Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

Sun, Yunfu; Jin, Kunlin; Clark, K. Reed; Peel, Alyson; Mao, XiaoOu; Chang, Qing; Simon, Roger P.; Greenberg, David A.

doi:10.1038/sj.gt.3301868

Cited by 37 publications

(37 citation statements)

References 35 publications

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“…The titer was determined with the AAV2 Titration ELISA Kit (PROGEN), finally yielding 2 ϫ 10 14 viral particles/ml. Injections (3 l/site) of viral particles (2 ϫ 10 14 /ml) were made at the following: A) ϩ1.5 mm posterior to bregma, Ϫ3.2 mm lateral to midline, ϩ5.5 mm ventral to the skull surface; B) ϩ1.0 mm, Ϫ3.4 mm, ϩ5.5 mm; C) ϩ0.5 mm, Ϫ3.8 mm, ϩ4.3 mm at an injection rate of 1 l/min according to published protocols (24,25). Exogenous GAPDH expression in the striatum (an ischemic core region) and the cortex (an ischemic penumbra region) was confirmed 1 month after injection.…”

Section: Methodsmentioning

confidence: 99%

Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

Nakajima

Kubo

Ihara

et al. 2015

Journal of Biological Chemistry

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Background:The link between poly(ADP-ribose) polymerase-1 (PARP-1) and nuclear-translocated glyceradehyde-3-phosphate dehydrogenase (GAPDH) in neurons under oxidative/nitrosative stress remains unknown. Results: The N terminus of nuclear GAPDH binds with PARP-1, and this complex promotes PARP-1 overactivation both in vitro and in vivo. Conclusion: Nuclear GAPDH is a key PARP-1 regulator. Significance: GAPDH/PARP-1 signaling underlies oxidative/nitrosative stress-induced brain damage such as stroke.

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Section: Methodsmentioning

confidence: 99%

Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

Nakajima

Kubo

Ihara

et al. 2015

Journal of Biological Chemistry

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“…Brains were perfused with 0.9% saline and then 4% paraformaldehyde in PBS (pH 7.4) and embedded in paraffin. Immunocytochemistry was performed on 6-m sections as described (19) by using rabbit polyclonal anti-mouse Ngb Focal Cerebral Ischemia. Ischemia was induced by using the suture occlusion technique (19).…”

Section: Methodsmentioning

confidence: 99%

“…Immunocytochemistry was performed on 6-m sections as described (19) by using rabbit polyclonal anti-mouse Ngb Focal Cerebral Ischemia. Ischemia was induced by using the suture occlusion technique (19). Rats were anesthetized as described above and a 19-mm, 3-0 monofilament nylon suture was inserted via the left external and internal carotid arteries to occlude the MCA at its origin for 90 min, followed by reperfusion.…”

Section: Methodsmentioning

confidence: 99%

Neuroglobin protects the brain from experimental stroke in vivo

Sun

Jin²,

Peel

et al. 2003

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

340

344

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Neuroglobin (Ngb) is an O2-binding protein localized to cerebral neurons of vertebrates, including humans. Its physiological role is unknown but, like hemoglobin, myoglobin, and cytoglobin͞histo-globin, it may transport O 2, detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported recently that hypoxia stimulates transcriptional activation of Ngb in cultured cortical neurons and that antisense inhibition of Ngb expression increases hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to hypoxia. These findings are consistent with a role for Ngb in promoting neuronal survival after hypoxic insults in vitro. Here we report that in rats, intracerebroventricular administration of an Ngb antisense, but not sense, oligodeoxynucleotide increases infarct volume and worsens functional neurological outcome, whereas intracerebral administration of a Ngb-expressing adenoassociated virus vector reduces infarct size and improves functional outcome, after focal cerebral ischemia induced by occlusion of the middle cerebral artery. We conclude that Ngb acts as an endogenous neuroprotective factor in focal cerebral ischemia and may therefore represent a target for the development of new treatments for stroke.T he ability to sense and respond to hypoxia is a universal attribute of eukaryotic cells, but the role of this ability in protecting cells from ischemic insults and its potential for therapeutic application are unclear. One prominent feature of cellular adaptation to hypoxia or ischemia consists of the increased expression of hypoxia-inducible proteins (1), including proteins with the capacity to protect the brain from ischemic insults (2, 3). Examples include hypoxia-inducible factor-1 (4), erythropoietin (5), vascular endothelial growth factor (6), heme oxygenase-1 (7), and adrenomedullin (8). These proteins are likely to exert their neuroprotective effects through diverse mechanisms but their hypoxia-responsiveness depends ultimately on O 2 -binding proteins that can sense hypoxia and trigger appropriate cellular adaptations (9, 10).The globins are a family of heme proteins that can bind, transport, scavenge, detoxify, and sense gases like O 2 and NO (11). Four vertebrate globins have been identified. Hemoglobin, which differs from other vertebrate globins in occurring as a tetramer, is localized to erythrocytes and transports O 2 between the lungs and other tissues. Myoglobin (Mgb) is monomeric and is localized to the cytoplasm of skeletal and cardiac myocytes. Cytoglobin or histoglobin (12, 13) is expressed widely in both neural and nonneural vertebrate tissues, but its functions are unknown. The recent discovery of neuroglobin (Ngb; ref. 14), which is expressed primarily in cerebral neurons (15), is induced by neuronal hypoxia and cerebral ischemia (16) and protects neurons from hypoxia in vitro (16), suggests that this protein may have a role in sensing or responding to neuronal hypoxia, which could have implications for the pathophysiology and treatment of stroke.To test the hy...

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“…AAV-Bcl-w [rAAV/cytomegalovirus (CMV)/Bcl-w] was produced and titrated as described previously (Sun et al, 2003) and was kindly provided by Dr. David A. Greenberg (Buck Institute for Age Research, Novato, CA). As a negative control, recombinant AAV vector encoding green fluorescent protein (GFP), AAV-GFP (rAAV/CMV/hrGFP), was produced using three-plasmid procedure (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

β-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w

Yao

Nguyen²,

Pike³

2005

J. Neurosci.

199

139

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␤-Amyloid protein (A␤) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). A␤ directly induces neuronal apoptosis, suggesting an important role of A␤ neurotoxicity in AD neurodegeneration. However, the mechanism(s) of A␤-induced neuronal apoptosis remain incompletely defined. In this study, we report that A␤-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that A␤ significantly reduces expression of antiapoptotic Bcl-w and Bcl-x L , mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3. A␤-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because A␤-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, A␤-induced neuronal apoptosis is characterized by mitochondrial release of second mitochondrion-derived activator of caspase (Smac), an important precursor event to cell death. We observed that Smac release was potentiated by suppression of Bcl-w and reduced by overexpression of Bcl-w. Next, we investigated the upstream mediator of A␤-induced Bcl-w downregulation and Smac release. We observed that A␤ rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of A␤ apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of A␤-induced neuronal apoptosis sequentially involves JNK activation, Bcl-w downregulation, and release of mitochondrial Smac, followed by cell death. Complete elucidation of the mechanism of A␤-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.

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Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

Cited by 37 publications

References 35 publications

Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

Neuroglobin protects the brain from experimental stroke in vivo

β-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w

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