Objective-The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST).Methods-Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry.Results-Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5 HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group.Conclusions-NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons. Keywords Spinal cord injury; Rubrospinal tract; NEP1-40Adult mammalian central nervous system (CNS) neurons do not spontaneously regenerate their axons. Contributors to this failure include the local environment of both the normal and injured adult CNS, which contains inhibitors that constitute a biochemical and physical barrier to regeneration. 1 Three molecules associated with myelin have been identified: NogoA, [2][3][4][5] Address correspondence to Yang Cao, Dept of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129. yc94@drexel.edu. NIH Public Access Author ManuscriptNeurorehabil Neural Repair. Author manuscript; available in PMC 2010 April 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript myelin-associated glycoprotein (MAG), 6,7 and oligodendrocyte-myelin glycoprotein (OMgp). 8,9 Nogo has 3 variants: NogoA, NogoB, and NogoC. NogoA is mainly expressed in the CNS, whereas the other 2 are more widely expressed outside the CNS. NogoA possesses a transmembrane loop region, Nogo66, which inhibits neurite outgrowth. 10,11 The Nogo-66 receptor, NgR1, 12 is a glycosylphosphatidylinositol-linked cell surface receptor that contains a leucine-rich repeat motif that also interacts with MAG [13][14][15] and OMgp. 15,16 All 3 myelin molecules bind to NgR1 in a complex with p75 neurotrophin receptor and a leucine-...