Does neuroglobin protect neurons from ischemic insult? A quantitative investigation of neuroglobin expression following transient MCAo in spontaneously hypertensive rats

Hundahl, Christian Ansgar; Kelsen, Jens; Kjær, Katrine; Rønn, Lars Christian B.; Weber, Roy E.; Geuens, Eva; Hay‐Schmidt, Anders; Nyengaard, Jens Randel

doi:10.1016/j.brainres.2006.02.040

Cited by 66 publications

(54 citation statements)

References 24 publications

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“…Cerebral ischemia is another stimulus to Ngb expression, although findings vary depending on the model used. Focal cerebral ischemia is most clearly associated with Ngb induction [11], perhaps because it involves complete interruption of blood flow and, therefore, profound hypoxia, although focal ischemia did not induce Ngb expression in spontaneously hypertensive rats [18]. Transient global forebrain ischemia increases Ngb expression in gerbil cerebral cortex but not hippocampus [19], and does not alter expression in rat brain [16].…”

Section: Injury-induced Ngb Expressionmentioning

confidence: 94%

Neuroglobin: an endogenous neuroprotectant

Greenberg

Jin

Khan

2008

Current Opinion in Pharmacology

142

112

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Cerebral hypoxia and ischemia trigger endogenous protective mechanisms that can prevent or limit brain damage. Understanding these mechanisms may lead to new therapeutic strategies for stroke and related disorders. Neuroglobin (Ngb), a recently discovered protein that is distantly related to hemoglobin and myoglobin, is expressed predominantly in brain neurons, and appears to modulate hypoxic-ischemic brain injury. Evidence includes the observations that neuronal hypoxia and cerebral ischemia induce Ngb expression, that enhancing Ngb expression reduces-and knocking down Ngb expression increases-hypoxic neuronal injury in vitro and ischemic cerebral injury in vivo, and that Ngb-overexpressing transgenic mice are resistant to cerebral infarction. However, the mechanisms that underlie hypoxic induction of and neuroprotection by Ngb are still unclear.

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Section: Injury-induced Ngb Expressionmentioning

confidence: 94%

Neuroglobin: an endogenous neuroprotectant

Greenberg

Jin

Khan

2008

Current Opinion in Pharmacology

142

112

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“…Our own experiments employing various hypoxia regimes never showed increased Ngb mRNA or protein levels in rat brain (A. Avivi, F. Gerlach, S. Reuss, T.B., E. Nevo, T.H., unpublished data). Likewise, in situ hybridisation, micro-array and quantitative real-time PCR studies showed that ischemia did not induce significant changes of Ngb (Hundahl et al, 2006b;Schmidt-Kastner et al, 2006 -to NO at low P O2 (C), act as a signal protein by inhibiting the dissociation of GDP from Gα (D) or prevent hypoxia-induced apoptosis via reduction of cytochrome c (E).…”

Section: Hypoxia Regulation Of Ngbmentioning

confidence: 99%

What is the function of neuroglobin?

Burmester¹,

Hankeln

2009

Journal of Experimental Biology

222

215

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SUMMARY For a long time, haemoglobin and myoglobin had been assumed to represent the only globin types of vertebrates. In 2000, however, we discovered a third globin type by mining the genome sequence data. Based on a preferential expression in the nervous system, this globin is referred to as neuroglobin. Despite nine years of research, its function is still uncertain and a number of hypotheses have been put forward. Neuroglobin enhances cell viability under hypoxia and under various types of oxidative stress in transgenic systems, but does not appear to be strongly upregulated in response to stress. A close phylogenetic relationship with invertebrate nerve globins and its positive correlation with the oxidative metabolism and mitochondria suggest a role in O2 supply. In vitro studies and cell culture experiments imply that neuroglobin may detoxify reactive oxygen or nitric oxide. Still other studies propose neuroglobin as being part of a signalling chain that transmits the redox state of the cell or that inhibits apoptosis. Although some functions are more probable than others, we conclude that it is still too early to definitively decide what may be the physiological role(s) of neuroglobin in vertebrates. Nevertheless, there is no doubt that neuroglobin has an essential, conserved function and is beneficial to neurons.

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“…In our hands the cortical and striatal Ngb expression was always very scarce despite ischemic challenge. 6 Mice even expressed less Ngb in the mentioned areas compared to rats. In addition we only found colocalization of Ngb and nNOS in very few neuronal populations residing outside the cortex and striatum.…”

Section: To the Editormentioning

confidence: 92%

Neuroglobin: Endogenous Neuroprotectant or Maintenance of Homeostasis?

Kelsen

Hundahl

Hay‐Schmidt

2008

Stroke

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Neuroglobin: Endogenous Neuroprotectant orMaintenance of Homeostasis?To the Editor:We would like to comment on the latest experimental stroke study in a neuroglobin (Ngb) knock-in mouse by Wang et al 1 The intriguing idea that Ngb could act as a reservoir of oxygen, facilitate oxygen transportation or act as a scavenger of reactive oxygen species in the brain has been the main research hypotheses since its discovery. 2 Notably, the investigation of the role of Ngb in pathophysiological conditions like hypoxia and ischemia has promoted the idea of an endogenous neuroprotectant. 3 However, we would like to challenge the ruling theory of a possible neuroprotective function of Ngb. Instead, we propose a homeostatic role based on the distinct expression pattern (Figure), 4 the old evolutionary history and highly conserved structure of Ngb. 5 Wang et al 1 thoroughly characterized the differences in infarct volume, malondialdehyde (MDA) formation and sensorimotor function in Ngb-overexpressing transgenic (Ngb-Tg) mice and wild-type littermates. Forced Ngb expression significantly reduced the cortical infarct volumes 22 hours after 2-hour intraluminal transient middle cerebral artery occlusion whereas no difference was seen in the subcortical structures at that time point. Surprisingly, subcortical structures were significantly spared in Ngb-Tg 14 days after 60-minute focal transient ischemia. Unfortunately, this phenomenon is not discussed by the authors. The less MDA formation after 8 and 22 hours in Ngb-Tg is interpreted as a possible antioxidative action of Ngb. We think MDA production reflects the significant difference in stroke volumes after 22 hours. MDA is not only a surrogate biomarker of reactive oxygen species but probably also of infarct size.Previously published differences in Ngb expression are attributable to the use of different antibodies and ribonucleotide probes. In our hands the cortical and striatal Ngb expression was always very scarce despite ischemic challenge. 6 Mice even expressed less Ngb in the mentioned areas compared to rats. In addition we only found colocalization of Ngb and nNOS in very few neuronal populations residing outside the cortex and striatum. 7 In our opinion Ngb does not have a pathophysiological action as oxygen buffer or sensor. We do not dispute that Ngb can act as an endogenous neuroprotectant in the brain, but we do dispute the notion that Ngb primarily offers protection against ischemia in cortical and subcortical areas. Finally, the possible mechanism of neuroprotective action remains to be elucidated and has not been further characterized by Wang et al. 1 Sources of Funding

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Does neuroglobin protect neurons from ischemic insult? A quantitative investigation of neuroglobin expression following transient MCAo in spontaneously hypertensive rats

Cited by 66 publications

References 24 publications

Neuroglobin: an endogenous neuroprotectant

Neuroglobin: an endogenous neuroprotectant

What is the function of neuroglobin?

Neuroglobin: Endogenous Neuroprotectant or Maintenance of Homeostasis?

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