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


METHODS
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 20 mg/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.


CONCLUSIONS
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.
Ryu
Samuel
S
Department of Radiation Oncology and Neurosurgery, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202, USA. sryu1@hfhs.org
Kolozsvary
Andrew
A
Jenrow
Kenneth A
KA
Brown
Stephen L
SL
Kim
Jae Ho
JH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D004307:Dose-Response Relationship, Radiation; D005074:Evoked Potentials, Visual / Q000528:radiation effects; D007274:Injections, Intraperitoneal; D008297:Male; D009900:Optic Nerve / Q000528:radiation effects*; D009901:Optic Nerve Diseases / Q000188:drug therapy* / Q000209:etiology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000209:etiology; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D017257:Ramipril / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D011837:Radiation-Protective Agents; D017257:Ramipril