Inhibition of Thyroid Hormone Signaling Protects Photoreceptors from Oxidative Damage and Cell Death Induced by Sodium Iodate

Abstract

Purpose : Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. Recent studies have shown that higher TH levels were associated with increased risk of age-related macular degeneration (AMD), a disease characterized by oxidative damage/progressive cell dystrophy of the retinal pigment epithelium and photoreceptors. This work investigated whether inhibition of TH signaling protects photoreceptors in mice after oxidative stress challenge.

Methods : C57BL/6 mice received antithyroid drug treatment via drinking water (1% sodium perchlorate monohydrate and 0.05% methomazole) for 13 days, beginning at postnatal day 20 (P20), and received a single injection of sodium iodate (NaIO₃, 30 mg/kg, i.p.) at P30. Thra1^-/-, Thrb^-/-, and Thrb2^-/- received NaIO₃ injection at P30. These mice were then analyzed for retinal function by electroretinography (ERG) and photoreceptor damage/cell death by biochemical and morphological approaches at 3 days post-NaIO₃ injection, and for gene expression alterations at 1 day post-NaIO₃ injection.

Results : Treatment with antithyroid drug protected photoreceptors from oxidative damage and cell death induced by NaIO₃, and preserved retinal function. The outer nuclear layer thickness and cone photoreceptor density were significantly increased in mice treated with antithyroid drug. Cone density was reduced by about 30% in mice after NaIO₃ challenge. Deletion of TH receptor nearly completely abolished this reduction. The number of TUNEL-positive cells, the number of the DNA damage marker p-γH2AX-positive cells and 8-OHdG-positive cells, and Müller glia activation were significantly reduced in mice treated with antithyroid drug. NaIO₃ treatment reduced scotopic and photopic ERG responses by about 40-50%, and treatment with antithyroid drug significantly preserved ERG responses. Gene expression analysis showed that the NaIO₃-induced photoreceptor damage/cell death involves multiple mechanisms, including cellular oxidative stress responses, activation of necroptosis/apoptosis signaling, and inflammatory responses. Treatment with antithyroid drug abolished these cellular stress/death responses.

Conclusions : Suppression of TH signaling protects photoreceptors from oxidative damage and cell death induced by NaIO₃ and may represent a strategy for photoreceptor protection in AMD.

This is a 2020 ARVO Annual Meeting abstract.