A neuroglobin-overexpressing transgenic mouse

Khan, Adil Aziz; Sun, Yunjuan; Jin, Kunlin; Mao, Xiao Ou; Chen, Sylvia; Ellerby, Lisa M.; Greenberg, David A.

doi:10.1016/j.gene.2007.02.044

Cited by 29 publications

(38 citation statements)

References 22 publications

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“…All previous experimental stroke reports of neuroprotection afforded by Ngb have been determined in normal mice or rats or using transgenic overexpression. [8][9][10][11] In using SHRSP, which exhibit a number of stroke-related comorbidities, we have addressed STAIR guidelines 5 as hypertension was reported as the strongest risk factor for stroke in a global case study. 7 Furthermore, all analyses were performed under masked conditions with animals randomly assigned to experimental groups and blood pressure monitoring throughout, in accordance with the preclinical stroke study guidelines.…”

Section: Discussionmentioning

confidence: 99%

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Ord

Shirley

McClure

et al. 2013

J Cereb Blood Flow Metab

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We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/ reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO þ control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO þ Ngb-expressing CAV-2, CAVNgb; tMCAO þ SP600125; tMCAO þ CAVNgb þ SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression þ SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb þ SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb þ SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.

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Section: Discussionmentioning

confidence: 99%

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Ord

Shirley

McClure

et al. 2013

J Cereb Blood Flow Metab

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“…Ngb-Tg mice were generated as described previously (2,3). Ngb ϩϩ /APP Sw,Ind transgenic mice were produced by crossing homozygous Ngb ϩϩ transgenic mice (FVB ϫ CD1) with heterozygous APP Sw,Ind line J9 transgenic mice (C57BL/6 ϫ DBA/2), which express human APP with Swedish (K670N and M671L) and Indiana (V717F) AD mutations and overproduce human A␤.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, raft polarization precedes caspase activation and mitochondrial release of cytochrome c, indicating that it is an earlyand, thus, potentially reversible-event in cell-death pathways. Neurons from Ngb-overexpressing transgenic (Ngb-Tg) mice (2,3) do not undergo membrane polarization in response to hypoxia and are resistant to hypoxic cell death, suggesting that Ngb may protect neurons from hypoxia by interfering with this cell-death signaling complex.…”

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confidence: 99%

Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo

Khan

Mao

Banwait

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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126

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Neuroglobin (Ngb), a vertebrate globin expressed primarily in neurons, is induced by and protects against neuronal hypoxia and cerebral ischemia. To investigate the spectrum and mechanism of Ngb's neuroprotective action, we studied the effect of transgenic overexpression of Ngb on NMDA and ␤-amyloid (A␤) toxicity in murine cortical neuron cultures in vitro and on the phenotype of Alzheimer's disease (AD) transgenic (APP Sw,Ind) mice. Compared with cortical neuron cultures from wild-type mice, cultures from Ngb-overexpressing transgenic (Ngb-Tg mice) were resistant to the toxic effects of NMDA and A␤(25-35), as measured by polarization of cell membrane lipid rafts, mitochondrial aggregation, lactate dehydrogenase release, and nuclear fragmentation. In addition, compared with APP Sw,Ind mice, double-transgenic (Ngb-Tg ؋ APP Sw,Ind) mice showed reductions in thioflavin-S-stained extracellular A␤ deposits, decreased levels of A␤(1-40) and A␤(1-42), and improved behavioral performance in a Y-maze test of spontaneous alternations. These findings suggest that the spectrum of Ngb's neuroprotective action extends beyond hypoxic-ischemic insults. Ngb may protect neurons from NMDA and A␤ toxicity by inhibiting the formation of a death-signaling membrane complex, and interventions that increase Ngb expression could have therapeutic application in AD and other neurodegenerative disorders.globin ͉ lipid raft ͉ neurodegeneration ͉ neuroprotection ͉ NMDA N euroglobin (Ngb) is a vertebrate globin that is localized to neurons, binds O 2 and other gaseous messengers, is transcriptionally induced by hypoxia and ischemia, and protects against hypoxic neuronal death and ischemic brain injury (1). However, the mechanism through which Ngb exerts its neuroprotective effect is unclear. We found recently that hypoxia induces polarization of plasma membrane lipid microdomains (rafts) that appear to mediate hypoxic neuronal death because inhibiting their formation enhances survival of hypoxic neurons (A.A.K., unpublished data). Moreover, raft polarization precedes caspase activation and mitochondrial release of cytochrome c, indicating that it is an earlyand, thus, potentially reversible-event in cell-death pathways. Neurons from Ngb-overexpressing transgenic (Ngb-Tg) mice (2, 3) do not undergo membrane polarization in response to hypoxia and are resistant to hypoxic cell death, suggesting that Ngb may protect neurons from hypoxia by interfering with this cell-death signaling complex.In addition to its protective effects against neuronal hypoxia in vitro and cerebral ischemia in vivo, Ngb also reduces oxidative injury from H 2 O 2 or paraquat (4) and ␤-amyloid (A␤)-induced toxicity (5) in cultured neural cell lines. To determine whether inhibition of membrane polarization-dependent neuronal death by Ngb extends to insults other than hypoxia, we investigated the effect of transgenic overexpression of Ngb on the neuronal toxicity of the excitatory amino acid, NMDA, and the Alzheimer's disease (AD)-related peptide, A␤. Compartmentalization by ...

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“…Thus, enhancing Ngb expression reduces-and knocking down Ngb expression increases-hypoxic neuronal injury in vitro [21] and ischemic cerebral injury in vivo [22]. In addition, Ngb-overexpressing transgenic mice are resistant to cerebral infarction from occlusion of the middle cerebral artery [10,11]. Ngb also reduces the toxicity of H 2 O 2 [5], paraquat [5] and β-amyloid [13] in vitro.…”

Section: Introductionmentioning

confidence: 99%

Neuroglobin protects against nitric oxide toxicity

Jin

Mao

Xie

et al. 2008

Neuroscience Letters

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Neuroglobin (Ngb) is a novel vertebrate globin expressed principally in neurons. Ngb expression is induced by hypoxia and ischemia, and Ngb protects neurons against these insults. The mechanism of Ngb's protective action is unknown, but its ability to bind NO suggests that NO scavenging might be involved. To test this hypothesis, we treated wild type and Ngb-transfected HN33 (mouse hippocampal neuron × N18TG2 neuroblastoma) cells with NO donors and compared their sensitivity to NO-induced cell death. Ngb overexpression shifted concentration-toxicity curves to the right, indicating reduced susceptibility to NO or is metabolites. The results suggest that the ability of Ngb to neutralize the neurotoxic effects of reactive nitrogen species may be an important contributor to its neuroprotective properties. KeywordsNeuroglobin; nitric oxide; hypoxia Neuroglobin (Ngb) is a monomeric globin that is distantly related to hemoglobin and myoglobin and is expressed predominantly in brain neurons [3]. Ngb expression is induced by neuronal hypoxia and cerebral ischemia [21] and Ngb, in turn, appears to modulate hypoxicischemic brain injury. Thus, enhancing Ngb expression reduces-and knocking down Ngb expression increases-hypoxic neuronal injury in vitro [21] and ischemic cerebral injury in vivo [22]. In addition, Ngb-overexpressing transgenic mice are resistant to cerebral infarction from occlusion of the middle cerebral artery [10,11]. Ngb also reduces the toxicity of H 2 O 2 [5], paraquat [5] and β-amyloid [13] in vitro. However, the mechanisms that underlie neuroprotection by Ngb are unknown.Ancestral globins served primarily as NO oxygenases, converting NO to nitrate, whereas their O 2 -transporting function evolved later [20]. This primordial oxygenase activity is still apparent in the capacity of hemoglobin [6] and myoglobin [4] to scavenge NO, and appears to have pathophysiological significance, since overexpression of inducible NO synthase (NOS) causes heart failure in myoglobin-knockout mice [7]. Because Ngb binds NO [23], its neuroprotective action may also relate to NO scavenging [1,8].Several lines of evidence point to a connection between Ngb and NO. In addition to the ability of Ngb to bind NO [23], some studies have shown parallelism between the distribution of Ngb and of neuronal NOS (nNOS) [15], and NOS expression is increased in several tissues of Ngboverexpressing transgenic mice [11]. Autooxidation of Ngb yields NgbO 2 , which is thought to react rapidly with NO to form a peroxynitrite (ONOO − )-bound intermediate that decays to * To whom correspondence should be addressed: dgreenberg@buckinstitute.org Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered ...

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A neuroglobin-overexpressing transgenic mouse

Cited by 29 publications

References 22 publications

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo

Neuroglobin protects against nitric oxide toxicity

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