Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways.
Several pharmacological approaches to promote neural repair and recovery after CNS injury have been identified. Blockade of either astrocyte-derived chondroitin sulfate proteoglycans (CSPGs) or oligodendrocyte-derived NogoReceptor (NgR1) ligands reduces extrinsic inhibition of axonal growth, though combined blockade of these distinct pathways has not been tested. The intrinsic growth potential of adult mammalian neurons can be promoted by several pathways, including pre-conditioning injury for dorsal root ganglion (DRG) neurons and macrophage activation for retinal ganglion cells (RGCs). Singly, pharmacological interventions have restricted efficacy without foreign cells, mechanical scaffolds or viral gene therapy. Here, we examined combinations of pharmacological approaches and assessed the degree of axonal regeneration. After mouse optic nerve crush injury, NgR1-/- neurons regenerate RGC axons as extensively as do zymosan-injected, macrophage-activated WT mice. Synergistic enhancement of regeneration is achieved by combining these interventions in zymosan-injected NgR1-/- mice. In rats with a spinal dorsal column crush injury, a preconditioning peripheral sciatic nerve axotomy, or NgR1(310)ecto-Fc decoy protein treatment or ChondroitinaseABC (ChABC) treatment independently support similar degrees of regeneration by ascending primary afferent fibers into the vicinity of the injury site. Treatment with two of these three interventions does not significantly enhance the degree of axonal regeneration. In contrast, triple therapy combining NgR1 decoy, ChABC and preconditioning, allows axons to regenerate millimeters past the spinal cord injury site. The benefit of a pre-conditioning injury is most robust, but a peripheral nerve injury coincident with, or 3 days after, spinal cord injury also synergizes with NgR1 decoy and ChABC. Thus, maximal axonal regeneration and neural repair are achieved by combining independently effective pharmacological approaches.
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA.
Xingxing
X
Wang
Omar
O
Hasan
Alexander
A
Arzeno
Larry I
LI
Benowitz
William B J
WB
Cafferty
Stephen M
SM
Strittmatter
D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D019765:Chondroitin ABC Lyase / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000627:therapeutic use; D008262:Macrophage Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000627:therapeutic use; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology*; D000070816:Nogo Receptor 1; D020221:Optic Nerve Injuries / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000235:genetics / Q000503:physiopathology* / Q000534:rehabilitation*; D015054:Zymosan / Q000008:administration & dosage
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; D015054:Zymosan; D019765:Chondroitin ABC Lyase