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. 2006 Nov;60(5):540-549.
doi: 10.1002/ana.20953.

Delayed Nogo receptor therapy improves recovery from spinal cord contusion

Xingxing Wang  1 , Kenneth W Baughman  1 , D Michele Basso  2 , Stephen M Strittmatter  1
Affiliations

Delayed Nogo receptor therapy improves recovery from spinal cord contusion

Xingxing Wang et al. Ann Neurol. 2006 Nov.

Abstract

Objective: Myelin-associated inhibitors play a role in limiting axonal growth in the adult central nervous system. Blocking these inhibitors may promote neurological recovery from spinal cord contusion.

Methods: The soluble Nogo-66 receptor (NgR(310)ecto-Fc) protein, which can neutralize three myelin inhibitors, was infused into rats after spinal cord contusion for 28 days. Treatment was initiated intrathecally at the time of injury or 3 days after injury by the intracerebroventricular route at a dose of 0.29 mg/kg/day. Recovery of locomotion and of axonal growth was assessed. Some animals received combination therapy with NgR(310)ecto-Fc plus rolipram, a cyclic adenosine monophosphate phosphodiesterase inhibitor.

Results: Seven weeks after spinal injury, the Basso-Beattie Bresnahan locomotor scores were significantly improved in the 3-day delayed NgR(310)ecto-Fc treatment group (9.5 +/- 0.7; n = 16) versus the vehicle-treated group, (6.75 +/- 0.7; n = 15) (p < or = 0.01, analysis of variance). The percentage of NgR(310)ecto-Fc-treated animals able to support their weight was twice that in the control group. Delayed therapy was as efficacious as acute therapy. Addition of rolipram did not alter recovery. The beneficial behavioral effects of NgR(310)ecto-Fc correlated with sprouting of raphespinal axons in the caudal spinal cord and of corticospinal axons in the rostral spinal cord.

Interpretation: NgR(310)ecto-Fc treatment improves outcome in a rodent model that closely mimicked human spinal cord injury.

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Figures

Fig 1
Fig 1
NgR(310)ecto-Fc treatment improves functional recovery after rat spinal contusion injury. (A) The locomotor Basso-Beattie Bresnahan (BBB) score is reported as a function of time after contusion injury at T8 spinal level in the acute intrathecal vehicle-(dashed line) or NgR(310)ecto-Fc–treated (solid line) rats. Treatment duration is indicated by the gray bar. Data are mean ± standard error of the mean (SEM); n = 8. Repeated-measures analysis of variance (ANOVA) for treatment group, time, and their interaction indicated an effect of NgR(310)ecto-Fc treatment with p = 0.054. Post hoc one-way ANOVA at 42 days after contusion demonstrated a significant (*p ≤ 0.03) improvement of locomotion at day 42 after contusion. (B) The percentage of the animals that support their body weight with at least one hind limb is greater in the NgR(310)ecto-Fc–treated animals than that in phosphate-buffered saline (PBS)–treated rats at day 42 after injury. (C) Delayed subacute intracerebroventricular (i.c.v.) treatment with PBS or NgR(310)ecto-Fc was provided to rats after the moderate contusion injury at T7 spinal level from days 3 to 31 (gray bar). The BBB score is reported as a function of time. The timing of biotin dextran amine (BDA) injection for axonal tracing is indicated. Repeated-measures ANOVA analysis for treatment group, time, and their interaction indicated an effect of NgR(310)ecto-Fc treatment with p ≤ 0.05. One-way ANOVA at 49 days after contusion demonstrated a significant (**p ≤ 0.01) improvement of locomotion at day 49 after contusion. Data are mean ± SEM; n = 15 to 16 animals per group. (D) The percentage of the animals with BBB score ≥ 9 (supporting their body with hind limbs) is reported for the subacute delayed i.c.v. treatment rats at 7 weeks after contusion.
Fig 2
Fig 2
Intracerebroventricular NgR(310)ecto-Fc treatment does not alter cavitation or spared tissue at the site of a contusion injury. (A, B) Parasagittal sections of the lesion segment of spinal cord from both the phosphate-buffered saline (PBS)– (A) and NgR(310)ecto-Fc–treated (B) animals show a large cystic cavity within the lesion center. The area of the cavity is outlined in black, and the spared tissue is indicated by the vertical bars. Rostral is to the left, and dorsal is up. Horizontal scale bar = 500µm. (C, D) There is no difference between the extent of spared tissue (C) or the area of cystic cavity (D) between two treatment groups. Data are mean ± standard error of the mean; n = 15 to 16 animals per group.
Fig 3
Fig 3
Raphespinal fiber growth is increased by NgR(310)ecto-Fc treatment after spinal contusion injury. (A, B) Transverse sections of spinal cord stained with anti-serotonin antibodies 11 to 15mm rostral to the lesion center from phosphate-buffered saline (PBS)–(A) and NgR(310)ecto-Fc–treated (B) animals show similar numbers of serotonergic fibers in the ventral horn. (C, D) Transverse sections of spinal cord stained with anti-serotonin antibodies 11 to 15mm caudal to the lesion center show a significantly greater number of serotonergic fibers in the ventral horn of NgR(310)ecto-Fc–treated (D) animals compared with the PBS-treated (C) animals. (E, F) Measurements of serotonergic fiber length per 100µm2 in the ventral horn rostral and caudal to the contusion indicate that there is a significant increase of serotonergic fibers in the ventral horn caudal to the lesion in the NgR(310)ecto-Fc–treated animals, but no difference above the lesion. Data are mean ± standard error of the mean; n = 15 to 16 animals per group. **p < 0.01, Student’s t test. (G, H) Low-magnification view of serotonin-stained parasagittal section from PBS- (G) and NgR(310)ecto-Fc–treated (H) animals. Rostral is to the left, and dorsal is up. (M) High-magnification view of squared area in (H) demonstrates the serotonin-positive stained fibers several millimeters caudal to the lesion. (N) Serotonergic fiber number at various distances rostral and caudal to the lesion center from NgR(310)ecto-Fc–treated (black bars) and control animals (gray bars denote PBS treatment) is reported. **p < 0.01, Student’s t test. For the x-axis, a positive value is rostral to the center of the contusion, and a negative value is caudal to the center of the lesion. (I–L) Camera Lucida drawings of 5-hydroxytryptamine (5-HT) fibers from four separate rats. Each drawing is a composite assembled from a set of 10 parasagittal sections spaced at intervals of 200µm across the spinal cord. The contusion cavity is encircled near the center of each image. Increased numbers of serotonergic fibers are observed in the caudal spinal cord in the NgR(310)ecto-Fc–treated (K, L) animals compared with the PBS-treated (I, J) animals. Scale bars = 25µm (A); 1,000µm (G, I).
Fig 4
Fig 4
Intracerebroventricular NgR(310)ecto-Fc treatment increases the sprouting of corticospinal tract (CST) fibers rostral to the injury. (A, B) Transverse sections at 11 to 15mm rostral to the lesion center from phosphate-buffered saline (PBS)– (n = 7) and NgR(310)ecto-Fc–treated (n = 9) rats show a greater number of biotin dextran amine (BDA)–labeled CST fibers outside of the dorsal column in NgR(310)ecto-Fc–treated animals (arrow). (inset) Schematic illustrates the orientation of the section. Dorsal is up. (C) Ratio of optical density of sprouting BDA-labeled fibers in the ipsilateral upper quarter outside of the dorsal column based on the density of BDA staining in the dorsal column was measured. There is no statistical difference of the value between two groups (Student’s t test). Data are mean ± standard error of the mean (SEM); n = 15 to 16 animals per group. (D, E) Parasagittal sections illustrate the distance of BDA-labeled descending corticospinal tract (dCST) fibers to the lesion center (D: PBS-treated animal; E: NgR(310)ecto-Fc– treated animal; C indicates lesion cystic cavity). Rostral is to the left, and dorsal is up. (F) Counts of CST fibers show a great number of BDA-labeled dCST fibers in the NgR(310)ecto-Fc–treated group than in control group from 2.0 to 4.0mm rostral to the lesion center. Data are mean ± SEM; n = 15 to 16 animals per group. *p < 0.05; **p < 0.01, Student’s t test. (G–J) Camera Lucida drawings of CST fibers from four spinal-contused animals (G, H: PBS-treated group; I, J: NgR(310)ecto-Fc–treated group). Images are generated from all serial parasagittal sections for each rat. Rostral is to the left, and dorsal is up. The contusion cavity is at the right. Scale bars = 100µm (B); 500µm (D, J).
Fig 5
Fig 5
Combined treatment of NgR(310)ecto-Fc and rolipram does not yield additional benefit for locomotor recovery after contusion injury. (A) Basso-Beattie-Bresnahan (BBB) scores as a function of time in rolipram- (n = 10) versus vehicle-treated (n = 15) rats after spinal injury. Data are mean ± standard error of the mean (SEM). Solid line indicates PBS treatment; dotted line indicates rolipram. (B) BBB scores are reported for the rolipram plus NgR(310)ecto-Fc combined treatment group (n = 8) relative to the vehicle- and NgR(310)ecto-Fc–treated groups from Figure 1C. One-way analysis of variance at 49 days after contusion demonstrated a significant (*p ≤ 0.05) improvement of locomotion in both the Nogo-66 receptor (NgR; dashed line) alone and the NgR+ rolipram groups (dotted line) relative to the phosphate-buffered saline (PBS; solid line) group at day 49 after contusion. Data are mean ± SEM. BDA = biotin dextran amine.
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