Nogo-66 Receptor Antagonist Peptide (NEP1-40) Administration Promotes Functional Recovery and Axonal Growth After Lateral Funiculus Injury in the Adult Rat

Abstract

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-...

Effects of Nogo-A receptor antagonist on the regulation of the Wnt signaling pathway and neural cell proliferation in newborn rats with hypoxic ischemic encephalopathy

“…The newborn hypoxic ischemic encephalopathy rat animal model was generated as described previously and rats were named hypoxic ischemic brain damage (HIBD) rats (9). The 40 HIBD rats were divided into a HIBD group and a HIBD + NEP1-40 group (n=20 in each group).…”

“…The 40 HIBD rats were divided into a HIBD group and a HIBD + NEP1-40 group (n=20 in each group). The HIBD + NEP1-40 group rats were treated with NEP1-40 for 7 days as previously described (9). Rats were sacrificed by inhalation of CO 2 for 3 min.…”

Neuroprotective effects of NEP1-40 and fasudil on Nogo-A expression in neonatal rats with hypoxic-ischemic brain damage

“…They were randomly divided into 4 groups on average: 1) the control group: intraperitoneally injected with normal saline; 2) HIBD group: intraperitoneally injected with normal saline; 3) NEP1-40 group: intraperitoneally injected with NEP1-40 (American Diagnostica Inc.) at a dose of 12.5 μg·kg -1 ·day -1 (Cao et al, 2008); 4) fasudil group: intraperitoneally injected with fasudil (American Diagnostica Inc.) at a dose of 10 mg·kg -1 ·day -1 (Vicari et al, 2005). In addition, rats of each group were randomly divided into 4 groups on average by observation time of 6, 24, 72 h, and 7 days (Guo et al, 2008).…”

“…NEP1-40, the competitive antagonist of Nogo-R for sequences of Nogo-66 amino, prevents the combination of central nervous system inhibitors with Nogo-R and contributes to nerve regeneration (Cao et al, 2008). Fasudil, the sole clinically available ROCK inhibitor, is already in use to treat cerebral vasospasm, and its anti-angina effect has also been confirmed in humans (Vicari et al, 2005).…”

Assessing Forelimb Function after Unilateral Cervical SCI using Novel Tasks: Limb Step-alternation, Postural Instability and Pasta Handling

“…Therefore, developing cSCI models and associated behavioral assays that are easy, sensitive and reliable to use is an important goal. There are several useful behavioral tests to assess forelimb function after cSCI in rodents [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , however, many of these tests are difficult to use and require specialized equipment. Pasta handling tests have been developed by other groups 18,19 , but these tests require that the animals be filmed in specific pasta eating cages, which requires a long training period, while the method we propose can be performed in the animals' home cage.…”