Purpose: Methimazole (MMI), an anti-thyroid drug known to reduce serum levels of L-thyroxine (T4) and insulin-like growth factor-1 (IGF-1), has been previously reported to increase the incidence of neovascularization (NV) in an oxygen-induced retinopathy (OIR) model of retinopathy of prematurity (ROP) in rats. We investigated the effect of MMI on the incidence and severity of NV in a non-oxygen-induced model of ROP, acidosis-induced retinopathy (AIR).
Methods: Newborn Sprague Dawley rats were raised in expanded litters of 25 in room air for four or ten days under one of the two following conditions: (1) Our established model of AIR (acidosis via NH4Cl gavage (10 mmol/kg) twice daily from days 2 to 7, followed by two days of recovery) or (2) MMI (given as a 0.1% solution to nursing mothers) in the above AIR model. Left eyes were fixed, and retinas were dissected and ADPase-stained. Flat mounted retinas were graded in a masked manner for presence and severity of NV, and retinal vascular areas were quantified. Serum IGF-1 and T4 concentrations were measured by radioimmunoassay on days 4 and 10. Arterial blood pH measurements were performed on day 4.
Results: The incidence and severity of NV were similar between AIR and MMI-AIR rats (incidence: 24% and 33%). Serum IGF-1 concentrations in 10 day MMI-AIR rats were significantly lower than untreated non-acidotic controls (medians: 158 ng/ml and 207 ng/ml; p=0.03). Serum IGF-1 concentrations were similar between 10 day AIR rats and untreated non-acidotic controls (medians: 189 ng/ml and 207 ng/ml; p>0.9).
Conclusions: MMI does not increase the incidence or severity of NV in an AIR neonatal rat model of ROP. Although serum IGF-1 has been considered permissive for NV in immature retinas, supranormal concentrations of serum IGF-1 may not be necessary for abnormal retinal angiogenesis. Further studies are warranted on the roles of serum IGF-1 and L-thyroxine in the pathogenesis of ROP.