Abstract
Study design
Experimental study.
Objectives
To evaluate the efficacy of Angiotensin-converting enzyme inhibitor Ramipril, as a mitigator of radiation-induced spinal cord injury.
Setting
Stony Brook University, Stony Brook, NY, USA.
Methods
Total of 22 rats were irradiated with single doses of 23.6–33 Gy at the C4-T2 spinal levels. After irradiation, the rats were randomized to the radiation only control group and the Ramipril-treated (radiation + Ramipril) experimental group. Ramipril 1.5 mg/kg/day was given in the drinking water starting 1 week after radiation through the study duration.
Results
All the rats irradiated with 28.5–33 Gy became paralyzed at 125 ± 4 days, whereas no rats became paralyzed after 23.6 Gy. The time to develop paralysis was delayed to 135 ± 4 days in Ramipril-treated group (P < 0.001). H&E and LFB showed microscopic structural restoration and remyelination with Ramipril treatment. VEGF expression was increased in the irradiated spinal cord, and the number of VEGF-positive cells was significantly decreased by Ramipril treatment (P < 0.001). Immunohistochemical stain with Iba-1 showed increased microglial infiltration in the irradiated spinal cords. The number of Iba-1-positive microglia was significantly reduced by Ramipril treatment (P < 0.05).
Conclusion
Ramipril reduced the rate of paralysis even at the paralysis-inducing radiation doses. It also significantly delayed the onset of paralysis. Neuroinflammation and endothelial cell damage may be the key mediators of radiation injury. Ramipril can be readily translatable to clinical application as a mitigatory of radiotherapeutic toxicity.
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Acknowledgements
The authors acknowledge that the animal irradiation was performed at Henry Ford Hospital (SR before moving to Stony Brook University), thank Andrew Koloszvary, Stephen Brown, Karen Lapanowski for technical help.
Funding
This work was supported by internal funds from Stony Brook University Hospital.
Author contributions
MGC was responsible for the methodology, project administration, software, visualization, writing-original draft and writing-review. AMS was responsible for the formal analysis, investigation, methodology, validation, visualization, writing-original draft and writing-review. SET was responsible for supervision, data interpretation, validation, visualization, writing-original draft and writing-review and editing. SR was responsible for the conceptualization, formal analysis, funding acquisition, investigation, methodology, supervision, validation, visualization, writing-original draft and writing-review and editing.
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Clausi, M.G., Stessin, A.M., Tsirka, S.E. et al. Mitigation of radiation myelopathy and reduction of microglial infiltration by Ramipril, ACE inhibitor. Spinal Cord 56, 733–740 (2018). https://doi.org/10.1038/s41393-018-0158-z
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DOI: https://doi.org/10.1038/s41393-018-0158-z
