Role of Nogo-A in neuronal survival in the reperfused ischemic brain
Open accessAbstract
Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of stroke. Nogo-A's role in the reperfused brain tissue was still unknown. By using Nogo-A −/− mice and mice in which Nogo-A was blocked with a neutralizing antibody (11C7) that was infused into the lateral ventricle or striatum, we show that Nogo-A inhibition goes along with decreased neuronal survival and more protracted neurologic recovery, when deactivation is constitutive or induced 24 h before, but not after focal cerebral ischemia. We show that in the presence of Nogo-A, RhoA is activated and Rac1 and RhoB are deactivated, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low. Nogo-A blockade leads to RhoA deactivation, thus overactivating Rac1 and RhoB, the former of which activates p38/MAPK and SAPK/JNK1/2 via direct interaction. RhoA and its effector Rho-associated coiled-coil protein kinase2 deactivation in turn stimulates PTEN, thus inhibiting Akt and ERK1/2, and initiating p53-dependent cell death. Our data suggest a novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance. Clinical trials should be aware of injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase.
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No effect on neuronal survival was reported when anti-NogoA antibodies were delivered after focal cerebral ischaemia.
“Importantly, no effect on neuronal survival was reported when anti-NogoA antibodies were delivered after focal cerebral ischaemia.93”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [93]
A recent study of NogoA deactivation after transient focal cerebral ischaemia in mice suggested that specific neurorestorative treatments can have unfavourable effects when given at an inappropriate timepoint.
“The possibility of unfavourable effects of specific neurorestorative treatments when given at an inappropriate timepoint was suggested in a recent study of the effects of NogoA deactivation after transient focal cerebral ischaemia in mice.93”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [93]
NogoA deactivation by genetic knockout or intracerebral ventricular delivery of neutralising antibodies decreased neuronal survival and delayed neuronal recovery when constitutive or initiated 24 h before stroke.
“NogoA deactivation initiated by genetic knockout or by intracerebral ventricular delivery of neutralising antibodies decreased neuronal survival and delayed neuronal recovery when the deactivation was constitutive or initiated 24 h before the stroke.93”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [93]
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- Authors
- Kilic, E., ElAli, A., Kilic, Ü., Guo, Z., Ugur, M., Uslu, U., Bassetti, C. L., Schwab, M. E., & Hermann, D. M.
- Affiliations
- Department of Neurology, University Hospital Essen, Essen, Germany
- University Hospital Zurich (CH)
- Departement of Neurology, University Hospital Zurich, Zurich, Switzerland
- Yeditepe University (TR)
- Departments of Physiology, Histology and Embryology, Yeditepe University, Istanbul, Turkey
- University of Zurich (CH)
- Corresponding author
- Hermann, Dirk M
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2010-01-20
- Volume
- 30
- Issue
- 5
- Pages
- 969-984
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC2949191
- OpenAlex
- W1980155382
- Cited by
- 79
- References
- 49
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 8 · 2018: 3 · 2017: 6 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 12 · 2012: 5
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (112056)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Nogo-A, neuronal survival, focal cerebral ischemia, ischemia-reperfusion injury, stroke, RhoA, Rac1, RhoB, p38 MAPK, SAPK/JNK, PTEN, Akt, ERK1/2, p53-dependent cell death, neutralizing antibodies, neurological recovery
- MeSH terms
- Nogo Proteins, Animals, Antibodies, Behavior, Animal, Brain, Cell Survival, Cerebrovascular Circulation, Enzyme Activation, Mice, Inbred C57BL, Myelin Proteins, Neurons, Signal Transduction, Reperfusion, Laser-Doppler Flowmetry, Mice, Knockout, rhoA GTP-Binding Protein, rhoB GTP-Binding Protein, rac1 GTP-Binding Protein, Hypoxia-Ischemia, Brain, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, rho-Associated Kinases
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