Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity

J Neurosci. 2004 Jul 7;24(27):6209-17. doi: 10.1523/JNEUROSCI.1643-04.2004.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / metabolism*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Disease Models, Animal
  • GPI-Linked Proteins
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / therapy
  • Male
  • Mice
  • Mice, Knockout
  • Myelin Proteins / genetics*
  • Myelin Proteins / metabolism
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Nogo Proteins
  • Nogo Receptor 1
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Receptors, Peptide / antagonists & inhibitors*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology*
  • Recovery of Function / drug effects
  • Recovery of Function / genetics*
  • Stroke / genetics
  • Stroke / metabolism
  • Stroke / therapy*
  • Treatment Outcome

Substances

  • GPI-Linked Proteins
  • Myelin Proteins
  • NgR(310) Ecto-Fc protein
  • Nogo Proteins
  • Nogo Receptor 1
  • Receptors, Cell Surface
  • Receptors, Peptide
  • Recombinant Fusion Proteins
  • Rtn4 protein, mouse
  • Rtn4 protein, rat
  • Rtn4r protein, mouse
  • Rtn4r protein, rat