Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity.
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. Mutant mice lacking NgR or Nogo-AB recover complex motor function after stroke more completely than do control animals. After a stroke, greater numbers of axons emanating from the undamaged cortex cross the midline to innervate the contralateral red nucleus and the ipsilateral cervical spinal cord; this axonal plasticity is enhanced in ngr -/- or nogo-ab -/- mice. In rats with middle cerebral artery occlusion, both the recovery of motor skills and corticofugal axonal plasticity are promoted by intracerebroventricular administration of a function-blocking NgR fragment. Behavioral improvement occurs when therapy is initiated 1 week after arterial occlusion. Thus, delayed pharmacological blockade of the NgR promotes subacute stroke recovery by facilitating axonal plasticity.
Lee
Jung-Kil
JK
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Kim
Ji-Eun
JE
Sivula
Michael
M
Strittmatter
Stephen M
SM
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics*; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016896:Treatment Outcome
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; C495858:NgR(310) Ecto-Fc protein; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D011993:Recombinant Fusion Proteins; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C419790:Rtn4r protein, mouse; C486581:Rtn4r protein, rat