title: α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.
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.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, Washington, United States of America. dinman@neomed.edu
authors.forename: Denise M
authors.initials: DM
authors.lastname: Inman
authors.forename: Wendi S
authors.initials: WS
authors.lastname: Lambert
authors.forename: David J
authors.initials: DJ
authors.lastname: Calkins
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001369:Axons / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage; D019587:Dietary Supplements; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology; D007429:Intraocular Pressure / Q000187:drug effects; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009410:Nerve Degeneration / Q000517:prevention & control; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000502:physiology; D008063:Thioctic Acid / Q000008:administration & dosage*; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D008063:Thioctic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse