischemia and again at reperfusion . Okada reported in transient global ischemia that CBF changes at the induction of ischemia and also at reperfusion within 1 min . Westermaier et al saw local cortical blood flow drop in 1 min while pO 2 dropped in 2–3 min in a subarachnoid hemorrhage model .…”

Section: Resultsmentioning

confidence: 98%

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Optimized Real-Time Monitoring of Glutathione Redox Status in Single Pyramidal Neurons in Organotypic Hippocampal Slices during Oxygen–Glucose Deprivation and Reperfusion

Yin

Barrionuevo

Weber

2015

ACS Chem. Neurosci.

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A redox-sensitive Grx1-roGFP2 fusion protein was introduced by transfection into single pyramidal neurons in the CA1 subfield of organotypic hippocampal slice cultures (OHSCs). We assessed changes in the GSH system in neuronal cytoplasm and mitochondria during oxygen-glucose deprivation and reperfusion (OGD/RP), an in vitro model of stroke. Pyramidal cells in a narrow range of depths below the surface of the OHSC were transfected by gene gun or single-cell electroporation with cyto- or mito-Grx1-roGFP2. To mimic the conditions of acute stroke, we developed an optimized superfusion system with the capability of rapid and reproducible exchange of the solution bathing the OHSCs. Measurements of pO2 as a function of tissue depth show that in the region containing the transfected cells, the pO2 is well-controlled. We also found that the pO2 changes on the same time scale as changes in intracranial pressure, cerebral blood flow, and pO2 during acute stroke. Determining the reduction potential, EGSH, from the ratiometric fluorescence signal requires an absolute intensity measurement during calibration of the Grx1-roGFP2. Using the signal from cotransfected tdTomato as an internal standard during calibration improves quantitative measurements of Grx1-roGFP2 redox status and allows EGSH to be determined. EGSH becomes more reducing during OGD and more oxidizing during RP in mitochondria while changes in cytoplasm are not significant compared with controls.

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Section: ■ Results and Discussionmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 98%

Optimized Real-Time Monitoring of Glutathione Redox Status in Single Pyramidal Neurons in Organotypic Hippocampal Slices during Oxygen–Glucose Deprivation and Reperfusion

Yin

Barrionuevo

Weber

2015

ACS Chem. Neurosci.

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“…Stabilization of calcium homeostasis may be in part supported by treatment with lithium, 46 magnesium, 47 and calcium channel blockers such as nimodipine. 48,49 Although these agents may or may not be effective when given alone, they may be combined with free radical scavengers 50,51 such as resveratrol, 52,53 tempol, 54 and edaravone. 55 Another approach is to combine agents that inhibit mitochondrial damage with those that support mitochondrial function.…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Reperfusion brain injury

Pundik

Sundararajan

2012

Neurology

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Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion. Neurology Stroke is a complex and dynamic disease of the brain that rates fourth in mortality and first in disability in the United States. The brain has certain unique physiologic properties that make it extremely sensitive to the loss of blood flow. In general, the energy demands of the brain are high, requiring a continual supply of oxygen and its principal substrate, glucose, mainly from the blood. Occluding blood flow to the brain disrupts the delicate balance between the energy generated by glucose oxidation and energy needed for cell processes, which leads to a rapid loss of function and cell homeostasis.The imbalance of the brain bioenergetics induced by the loss of blood flow has been shown to lead to cellular infarction of all brain cells, including neurons, astrocytes, endothelial cells, oligodendrocytes, and subpopulations of these cells. Conversely, a pronounced deranged cellular milieu resulting from ischemia elicits a plethora of reactions upon re-establishment of reflow. It is increasingly evident that many of the events center on the neurovascular unit, a functional composite of microvessels, pericytes, astrocytes, neurons, axons, and other supporting cells such as microglia and oligodendrocytes. Although many of the reflow-induced events may be pathologic and their prevention potentially beneficial, it is our contention that the status of cellular bioenergetics is the major determinant of many of the pathophysiologic sequelae manifested in the neurovascular unit and therefore is fundamental to the outcome for the tissue, following reversible focal ischemia.In the past 50 years, basic science investigations first established that loss of blood flow to the brain resulted in rapid failure of cell bioenergetics, followed by an ever-increasing list of cellular perturbations. A schematic of ischemia-induced events is shown in figure 1. Rapid energy depletion reflects very low energy reserves within the brain, a high metabolic rate, and almost a total reliance on glucose oxidation for energy production. The ischemic cascade is initiated during ischemia. Ischemia depletes adenosine triphosphate (ATP) within minutes, leading to a failure of a

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“…Inducible nitric oxide synthase (iNOS), a subtype of nitric oxide synthase that is only induced under pathological conditions, is regulated by NF-κB. When iNOS is activated, it can release a large amount of NO, which leads to the excessive production of ROS/RNS [33][34][35][36]. In the brain, the unchecked ROS/RNS release leads to lipid peroxidation of cell membranes.…”

Section: Introductionmentioning

confidence: 99%

“…In the brain, the unchecked ROS/RNS release leads to lipid peroxidation of cell membranes. This in turn disrupts phospholipid-dependent enzymes and ionic gradients resulting in other sequelae, including disturbances of the CBF, BBB permeability changes, and the development of edema [33]. Among the many studies concerning the role(s) of ROS/RNS molecules are those that have demonstrated their major role in the signal transduction pathways associated with vascular contraction and relaxation [33,37].…”

Section: Introductionmentioning

confidence: 99%

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

Zheng

Wang

Lin

et al. 2023

Journal of Neurotrauma

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BackgroundSecondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates neuroin ammation and oxidative damage, which may act as triggers for pathological processes after TBI. However, the role of TNF-α/NF-κB in pericyte-mediated cerebral microcirculation are currently unknown. MethodsWe assessed the activity and mechanisms of the TNF-α/NF-κB signaling axis on pericyte-mediated microcirculation using the mouse controlled cortical impact model and BV2 cells. Immuno uorescent staining and western blot analysis were used to detect activation of the TNF-α/NF-κB signaling pathway and the expression of inducible nitric oxide synthase (iNOS) to evaluate the effects of the TNF-α speci c inhibitor in iximab (IFX). Modi ed neurological severity scores, Garcia test, Nissl staining, and TUNEL staining were employed to determine the neuroprotective effects of IFX supplementation. The relative blood ow values in the capillary areas surrounding the impinging lesion were observed by Laser speckle contrast imaging. The impact of IFX on pericyte markers was assessed to evaluate whether pericyte damage was dependent on the TNF-α/NF-κB/iNOS axis to gain further insight into the mechanisms underlying the development of the microcirculation disturbance after TBI. ResultsMicroglia were activated after TBI, and the expression of NF-κB, iNOS, a disintegrin and metalloproteinase 17, in ammatory factors, and free radicals increased around the injury areas. After lipopolysaccharide treatment, the expression of TNF-α and downstream NF-κB/iNOS in BV2 cells was signi cantly upregulated. Pharmacological inhibition of TNF-α via IFX signi cantly reduced NF-κB p65 phosphorylation and nuclear translocation and downregulated iNOS expression. Meanwhile, we found that speci c inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and cerebral microcirculation perfusion after TBI, which could attenuate in ammation and oxidative damage, reduce neuronal cell damage and apoptosis, and play a neuroprotective role. ConclusionThe results of this study suggested that microglia activated and released TNF-α after TBI, which promoted neuroin ammation and oxidative stress by activating downstream NF-κB/iNOS signals, and

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Reversal of Postischemic Hypoperfusion by Tempol: Endothelial Signal Transduction Mechanism

Cited by 5 publications

References 45 publications

Optimized Real-Time Monitoring of Glutathione Redox Status in Single Pyramidal Neurons in Organotypic Hippocampal Slices during Oxygen–Glucose Deprivation and Reperfusion

Optimized Real-Time Monitoring of Glutathione Redox Status in Single Pyramidal Neurons in Organotypic Hippocampal Slices during Oxygen–Glucose Deprivation and Reperfusion

Reperfusion brain injury

TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

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