Anti-Nogo-A antibody infusion improves behavioral outcome and corticospinal plasticity after experimental stroke

Abstract

Stroke is associated with high incidence of mortality and functional disabilities. There is no specific treatment to improve functional recovery after the acute stage of stroke except extensive rehabilitation which results in limited improvement. The main reason for the limited recovery is that regeneration and plastic hardware changes in the adult central nervous system are extremely restricted after injury. One of the most potent neurite growth inhibitory molecules in myelin is Nogo-A, a membrane protein comprising multiple inhibitory domains. There is a growing body of literature documenting the effects of Nogo-A neutralization on neuronal regeneration and plasticity and recovery of functional deficits after CNS lesions in adult rats. Monoclonal antibodies neutralizing the inhibitory effect of Nogo-A have been evaluated in experimental stroke. Intraventricular infusion of Nogo-A antibody resulted consistently in improvements in recovery of skilled forelimb reaching ability when treatment was initiated 24 hours after focal cerebral ischemia induced by photothrombosis or permanent middle cerebral artery occlusion (MCAO) in normotensive or spontaneously hypertensive adult rats, respectively. Nogo-A antibody treatment was also effective in 1.5 year aged rats with 7 days delayed treatment following MCAO. Improvement in function in these studies was associated with increased corticospinal mid line crossing fibers to cervical spinal cord and the thalamus from the intact hemisphere. Moreover, using functional magnetic resonance imaging a significant increase in activation was found in the thalamus during stimulation of the previously impaired forepaw in the animals that had recovered with anti-Nogo-A therapy. These results suggest that neuroanatomical changes in corticospinal plasticity and subcortical regions, ie the thalamus, may contribute to the functional recovery after Nogo-A antibody treatment. The mechanism of action of Nogo-A antibodies likely involves steric hindrance of the inhibitory domains of Nogo-A and down regulation of the protein by internalization of the Nogo-A-antibody complex. These results suggest that treatment with Nogo-A antibodies bears potential as a new rehabilitative treatment for ischemic stroke and the window of opportunity for treatment is much longer as compared to neuroprotective treatment approaches.