Mitigation of radiation myelopathy and reduction of microglial infiltration by Ramipril, ACE inhibitor

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 L1-13 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 lba-1 showed increased microglial infiltration in the irradiated spinal cords. The number of lba-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.