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

• Published in: PloS one 2013-06, Vol.8 (6), p.e65389
• Main Authors: Inman, Denise M, Lambert, Wendi S, Calkins, David J, Horner, Philip J
• Format: Article
• Language: English
• Subjects: Acids; Administration, Oral; Age; Animal models; Animals; Antioxidants; Antioxidants - administration & dosage; Axonal transport; Axons - drug effects; Axons - physiology; Biology; Cell death; Cell Death - drug effects; Deoxyribonucleic acid; Diabetes; Diabetic retinopathy; Diet; Dietary Supplements; Disease; DNA; DNA Damage; Drug Evaluation, Preclinical; Free radicals; Gene Expression; Glaucoma; Glaucoma - drug therapy; Glaucoma - pathology; Hypertension; Intervention; Intraocular Pressure - drug effects; Lipid Peroxidation; Lipids; Lipoic acid; Macular degeneration; Medicine; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; mRNA; Nerve Degeneration - prevention & control; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nutrition therapy; Oxidation; Oxidation resistance; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Peroxidation; Prevention; Proteins; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Retina; Retina - drug effects; Retina - metabolism; Retina - pathology; Retinal ganglion cells; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - physiology; Retrograde transport; Rodents; Therapy; Thioctic Acid - administration & dosage; Transport; Treatment Outcome; Up-Regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065389

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.