Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril: Importance of ramipril dose and treatment time

Purpose: Radiation-induced optic nerve damage was reduced by ramipril, a prodrug angiotensin-converting enzyme inhibitor (ACEI). This study was to determine the optimum dose and administration time of ramipril for mitigating radiation-induced optic neuropathy. Materials and method: Adult Fischer 344 male rats were treated with a single dose radiation 30 Gy by using radiosurgical technique. After irradiation, the animals were randomly assigned into groups of different ramipril doses and administration time; control (no treatment), radiation alone, radiation+ramipril in different doses and starting times of drug. Ramipril was given 0.5-1.5 mg/kg/day and AT1R blocker Losartan 20mg/kg/day in drinking water for 180 days. Functional endpoint with visual evoked potential (VEP) and anatomical endpoint with gross and histological analysis with immunohistochemical (IHC) stain were used. Results: Normal VEP measurements in un-irradiated rats were 46.2 ± 7.9 ms. There was no change of VEP value until 4 months, but was lengthened to 188.1 ± 58.7 ms at 6 months after radiation. By ramipril treatment with the dose of 1.5 mg starting at 2 weeks after radiation, VEP was significantly shortened to 105.7 ± 88.5 ms at 6 months. Gross and microscopic structure of the irradiated optic nerve was well preserved in the ramipril-treated group. Conclusion: Ramipril can mitigate the radiation-induced optic nerve damage and preserve the functional integrity of the nerve. The results support early treatment with a high dose of ramipril after radiation.