α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.

Philip J Horner,Denise M Inman,Wendi S Lambert,David J Calkins,Andreas Ohlmann

doi:10.1371/journal.pone.0065389

Philip J Horner, Denise M Inman + Show 3 more

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https://doi.org/10.1371/journal.pone.0065389

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Abstract

Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant α-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma.

Highlights

Age is a major risk factor for glaucoma
Oxidative Stress in the DBA/2J To determine if DBA/2J retinas undergo oxidative stress with age and increasing intraocular pressure, we measured Intraocular pressure (IOP) and the levels of malondialdehyde (MDA), a common by-product of lipid peroxidation (Figure 1)
Lipid peroxidation levels (Figure 1B) in C57 retinas did not change with age (p.0.71), averaging 0.99 6 0.1 nmoles MDA/ mg protein

Summary

Introduction

Age is a major risk factor for glaucoma. The free radical theory of aging promulgated the concept that oxidative stress is a key component of age-related cellular decline [1]. Effective management of ROS appears to decline with age [1,2,3], thereby increasing the load of dysfunctional cellular components over time. These oxidative insults disrupt specific proteins and pathways. Our studies with the DBA/2J model of glaucoma have demonstrated increased DNA oxidation, protein nitrosylation and lipid peroxidation in the glaucomatous retina [12]. These data indicate that oxidative stress exacerbates the pathology of neurodegenerative diseases such as glaucoma

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