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Assessment of Nogo-66 Receptor 1 Function In Vivo After Spinal Cord Injury

Tong, Jing MD*,‡,§; Ren, Yi BS*,‡; Wang, Xiaowei BS*,‡; Dimopoulos, Vassilios G. MD*,‡; Kesler, Henry N. MD*,‡; Liu, Weimin MD, PhD; He, Xiaosheng MD, PhD; Nedergaard, Maiken MD, PhD; Huang, Jason H. MD#

Neurosurgery:
doi: 10.1227/NEU.0000000000000337
Research-Animal
Abstract

BACKGROUND: Neuronal Nogo-66 receptor 1 (NgR1) has attracted attention as a converging point for mediating the effects of myelin-associate inhibitory ligands in the central nervous system, establishing the growth-restrictive environment, and limiting axon regeneration after traumatic injury.

OBJECTIVE: To investigate the factors that may be contributing to the discrepancy in the importance of NgR1, which has been undermined by several studies that have shown the lack of substantial axon regeneration after spinal cord injury (SCI) in NgR1-knockout or -knockdown animal models.

METHODS: We used mice carrying either a homozygous or heterozygous null mutation in the NgR1 gene and subjected them to either a moderate or severe SCI.

RESULTS: Locomotor function assessments revealed that the level of functional recovery is affected by the degree of injury suffered. NgR1 ablation enhanced local collateral sprouting in the mutant mice. Reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs) are upregulated surrounding the injury site. Matrix metalloproteinase-9, which has been shown to degrade CSPGs, was significantly upregulated in the homozygous mutant mice compared with the heterozygous or wild-type mice. However, CSPG levels remained higher in the homozygous compared with the heterozygous mice, suggesting that CSPG-degrading activity of matrix metalloproteinase-9 may require the presence of NgR1.

CONCLUSION: Genetic ablation of NgR1 may lead to significant recovery in locomotor function after SCI. The difference in locomotor recovery we observed between the groups that suffered various degrees of injury suggests that injury severity may be a confounding factor in functional recovery after SCI.

ABBREVIATIONS: BMS, Basso Mouse Scale

CSPG, chondroitin sulfate proteoglycan

CST, corticospinal tract

GFAP, glial fibrillary acidic protein

MMP, matrix metalloproteinase

NgR1, Nogo-66 receptor 1

PBS, phosphate-buffered saline

SCI, spinal cord injury

Author Information

Department of Neurosurgery and

Center for Translational Neuromedicine, University of Rochester, Rochester, New York;

§Department of Neurosurgery, Fourth Affiliated Hospital of Hebei Medical University, Hebei, China;

Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China; and

#Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas

Correspondence: Jason H. Huang, MD, FACS, Department of Neurosurgery, Baylor Scott & White Health, 2401 S 31st St, Temple, TX 76508. E-mail: jhuang@sw.org

* These authors contributed to this article equally.

Received August 30, 2013

Accepted February 12, 2014

Copyright © by the Congress of Neurological Surgeons