title: 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.
authors.affiliation: Nervous Systeme Research, Novartis Parma AG, Basel, Switzerland. christoph.wiessner@pharma.novartis.com
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiessner
authors.forename: Florence M
authors.initials: FM
authors.lastname: Bareyre
authors.forename: Peter R
authors.initials: PR
authors.lastname: Allegrini
authors.forename: Anis K
authors.initials: AK
authors.lastname: Mir
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.forename: Mauro
authors.initials: M
authors.lastname: Zurini
authors.forename: Lisa
authors.initials: L
authors.lastname: Schnell
authors.forename: Thomas
authors.initials: T
authors.lastname: Oertle
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001157:Arterial Occlusive Diseases / Q000150:complications; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D002536:Cerebral Arteries; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000523:psychology; D004334:Drug Administration Schedule; D006973:Hypertension / Q000150:complications*; D007276:Injections, Intraventricular; D008297:Male; D009185:Myelin Proteins / Q000276:immunology*; D009473:Neuronal Plasticity / Q000187:drug effects; D000070798:Nogo Proteins; D011712:Pyramidal Tracts / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology / Q000503:physiopathology* / Q000523:psychology*; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat