title: The anti-thyroid drug methimazole induces neovascularization in the neonatal rat analogous to ROP.
abstract: OBJECTIVE
  To determine the effect of methimazole (MMI), an anti-thyroid drug known to reduce serum l-thyroxine (T4), and insulin-like growth factor (IGF)-1 concentrations, on retinal vascular development in neonatal rats.
  
  
  METHODS
  Sprague-Dawley rats (n=175) were raised in expanded litters of 25 in room air and were exposed to MMI from birth (given as a 0.1% solution to nursing mothers for either 4 or 10 days). Experiments ended on day 4 (n=25) or 10 (n=50) of life. A third group was exposed to MMI for the initial 4 days of life and then allowed to recover for the next 6 days (n=50). Fifty control rats were analyzed on day 4 (n=25) or 10 (n=25) of life. Left eyes were fixed, and retinas were dissected and stained with adenosine diphosphatase (ADPase). Retinas were graded for presence and severity of neovascularization (NV) in a masked manner, and retinal vascular areas were quantified. In a subsequent study, serum IGF-1 and T4 levels were measured by radioimmunoassay in an additional 200 rats exposed to treatments identical to those described.
  
  
  RESULTS
  Retinal NV occurred in 31% of rats exposed to 10 days of MMI and 4% (P=0.02) of rats exposed to 4 days of MMI, followed by 6 days of recovery. None of the rats exposed to 4 days of MMI alone and none of the control animals was graded positive for NV. Retinal vascular areas were significantly reduced in rats exposed to 4 days of MMI compared with 4-day control animals (36% +/- 6% vs. 50% +/- 6%, P=0.0001). Serum IGF-1 levels were markedly reduced in 4-day MMI rats compared with age-matched control animals (42 ng/mL vs. 133 ng/mL, P=0.0001) and in 10-day MMI rats compared with 10-day control animals (133 ng/mL vs. 206.5 ng/mL, P=0.005). Serum T4 levels were similarly suppressed in the MMI-exposed litters compared with control animals at day 10 (P=0.008). In contrast, rats exposed to 4 days of MMI followed by 6 days of recovery had normal serum IGF-1 and T4 levels by day 10.
  
  
  CONCLUSIONS
  The anti-thyroid drug, MMI, induces NV in neonatal rats. This may be mediated by the initial suppression of serum IGF-1. Nevertheless, the lower incidence of NV when serum IGF-1 levels are initially suppressed followed by complete recovery, is contrary to a purely permissive role for serum IGF-1, as reported previously. The relationship between the temporal course of serum IGF-1 and NV in immature retinas needs further investigation.
authors.affiliation: Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Mookadam
authors.forename: David A
authors.initials: DA
authors.lastname: Leske
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fautsch
authors.forename: William L
authors.initials: WL
authors.lastname: Lanier
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Holmes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000633:toxicity*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D008713:Methimazole / Q000633:toxicity*; D011247:Pregnancy; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects*; D012178:Retinopathy of Prematurity / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D013974:Thyroxine / Q000097:blood
chemical_list: D013956:Antithyroid Agents; D008713:Methimazole; D007334:Insulin-Like Growth Factor I; D013974:Thyroxine