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.

Nogo Receptor Antagonism Promotes Stroke Recovery by Enhancing Axonal Plasticity

“…The NgR fusion protein binding to myelin inhibitors does not incite an experimental allergic encephalitis-like loss of function, and histologic examination of NgR(310)Ecto-Fctreated brain reveals no increased inflammation and no white matter loss (data not shown). The behavioral and anatomical results obtained here with Nogo-NgR perturbation are similar to, but of greater magnitude than, those observed with anti-Nogo-A antibodies (Papadopoulos et al, 2002;Wiessner et al, 2003). These antibodies target an independent activity of the amino-Nogo domain of Nogo-A, but they may impinge allosterically on Nogo-66 signaling (Fournier et al, 2001;Wiessner et al, 2003).…”

“…There have been previous reports of some benefit from antiNogo antibody treatment of rats with middle cerebral artery occlusion (MCAO) (Papadopoulos et al, 2002;Wiessner et al, 2003). No genetic analysis of the Nogo-NgR system has been made in stroke.…”

Functional and Anatomical Reorganization of the Sensory-Motor Cortex after Incomplete Spinal Cord Injury in Adult Rats

“…Unilateral cortical injury or pyramidotomy also deprives the spinal cord unilaterally of direct cortical input. In adult rodents, sprouting of the CST from the intact side across the midline can be induced by suppression of the neurite growth inhibitor Nogo pathway (Thallmair et al, 1998;Wiessner et al, 2003), by local neurotrophic factors (Zhou and Shine, 2003), or by electrical stimulation of the injury-spared CST (Brus-Ramer et al, 2007). The rearranged CST is crucial for the observed recovery of skilled movements (Kartje-Tillotson et al, 1987).…”

Myelin—Associated Inhibitory Signaling and Strategies to Overcome Inhibition

“…The enhanced neuronal plasticity in the absence of inhibitors is thought to be the underlying mechanism for stroke recovery in these mice. Treatment with monoclonal antibody IN-1 that neutralizes Nogo-A also revealed similar improvements in functional recovery (Papadopoulos et al, 2002;Wiessner et al, 2003;Seymour et al, 2005). Nogo-A neutralization resulted in up to 80% of forelimb functional recovery within 8 to 9 weeks after stroke.…”