Wedelolactone Attenuates N-methyl-N-nitrosourea-Induced Retinal Neurodegeneration through Suppression of the AIM2/CASP11 Pathway.

Kevin Harkin,Mei Chen,Josy Augustine,Alan W Stitt,Heping Xu

doi:10.3390/biomedicines10020311

Abstract

N-methyl-N-nitrosourea (NMU) is widely used to model oxidative stress and inflammation mediated retinal neurodegeneration. Wedelolactone (WD) is known to have antioxidant, anti-inflammatory, and neuroprotective roles. This study tested the therapeutic potential of WD in NMU-induced retinal neurodegeneration and investigated the underlying mechanisms in mice. NMU (40 mg/kg) was injected intraperitoneally into C57BL/6J mice with/without an intravitreal injection of WD (1 μL/eye, 200 μM). Seven days later, retinal function and structure were evaluated by electroretinography (ERG) and Spectral Domain Optical Coherence Tomography (SD-OCT). The expression of inflammasome components (Aim2, Caspase 1/11, and Il1b/Il18) in the total retina lysate was evaluated by RT-qPCR. In vitro, 661W photoreceptor cells were transfected with synthetic double-strand DNA (Poly(dA:dT)) with/without WD pre-incubation. The aim2-related inflammasome expression was evaluated by RT-qPCR and immunocytochemistry. The production of IL18 was measured by ELISA. NMU treatment significantly impaired A- and B-wave response (ERG) and reduced neuroretina thickness (OCT). This was significantly attenuated upon intravitreal injection of WD. The expression of Aim2, ACasp1, and Casp11 was increased in the retina from NMU-treated mice, and this was prevented by WD treatment. Transfection of Poly(dA:dT) upregulated Aim2, Casp11, and Il18 expression in 661W cells. WD prevented their upregulation and reduced IL18 production. Aim2 inflammasome activation is critically involved in NMU-induced retinal neurodegeneration and WD can protect the retina particularly through the suppression of this inflammasome-linked pathway.

Highlights

Publisher’s Note: MDPI stays neutralThe degeneration of retinal photoreceptors is the ultimate cause of vision loss in retinal degenerative diseases such as retinitis pigmentosa (RP) [1], age-related macular degeneration (AMD) [2,3], and retinal detachment (RD)
Our results suggest that Poly(dA:dT) might induce photoreceptor death through activating the Aim2/Casp11/Il18 inflammasome pathway
We show that Aim2/Casp11/Il18 inflammasome activation plays a key role in NMU-induced photoreceptor death

Summary

Introduction

The degeneration of retinal photoreceptors is the ultimate cause of vision loss in retinal degenerative diseases such as retinitis pigmentosa (RP) [1], age-related macular degeneration (AMD) [2,3], and retinal detachment (RD). While mitochondria are critical to meet photoreceptor ATP requirements, in some disease states, the dysfunction of these organelles can lead to the release of damaging free radicals or when protective mechanism are compromised, they can themselves become subject to oxidative species. Oxidative stress mediated photoreceptor damage is involved in the pathogenesis of various retinal diseases such as, AMD [7], Glaucoma [8], and DR [9]. Oxidative stress-induced mitochondrial dysfunction has been found in glaucoma [8] and DR [10], as well as other conditions such as Alzheimer’s disease [11]

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