Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush.
A major impediment for regeneration of axons within the CNS is the presence of multiple inhibitory factors associated with myelin. Three of these factors bind to the Nogo receptor, NgR, which is expressed on axons. Administration of exogenous blockers of NgR or NgR ligands promotes the regeneration of descending axonal projections after spinal cord hemisection. A more detailed analysis of CNS regeneration can be made by examining the growth of specific classes of sensory axons into the spinal cord after dorsal root crush injury. In this study, we assessed whether administration of a soluble peptide fragment of the NgR (sNgR) that binds to and blocks all three NgR ligands can promote regeneration after brachial dorsal root crush in adult rats. Intraventricular infusion of sNgR for 1 month results in extensive regrowth of myelinated sensory axons into the white and gray matter of the dorsal spinal cord, but unmyelinated sensory afferents do not regenerate. In concert with the anatomical growth of sensory axons into the cord, there is a gradual restoration of synaptic function in the denervated region, as revealed by extracellular microelectrode recordings from the spinal gray matter in response to stimulation of peripheral nerves. These positive synaptic responses are correlated with substantial improvements in use of the forelimb, as assessed by paw preference, paw withdrawal to tactile stimuli and the ability to grasp. These results suggest that sNgR may be a potential therapy for restoring sensory function after injuries to sensory roots.
Harvey
Pamela A
PA
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Lee
Daniel H S
DH
Qian
Fang
F
Weinreb
Paul H
PH
Frank
Eric
E
D000818:Animals; D001369:Axons / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005552:Forelimb / Q000502:physiology; D058851:GPI-Linked Proteins; D006801:Humans; D009043:Motor Activity; D009185:Myelin Proteins / Q000378:metabolism*; D009409:Nerve Crush; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology*; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D020127:Recovery of Function; D011984:Sensory Receptor Cells / Q000502:physiology*; D013116:Spinal Cord / Q000503:physiopathology; D013126:Spinal Nerve Roots / Q000293:injuries*
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C486581:Rtn4r protein, rat; D015740:Calcitonin Gene-Related Peptide