Delayed Intraventricular Nogo Receptor Antagonist Promotes Recovery from Stroke by Enhancing Axonal Plasticity

Kim, Tae Won; Lee, Jung Kil; Joo, Sung Pil; Kim, Tae Sun; Kim, Jae Hyoo; Kim, Soo Han

Abstract

OBJECTIVE
After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo/NogoReceptor(NgR) pathway might enhance axonal sprouting and thereby recovery after focal brain infarction.
METHODS
Adult male Sprague Dawley rats weighing 250~350g were used. Left middle cerebral artery occlusion(MCAO) was induced with a intraluminal filament. An osmotic minipump (Alzet 2ML4, Alza Scientific Products, Palo Alto, CA) for the infusion of NgR-Ecto(310)-Fc to block Nogo/NgR pathway was implanted 1 week after cerebral ischemia. Prior to induction of ischemia, all animals received training in the staircase and rotarod test. Two weeks after biotin dextran amine injection, animals were perfused transcardially with PBS, followed by 4% paraformadehyde/PBS solution. Brain and cervical spinal cord were dissected. Eight coronal sections spaced at 1 mm intervals throughout the forebrain of each animal were stained with cresyl violet acetate for determination of infarction size. Images of each section were digitized and the infarct area per section was measured with image analysis software.
RESULTS
Histological examination at 11 weeks post-MCAO demonstrates reproducible stroke lesions and no significant difference in the size of the stroke between the NgR(310)Ecto-Fc protein treated group and the control group. Behavioral recovery is significantly better and more rapid in the NgR-Ecto(310)-Fc treated group. Blockade of NgR enhances axonal sprouting from the uninjured cerebral cortex and improves the return of motor task performance.
CONCLUSION
Pharmacological interruption of NgR allows a greater degree of axonal plasticity in response to stroke and this is associated with improved functional recovery of complicated motor tasks.