Nogo Receptor Antagonism Promotes Stroke Recovery by Enhancing Axonal Plasticity

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.

Neuronal PirB Upregulated in Cerebral Ischemia Acts as an Attractive Theranostic Target for Ischemic Stroke

“…The greater recovery in PirB versus H2‐Db/H2‐Kb knockout mice fits well with a model in PirB that binds multiple ligands in the central nervous system 14. Furthermore, mutant mice lacking Nogo‐AB recover complex motor function poststroke more completely than do control animals 40. In our study, sPirB protein was used as a therapeutic reagent to improve cerebral ischemic stroke model recovery by blocking PirB binding to endogenous ligands.…”

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…Stroke triggers new connections to form in motor, somatosensory, and premotor cortex adjacent to the stroke site, and in projections from cortex contralateral to the stroke site into distant connections in the striatum, midbrain, and spinal cord 11, 12, 13, 27, 28, 29, 30, 31, 32. In both the cortex contralateral to the stroke, and ipsilateral or peri‐infarct cortex, animal models indicate that axonal sprouting establishes new patterns of connections that are causally linked to recovery.…”

“…Human studies image large white matter tracts and, through the diffusion of water, their myelination state and their directional organization 35, 37. Rodent studies image truly small axonal collaterals and fine synaptic terminations within the cervical spinal cord 27, 28, 29, 30, 31. One set of studies is looking at the cross‐country electrical power transmission lines and the other is looking at the electrical wiring of the end‐user's house.…”

“…Axonal connections are confined by the expression of glial growth inhibitory molecules, such as NogoA, EphrinA5, and chondroitin sulfate proteoglycans 11, 12, 27, 28, 29, 30, 31, 32, 33. Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13.…”

“…This axonal sprouting response is into the portion of the cervical spinal cord that lost its corticospinal projection from the stroke site 12, 27. Blocking the myelin growth inhibitory protein NogoA or stimulating axonal sprouting with inosine enhances this axonal sprouting response 27, 28, 29, 30, 31. Stimulating behavioral activity after stroke, such as with an enriched environment or repetitive forelimb tasks, also stimulates axonal sprouting from the cortex contralateral to the stroke into this denervated spinal cord 28, 31, 32.…”