Skip to main content
SpringerLink
Log in

Molecular Imaging Detects Impairment in the Retrograde Axonal Transport Mechanism After Radiation-Induced Spinal Cord Injury

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The goal of this study was to determine whether molecular imaging of retrograde axonal transport is a suitable technique to detect changes in the spinal cord in response to radiation injury.

Procedures

The lower thoracic spinal cords of adult female BALB/c mice were irradiated with single doses of 2, 10, or 80 Gy. An optical imaging method was used to observe the migration of the fluorescently labeled nontoxic C-fragment of tetanus toxin (TTc) from an injection site in the calf muscles to the spinal cord. Changes in migration patterns compared with baseline and controls allowed assessment of radiation-induced alterations in the retrograde neuronal axonal transport mechanism. Subsequently, tissues were harvested and histological examination of the spinal cords performed.

Results

Transport of TTc in the thoracic spinal cord was impaired in a dose-dependent manner. Transport was significantly decreased by 16 days in animals exposed to either 10 or 80 Gy, while animals exposed to 2 Gy were affected only minimally. Further, animals exposed to the highest dose also experienced significant weight loss by 9 days and developed posterior paralysis by 45 days. Marked histological changes including vacuolization, and white matter necrosis were observed in radiated cords after 30 days for mice exposed to 80 Gy.

Conclusion

Radiation of the spinal cord induces dose-dependent changes in retrograde axonal transport, which can be monitored by molecular imaging. This approach suggests a novel diagnostic modality to assess nerve injury and monitor therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Atkinson S, Li YQ, Wong CS (2003) Changes in oligodendrocytes and myelin gene expression after radiation in the rodent spinal cord. Int J Radiat Oncol Biol Phys 57:1093–1100

    Article  CAS  PubMed  Google Scholar 

  2. Dropcho EJ (2010) Neurotoxicity of radiation therapy. Neurol Clin 28:217–234

    Article  PubMed  Google Scholar 

  3. Garg AK, Shiu AS, Yang J et al (2012) Phase 1/2 trial of single-session stereotactic body radiotherapy for previously unirradiated spinal metastases. Cancer 118:5069–5077

    Article  PubMed Central  PubMed  Google Scholar 

  4. Medin PM, Boike TP (2011) Spinal cord tolerance in the age of spinal radiosurgery: lessons from preclinical studies. Int J Radiat Oncol Biol Phys 79:1302–1309

    Article  PubMed Central  PubMed  Google Scholar 

  5. Medin PM, Foster RD, van der Kogel AJ et al (2012) Spinal cord tolerance to reirradiation with single-fraction radiosurgery: a swine model. Int J Radiat Oncol Biol Phys 83:1031–1037

    Article  PubMed Central  PubMed  Google Scholar 

  6. Medin PM, Foster RD, van der Kogel AJ, Sayre JW et al (2011) Spinal cord tolerance to single-fraction partial-volume irradiation: a swine model. Int J Radiat Oncol Biol Phys 79:226–232

    Article  PubMed Central  PubMed  Google Scholar 

  7. Levi-Montalcini R, Hamburger V (1951) Selective growth stimulating effects of mouse sarcoma on the sensory and sympathetic nervous system of the chick embryo. J Exp Zool 116:321–361

    Article  CAS  PubMed  Google Scholar 

  8. Helting TB, Zwisler O (1977) Structure of tetanus toxin. I. Breakdown of the toxin molecule and discrimination between polypeptide fragments. J Biol Chem 252:187–193

    CAS  PubMed  Google Scholar 

  9. Helting TB, Zwisler O, Wiegandt H (1977) Structure of tetanus toxin. II. Toxin binding to ganglioside. J Biol Chem 252:194–198

    CAS  PubMed  Google Scholar 

  10. Schellingerhout D, Le Roux LG, Bredow S, Gelovani JG (2009) Fluorescence imaging of fast retrograde axonal transport in living animals. Mol Imaging 8:319–329

    CAS  PubMed  Google Scholar 

  11. Schellingerhout D, LeRoux LG, Hobbs BP, Bredow S (2012) Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging. PLoS One 7:e45776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Carson F, Hladil C (2009) Histotechnology: a self-instructional text. American Society for Clinical Pathology, Hong Kong

    Google Scholar 

  13. Sahgal A, Ma L, Gibbs I et al (2010) Spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 77:548–553

    Article  PubMed  Google Scholar 

  14. Okada S, Okeda R (2001) Pathology of radiation myelopathy. Neuropathology 21:247–265

    Article  CAS  PubMed  Google Scholar 

  15. Lo YC, McBride WH, Withers HR (1992) The effect of single doses of radiation on mouse spinal cord. Int J Radiat Oncol Biol Phys 22:57–63

    Article  CAS  PubMed  Google Scholar 

  16. Bijl HP, van Luijk P, Coppes RP et al (2002) Dose-volume effects in the rat cervical spinal cord after proton irradiation. Int J Radiat Oncol Biol Phys 52:205–211

    Article  PubMed  Google Scholar 

  17. Medin PM, Foster RD, van der Kogel AJ et al (2011) Spinal cord tolerance to single-fraction partial-volume irradiation: a swine model. Int J Radiat Oncol Biol Phys 79:226–232

    Article  PubMed Central  PubMed  Google Scholar 

  18. Pan H, Simpson DR, Mell LK et al (2011) A survey of stereotactic body radiotherapy use in the United States. Cancer 117:4566–4572

    Article  PubMed Central  PubMed  Google Scholar 

  19. Sahgal A, Weinberg V, Ma L et al (2012) Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys 71:652–665

    Article  Google Scholar 

  20. Schoemaker JH (1994) Impaired axonal transport in diabetic neuropathy. Diabetes Care 17:1362

    CAS  PubMed  Google Scholar 

  21. Green LS, Donoso JA, Heller-Bettinger IE, Samson FE (1977) Axonal transport disturbances in vincristine-induced peripheral neuropathy. Ann Neurol 1:255–262

    Article  CAS  PubMed  Google Scholar 

  22. Lapointe NE, Morfini G, Brady ST et al (2013) Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 37:231–239

    Article  CAS  PubMed  Google Scholar 

  23. Nagata H, Ohkoshi N, Kanazawa I et al (1992) Rapid axonal transport velocity is reduced in experimental ethylene oxide neuropathy. Mol Chem Neuropathol 17:209–217

    Article  CAS  PubMed  Google Scholar 

  24. Wakabayashi M, Araki K, Takahashi Y (1976) Increased rate of fast axonal transport in methylmercury-induced neuropathy. Brain Res 117:524–528

    Article  CAS  PubMed  Google Scholar 

  25. Holzbaur EL, Scherer SS (2011) Microtubules, axonal transport, and neuropathy. N Engl J Med 365:2330–2332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Boyette-Davis J, Dougherty PM (2011) Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline. Exp Neurol 229:353–357

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Dr. Daniel Young for assisting us with the embedding and sectioning of animal material.

Conflict of Interest

The authors declare no potential conflicts of interest.

Funding Sources

The support of the Mike Hogg Award, the M D Anderson Cancer Center Institutional Research Grant, the National Institute for Neurological Disorders and Stroke R01NS070742-01A1, and The John S. Dunn, Sr. Distinguished Chair in Diagnostic Imaging is gratefully acknowledged. The sponsors had no role in study design, research execution, analysis, or decision to publish.

Author information

Authors and Affiliations

  1. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lucia G. LeRoux, Sebastian Bredow & Dawid Schellingerhout

  2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    David Grosshans

  3. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Dawid Schellingerhout

  4. 1400 Pressler Street, Unit 1482, Houston, TX, 77030, USA

    Dawid Schellingerhout

Authors
  1. Lucia G. LeRoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sebastian Bredow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Grosshans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dawid Schellingerhout
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dawid Schellingerhout.

Additional information

Lucia G. LeRoux and Sebastian Bredow contributed equally

Rights and permissions

Reprints and permissions

About this article

Cite this article

LeRoux, L.G., Bredow, S., Grosshans, D. et al. Molecular Imaging Detects Impairment in the Retrograde Axonal Transport Mechanism After Radiation-Induced Spinal Cord Injury. Mol Imaging Biol 16, 504–510 (2014). https://doi.org/10.1007/s11307-013-0713-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-013-0713-0

Key words

Search

Navigation