methimazole and Retinal-Neovascularization

To determine the effect of methimazole (MMI) on retinal vascular development in the oxygen-induced retinopathy neonatal rat.. It was an experimental study. Control and MMI-exposed newborn rats were raised either in room air or variable oxygen (40%/15%) every 24 hours until P14. All groups were then exposed to room air between postnatal day P14 and P18. Dams drank either tap water or water containing 0.1% MMI. Eyes in all groups were fixed, and retinas were dissected and stained with adenosine diphosphatase, then analyzed for retinal vascular areas, vascular density, and NV incidence and severity. Serum IGF-1 level was measured by radioimmunoassay. Body weight were measured every day. NV incidence between groups were analyzed with Chi-square tests. Ratio of peripheral avascular area to the whole retina area, vascular density, the nucleus of vascular endothelial cells breaking inner limiting membrane count and Serum IGF-1 level between groups were tested by One-Way ANOVA analysis and independent-samples t-test.. Compared with untreated 40%/15% pups, 40%/15% newborn rats receiving MMI exhibited significant changes in NV incidence (26%:57%, χ(2) = 4.38 P = 0.04) and the nucleus of vascular endothelial cells breaking inner limiting membrane count (33.17 ± 3.06:65.64 ± 3.85, t = 17.73, P = 0.00). Ratio of peripheral avascular area to the whole retina area of MMI treated 40%/15% rats was 6.37% ± 1.23%, and the development of retinal blood vessels in other groups reached periphery. Retinal NV was not found in MMI control retinas, although retinal vascular density was significantly lower (P < 0.05) in MMI-treated pups (52.57 ± 4.14) than in the control group (95.21 ± 6.17). Serum IGF-1 levels were markedly (P < 0.05) reduced in MMI treated control rats (235.94 ± 29.09) mg/L compared with untreated control animals (536.43 ± 32.65) mg/L and in MMI treated 40%/15% rats (227.24 ± 19.59) mg/L compared with untreated 40%/15% group (526.50 ± 26.83) mg/L. Compared with non-MMI pups, newborn rats receiving MMI exhibited significant growth retardation in body weight.. MMI aggravates NV in oxygen-induced retinopathy neonatal rats. This may be mediated by the initial suppression of serum IGF-1. The relationship between the temporal course of serum IGF-1 and NV in immature retinas needs further investigation.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Insulin-Like Growth Factor I; Male; Methimazole; Oxygen; Rats; Rats, Sprague-Dawley; Retinal Neovascularization

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).. 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.. 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).. 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.

Topics: Acidosis; Ammonium Chloride; Animals; Animals, Newborn; Antithyroid Agents; Blood Gas Analysis; Disease Models, Animal; Female; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Insulin-Like Growth Factor I; Methimazole; Pregnancy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Thyroxine

To determine the effect of methylimidazole (MMI)-induced hypothyroidism in a newborn rat model of low retinal neovascular (NV) incidence.. Control and MMI-exposed newborn rats were raised either in room air or variable oxygen (40/15) until P14. All groups were then exposed to room air between postnatal day (P)14 and P20. Dams drank either tap water or water containing MMI. Eyes of animals in all groups were enucleated, and retinas were removed and stained with adenosine diphosphatase and analyzed for peripheral avascularity, vascular density, and NV incidence and severity.. In the control group, MMI treatment did not promote the development of retinal NV although a linear relationship (r = 0.99, P < 0.01) was found between increased MMI dose and lower peripheral retinal vascular densities. In all the 40/15 groups, peripheral retinal vascular densities were lower (P < 0.05) than normal and were not a function of MMI dose. Increased MMI dose produced increased retinal incidence of NV (r = 0.99, P < 0.05).. These data are consistent with the notions that thyroid function contributes to normal retinal vascular density and that hypothyroidism can play a permissive role in the development of retinal NV.

Topics: Adenosine Diphosphate; Animals; Animals, Newborn; Antithyroid Agents; Disease Models, Animal; Hyperoxia; Hypothyroidism; Incidence; Methimazole; Oxygen; Rats; Rats, Sprague-Dawley; Retinal Neovascularization; Retinal Vessels; Thyroid Gland

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.. 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.. 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.. 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.

Topics: Animals; Animals, Newborn; Antithyroid Agents; Female; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Maternal-Fetal Exchange; Methimazole; Pregnancy; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity; Thyroxine