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Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats
Abstract
Nogo-A is a myelin-associated neurite outgrowth inhibitory protein limiting recovery and plasticity after central nervous system injury. In this study, a purified monoclonal anti-Nogo-A antibody (7B12) was evaluated in two rat stroke models with a time-to-treatment of 24 hours after injury. After photothrombotic cortical injury (PCI) and intraventricular infusion of a control mouse immunoglobulin G for 2 weeks, long-term contralateral forepaw function was reduced to about 55% of prelesion performance until the latest time point investigated (9 weeks). Forepaw function was significantly better in the 7B12-treated group 6 to 9 weeks after PCI, and reached about 70% of prelesion levels. Cortical infarcts were also produced in spontaneously hypertensive rats (SHR) by permanent middle cerebral artery occlusion (MCAO). In the control group, forepaw function remained between 40% and 50% of prelesion levels 4 to 12 weeks after MCAO. In contrast, 7B12-treated groups showed significant improvement between 4 and 7 weeks after MCAO from around 40% of prelesion levels at week 4 to about 60% to 70% at 7 to 12 weeks after MCAO. Treatment in both models was efficacious without influencing infarct volume or brain atrophy. Neuroanatomically in the spinal cord, a significant increase of midline crossing corticospinal fibers originating in the unlesioned sensorimotor cortex was found in 7B12-treated groups, reaching 2.3 +/- 1.5% after PCI (control group: 1.1 +/- 0.5%) and 4.5 +/- 2.2% after MCAO in SHR rats (control group: 1.8 +/- 0.8%). Behavioral outcome and the presence of midline crossing fibers in the cervical spinal cord correlated significantly, suggesting a possible contribution of the crossing fibers for forepaw function after PCI and MCAO. The results suggest that specific anti-Nogo-A antibodies bear potential as a new rehabilitative treatment approach for ischemic stroke with a prolonged time-to-treatment window.
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“By sharp contrast with neuroprotection, the efficacy of neuro restorative therapies does not depend on the successful reperfusion of ischaemic brain tissue.11,12,15,17,21”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“By contrast with neuroprotection, which requires an acute intervention, treatments promoting neurological recovery by remodelling of brain tissue can be instituted during the stroke recovery phase.10–15”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“Instead, homologous fibres originating from the contralesional motor cortex grow out across the midline to reach denervated neurons in target structures of the lesioned pyramidal tract (figure 1).10–12,15,17,19,24”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“This lesion-remote plasticity involves the midline crossing of fibres from the contralesional to the ipsilesional hemisphere at the level of the red nucleus10,17,19,24 and the re-entry of fibres into the contralesional hemicord at the level of the cervical spinal cord (figure 1).11,12,15”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“Importantly, axonal growth responses are relatively uniform for different types of treatment: contralesional sprouting was evident after delivery of growth factors,19,24 neutralising antibodies directed against the axonal growth inhibitor NogoA,11,17 neurostimulants (eg, amphetamine), 29 and cell-based therapeutics, namely bone-marrow-derived stromal cells12,30 or neural pre cursor cells.15”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“Contralesional plasticity as a basis for neurological recovery occurs in several species (eg, in rats,11,15,17 mice,12,19,24 and macaques32).”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“In focal cerebral ischaemia, spontaneously hypertensive rats had preserved contralesional pyramidal tract sprouting in response to treatment with neutralising antibodies directed against NogoA, which was consistent with functional neurological improvements that were very similar to those in non-hypertensive rats.11”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
In the citing paper
“This preserved response to NogoA antibodies suggests that the growth factor abnormalities might not be clinically relevant.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [11]
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Metadata
- Authors
- Wiessner, C., Bareyre, F. M., Allegrini, P. R., Mir, A. K., Frentzel, S., Zurini, M., Schnell, L., Oertle, T., & Schwab, M. E.
- Affiliations
- Novartis (Switzerland) (CH)
- University of Zurich (CH)
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2003-02
- Volume
- 23
- Issue
- 2
- Pages
- 154-165
- ISSN
- 0271-678X (ISSN-L)
- OpenAlex
- W2051058230
- Cited by
- 209
- References
- 61
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 22 · 2013: 8 · 2012: 14
- FWCI
- 14.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- Nogo-A, anti-Nogo-A antibody, ischemic stroke, corticospinal plasticity, middle cerebral artery occlusion, spontaneously hypertensive rats, stroke rehabilitation, spinal cord
- MeSH terms
- Nogo Proteins, Animals, Antibodies, Monoclonal, Arterial Occlusive Diseases, Behavior, Animal, Brain, Cerebral Arteries, Cerebral Infarction, Drug Administration Schedule, Hypertension, Injections, Intraventricular, Male, Myelin Proteins, Neuronal Plasticity, Pyramidal Tracts, Rats, Inbred F344, Rats, Inbred SHR, Tissue Distribution, Stroke, Rats
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