Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 12:16:1128545.
doi: 10.3389/fnmol.2023.1128545. eCollection 2023.

Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model

Guoli Zheng  1 , Anna-Kathrin Harms  1 , Mohamed Tail  1 , Hao Zhang  1 , Alan Nimmo  2 , Thomas Skutella  3 , Karl Kiening  1 , Andreas Unterberg  1 , Klaus Zweckberger  1 , Alexander Younsi  1
Affiliations

Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model

Guoli Zheng et al. Front Mol Neurosci. .

Abstract

Objective: Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model.

Methods: Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted.

Results: Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters.

Conclusion: Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery.

Keywords: animal model; behavioral assessment; blood spinal cord barrier; inflammation; neurokinin-1 (NK1) antagonist; spinal cord injury.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Spinal cord cross-sections of one NK1 receptor antagonist (NRA) and one vehicle animal at 10 × and 40 × magnification stained for SP (A, red) and NK-1R (B, yellow). (C) Mean immunointensity of SP in the spinal cord 7 days after SCI/sham surgery. (D) Mean cell density (cells/mm2) of DAPI+&NK-1R+ cells in the spinal cord 7 days after SCI/sham surgery (Orange cross, microvessel in the spinal cord) (n = 6/group; one-way repeated measures ANOVA followed by post-hoc Tukey-HSD-test; ***p < 0.001; *p < 0.05).
Figure 2
Figure 2
(A) Sagittal view of a T2-weighted MRI of a vehicle animals’ spinal cord 7 days after SCI. The red arrow indicates the epicenter of the spinal cord lesion at T9, and the yellow lines indicate three representative axials views (A). (B–D) Axial views of the vehicle animals’ T2-weighted MRI according to the yellow lines in (A). The red arrows point at the spinal cord, surrounded by the cerebrospinal fluid. (E) Mean signal intensity of the spinal cords on T2-weighted MRI in the Sham, NRA, and vehicle group 1, 3, and 7 days after SCI/sham surgery (n = 3/group; one-way repeated measures ANOVAs followed by post-hoc Tukey-HSD-tests; *p < 0.05; ns = not significant). (F) Corrected water loss (%) in the thoracic spinal cord of the Sham, NRA, and vehicle animals 7 days after SCI/sham surgery (n = 6/group; one-way repeated measures ANOVA followed by post-hoc Tukey-HSD-test; ns = not significant).
Figure 3
Figure 3
Spinal cord cross-sections of a vehicle animal at 10 × and 40 × magnification stained for Fibrinogen (A, yellow), CD3 (C, yellow), and CD31 (E, red). (B) Mean immunointensity of Fibrinogen in the spinal cord 7 days after injury. (D,F) Mean cell density (cells/mm2) of DAPI+&CD3+ T-lymphocytes (D) and DAPI+&CD31+ endothelial cells (F) in the spinal cord 7 days after SCI/sham surgery (n = 6/group; one-way repeated measures ANOVA followed by post-hoc Tukey-HSD-test; ***p < 0.001; **p < 0.01; *p < 0.05; ns = not significant).
Figure 4
Figure 4
Spinal cord cross-sections of a vehicle animal at 10 × and 40 × magnification stained for Iba1 (A, yellow), TMEM119 (C, red), and Arg1 (E, yellow). (B,D,F) Mean cell density (cells/mm2) of DAPI+&Iba1+ infiltrating macrophages (B), DAPI+&TMEM119+ resident microglia (D), and DAPI+&Arg1+ M2-polarized microglia (F) in the spinal cord 7 days after SCI/sham surgery (n = 6/group; one-way repeated measures ANOVA followed by post-hoc Tukey-HSD-test; ***p < 0.001; ns = not significant).
Figure 5
Figure 5
Spinal cord cross-sections of a vehicle animal at 10 × and 40 × magnification stained for Caspase 3 (A, red), CSPG (C, yellow), and GFAP (E, yellow). (B) Mean cell density (cells/mm2) of DAPI+&Caspase 3+ apoptotic cells and mean immunointensity of CSPG (D) and GFAP (F) in the spinal cord 7 days after SCI/sham surgery (n = 6/group; one-way repeated measures ANOVA followed by post-hoc Tukey-HSD-test; ***p < 0.001; **p < 0.01; *p < 0.05; ns = not significant).
Figure 6
Figure 6
(A) Blood–brain–barrier (BBB) open field scores of the animals from baseline until 7 days after SCI/sham surgery. (B) Number of stepping errors in the Gridwalk test at baseline and 7 days after SCI/sham surgery. (C) Mean Intensity, (D) Max Contact Mean Intensity, (E) Swing Speed, and (F) duty cycle of the hindlimbs as CatWalk XT® automated gait analysis parameters at baseline and 7 days after SCI/sham surgery (n = 12/group; two-way repeated measure ANOVAs, followed by Tukey tests for multiple comparisons; *p < 0.05, **p < 0.01, ***p < 0.001; ns = not significant).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Ackery A., Tator C., Krassioukov A. (2004). A global perspective on spinal cord injury epidemiology. J. Neurotrauma 21, 1355–1370. doi: 10.1089/neu.2004.21.1355, PMID: - DOI - PubMed
    1. Ameliorate J. L., Ghabriel M. N., Vink R. (2017). Magnesium enhances the beneficial effects of NK1 antagonist administration on blood-brain barrier permeability and motor outcome after traumatic brain injury. Magnes. Res. 30, 88–97. doi: 10.1684/mrh.2017.0427, PMID: - DOI - PubMed
    1. Badhiwala J. H., Wilson J. R., Witiw C. D., Harrop J. S., Vaccaro A. R., Aarabi B., et al. . (2021). The influence of timing of surgical decompression for acute spinal cord injury: a pooled analysis of individual patient data. Lancet. Neurol. 20, 117–126. doi: 10.1016/S1474-4422(20)30406-3, PMID: - DOI - PubMed
    1. Bartanusz V., Jezova D., Alajajian B., Digicaylioglu M. (2011). The blood-spinal cord barrier: morphology and clinical implications. Ann. Neurol. 70, 194–206. doi: 10.1002/ana.22421, PMID: - DOI - PubMed
    1. Basso D. M., Beattie M. S., Bresnahan J. C. (1995). A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21. doi: 10.1089/neu.1995.12.1, PMID: - DOI - PubMed

LinkOut - more resources