Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat
Free accessResearch articleFirst published online May, 2008
Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat
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 5HT 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.
Hunt D., Coffin RS, Anderson PNThe Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review. J Neurocytol. 2002;31:93-120.
2.
Savio T., Schwab MELesioned corticospinal tract axons regenerate in myelin-free rat spinal cord . Proc Natl Acad Sci U S A. 1990;87:4130-4133.
3.
Chen MS, Huber AB, van der Haar ME, et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature. 2000;403:434-439.
4.
Prinjha R., Moore SE, Vinson M., et al. Inhibitor of neurite outgrowth in humans. Nature . 2000;403:383-384.
5.
Oertle T., van der Haar ME, Bandtlow CE, et al. Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci. 2003;23:5393-5406.
6.
McKerracher L., David S., Jackson DL, et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron. 1994;13:805-811.
7.
Mukhopadhyay G., Doherty P., Walsh FS, et al. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron . 1994;13:757-767.
8.
Kottis V., Thibault P., Mikol D., et al. Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. J Neurochem. 2002;82:1566-1569.
9.
Wong ST, Henley JR, Kanning KC, et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci. 2002;5:1302-1308.
10.
GrandPré T., Nakamura F., Vartanian T., et al. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature. 2000;403:439-444.
Fournier AE, GrandPré T., Strittmatter SMIdentification of a receptor mediating Nogo-66 inhibition of axonal regeneration . Nature. 2001;409:341-346.
13.
Domeniconi M., Cao Z., Spencer T., et al. Myelin-associated glycoprotein interacts with the nog066 receptor to inhibit neurite outgrowth. Neuron . 2002;35:283-290.
14.
Liu BP, Fournier A., GrandPré T., et al. Myelin-associated glycoprotein as a functional ligand for the nogo-66 receptor. Science. 2002;297:1190-1193.
15.
Wang KC, Koprivica V., Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature. 2002 ;417:941-944.
16.
Wang KC, Kim JA, Sivasankaran R., et al. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature. 2002; 420:74-78.
17.
McGee AW , Strittmatter SMThe Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends Neurosci. 2003 ;26:193-198.
18.
Mi S.LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7:221-228.
19.
Park JB, Yiu G., Kaneko S., et al. A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors. Neuron. 2005;45:345-351. Erratum in: Neuron. 2005;45:815.
20.
Shao Z., Browning JL, Lee X., et al. TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron. 2005;45:353-359.
21.
Schnell L., Schwab MEAxonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature. 1990;343:269-272.
22.
Bregman BS, Kunkel-Bagden E., Schnell L., et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature. 1995;378:498-501.
23.
Brösamle C. , Huber AB, Fiedler M., et al. Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment. J Neurosci. 2000; 20:8061-8068.
24.
Li S., Strittmatter SMDelayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J Neurosci. 2003;23:4219-4227.
25.
Li S., Liu BP, Budel S., et al. Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci. 2004;24:10511-10520.
26.
Ji B., Li M., Budel S., et al. Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury. Eur J Neurosci . 2005;22:587-594.
27.
Liu Y., Kim D., Himes BT, et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J Neurosci. 1999;19:4370-4387.
28.
Xiao M., Klueber KM, Lu C., et al. Human adult olfactory neural progenitors rescue axotomized rodent rubrospinal neurons and promote functional recovery. Exp Neurol . 2005;194:12-30.
29.
Yaksh TL, Rudy TAChronic catheterization of the spinal sub-arachnoid space. Physiol Behav. 1976;17:1031-1036.
30.
Jones LL, Tuszynski MHChronic intrathecal infusions after spinal cord injury cause scarring and compression. Microscopy Res Technique. 2001 ;54:317-324.
31.
Hayashi Y., Shumsky JS, Connors T., et al. Immunosuppression with either cyclosporine A or FK506 supports survival of transplanted fibroblasts and promotes growth of host axons into the transplant after spinal cord injury. J Neurotrauma. 2005;22:1267-1281.
32.
Nothias J-M. , Mitsui T., Shumsky JS, et al. Combined effects of neurotrophin secreting transplants, exercise, and serotonergic drug challenge improve function in spinal rats. Neurorehabil Neural Repair. 2005 ;19:296-312.
33.
Basso DM, Beattie MS, Bresnahan JCA sensitive and reliable loco-motor rating scale for open field testing in rats. J Neurotrauma. 1995;12:1-21.
34.
Shumsky JS, Tobias CA, Tumolo M., et al. Delayed transplantation of fibroblasts genetically modified to secrete BDNF and NT-3 into a spinal cord injury site is associated with limited recovery of function. Exp Neurol. 2003;184:114-130.
35.
Hamers FP, Lankhorst AJ, van Laar TJ, et al. Automated quantitative gait analysis during overground locomotion in the rat: its application to spinal cord contusion and transection injuries . J Neurotrauma. 2001;18:187-201.
36.
Vrinten DH, Hamers FPT.`CatWalk' automated quantitative gait analysis as a novel method to assess mechanical allodynia in the rat; a comparison with von Frey testing. Pain. 2003;102:203-209.
37.
Betts RP, Duckworth T.A device for measuring plantar pressures under the sole of the foot. Eng Med. 1978;7:223-228.
38.
Clarke KAA technique for the study of spatiotemporal aspects of paw contact patterns, applied to rats treated with a TRH analogue. Beh Res Methods Instr Comp. 1992;24:407-411.
39.
Cheng H., Almstrom S., Gimenez-Llort L., et al. Gait analysis of adult paraplegic rats after spinal cord repair . Exp Neurol. 1997; 148:544-557.
40.
Eliav E., Herzberg U., Ruda MA, et al. Neuropathic pain from an experimental neuritis of the rat sciatic nerve. Pain. 1999;83:169-182.
41.
Hargreaves K., Dubner R., Brown F., et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77-88.
42.
Yezierski RP , Liu S., Ruenes GL, et al. Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain. 1998;75:141-155.
43.
Houle JD, Jin Y.Chronically injured supraspinal neurons exhibit only modest axonal dieback in response to a cervical hemisection lesion. Exp Neurol. 2001;169:208-217.
44.
Liebscher T. , Schnell L., Schnell D., et al. Nogo-A antibody improves regeneration and locomotion of spinal cord-injured rats. Ann Neurol. 2005;58:706-719.
45.
Freund P., Schmidlin E., Wannier T., et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat Med . 2006;12(7): 790-792.
46.
Ruitenberg MJ, Plant GW, Hamers FPT , et al. Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. J Neurosci. 2003;23:7045-7058.
47.
Steeves JD, Jordan LMLocalization of a descending pathway in the spinal cord which is necessary for controlled treadmill locomotion. Neurosci Lett. 1980;20:283-288.
48.
Bem T., Gorska T., Majczynski H., et al. Different patterns of fore-hindlimb coordination during overground locomotion in cats with ventral and lateral spinal lesions. Exp Brain Res. 1995; 104:70-80.
49.
Christensen MD , Everhart AW, Pickelman JT, et al. Mechanical and thermal allodynia in chronic central pain following spinal cord injury. Pain. 1996;68:97-107.
50.
Christensen MD , Hulsebosch CEChronic central pain after spinal cord injury . J Neurotrauma. 1997;14:517-537.
51.
Hains BC, Chastain KM, Everhart AW, McAdoo DJ, et al. Transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb allodynia in a rodent model of chronic central pain after spinal cord hemisection injury. Exp Neurol. 2000; 164:426-437.
52.
Wang X., Baughman KW, Basso DM, et al. Delayed Nogo receptor therapy improves recovery from spinal cord contusion. Ann Neurol. 2006;60(5):540-549.
53.
Freund P., Wannier T., Schmidlin E., Bloch J., et al. Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey. J Comp Neurol. 2007;502(4):644-659.
54.
Romero MI, Rangappa N., Garry MG, et al. Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J Neurosci. 2001;21:8408-8416.
55.
Tobias CA, Shumsky JS, Shibata M., et al. Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration . Exp Neurol. 2003;184:97-113.
56.
Ramer LM, Au E., Richter MW, et al. Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol. 2004;473:1-15.
57.
Hagg T., Baker KA, Emsley JG, et al. Prolonged local neurotrophin-3 infusion reduces ipsilateral collateral sprouting of spared corticospinal axons in adult rats. Neuroscience. 2005;130:875-887.
58.
ScottAL,Borisoff JF, Ramer MSDeafferentation and neurotrophin-mediated intraspinal sprouting: a central role for the p75 neurotrophin receptor. Eur J Neurosci. 2005;21:81-92.
59.
Grider MH, Mamounas LA, Le W., et al. In situ expression of brain-derived neurotrophic factor or neurotrophin-3 promotes sprouting of cortical serotonergic axons following a neurotoxic lesion . J Neurosci Res. 2005;82:404-412.
60.
Schwab MENogo and axon regeneration. Curr Opin Neurobiol. 2004;14:118-124.
Schnell L., Liebscher T., Weinmann O., et al. Increased regeneration and functional recovery in rats treated with antibodies to Nogo-A and in Nogo-A knockout mice. Program no. 43.11. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.
63.
Buchli AD, Schwab MEInhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system. Ann Med. 2005;37(8):556-567.
64.
Liu BP, Cafferty WB, Budel SO, et al. Extracellular regulators of axonal growth in the adult central nervous system. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1593-1610.
65.
Simonen M., Pedersen V., Weinmann O., et al. Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury . Neuron. 2003;38:201-211.
66.
Kim JE, Li S., GrandPré T., et al. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron. 2003;38:187-199.
67.
Zheng B., Ho C., Li S., et al. Lack of enhanced spinal regeneration in Nogo-deficient mice . Neuron. 2003;38:213-224.
68.
Kim JE, Liu BP, Park JH, et al. Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury. Neuron . 2004;44:439-451.
69.
Zheng B., Atwal J., Ho C., et al. Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc Natl Acad Sci U S A. 2005;102:1205-1210.
70.
Dimou L., Schnell L., Montani L., et al. Nogo-A-deficient mice reveal strain-dependent differences in axonal regeneration. J Neurosci. 2006;26:5591-5603.
71.
Cafferty WB , Kim JE, Lee JK, et al. Response to correspondence: Kim et al., "Axon regeneration in young adult mice lacking Nogo-A/B."Neuron38, 187-199. Neuron. 2007;54:195-199.
72.
Hasegawa Y. , Fujitani M., Hata K., et al. Promotion of axon regeneration by myelin-associated glycoprotein and Nogo through divergent signals downstream of Gi/G. J Neurosci. 2004;24:6826-6832.
73.
Bareyre FM, Haudenschild B., Schwab MELong-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J Neurosci. 2002;22:7097-7110.
