Anti-thyroid methimazole in an acidosis-induced retinopathy rat model of retinopathy of prematurity.
OBJECTIVE
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.
Mookadam
Martina
M
Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Leske
David A
DA
Fautsch
Michael P
MP
Lanier
William L
WL
Holmes
Jonathan M
JM
D000138:Acidosis / Q000097:blood / Q000503:physiopathology*; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000494:pharmacology*; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008713:Methimazole / Q000494:pharmacology*; D011247:Pregnancy; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects; D015861:Retinal Neovascularization / Q000097:blood / Q000503:physiopathology*; D012178:Retinopathy of Prematurity / Q000097:blood / Q000503:physiopathology*; D013974:Thyroxine / Q000097:blood
D013956:Antithyroid Agents; D000643:Ammonium Chloride; D008713:Methimazole; D007334:Insulin-Like Growth Factor I; D013974:Thyroxine