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The Anti-thyroid Drug Methimazole Induces Neovascularization in the Neonatal Rat Analogous to ROP

¹From the Departments of Ophthalmology and ²Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.

PURPOSE. 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.