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T. C. MacPherson, K. C. Leonard, C. M. L. Hutnik, K. A. Hill; In Vivo Model for Drug Delivery Testing: Multi-Parameter Ocular Phenotyping in a Memantine-Treated Mouse Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6210.
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Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world becoming more prevalent in an increasingly aged population. Although the pathogenesis of AMD remains poorly understood, current research provides strong evidence for a role of oxidative stress induced excitotoxicity. Excitotoxicity results from an increase of glutamate in the synaptic cleft leading to lethal levels of oxidative stress in downstream neurons. The harlequin (hq) mouse is a model of retinal degeneration associated with increased oxidative stress ideally suited for in vivo testing of drugs targeting excitotoxicity or oxidative stress.
Memantine hydrocholoride is currently used to treat dementia in Alzheimer’s disease due to its moderation of excitotoxicity. Male, age-matched hq and wild type (WT) mice received untreated drinking water or memantine dissolved in drinking water (30 mg/kg/day) at 1 month of age (mo) and were continued on this treatment to 4, 6, 8 and 10 mo (5 mice in each genotype and age cohort). At 2 mo and monthly thereafter, eye function and structure were assessed using electroretinography (ERG) and optical coherence tomography (OCT). Data were analyzed using ANOVA.
WT mice receiving untreated drinking water have normal retinal function up to 10 mo. Hq mice receiving untreated drinking water have reduced retinal function by 2 mo (p=0.01) with an average 71µV/mo rate of degeneration. In vivo OCT and post mortem histology confirmed outer nuclear layer thinning compared to WT at 10 mo. Both hq and WT control mice have normal corneal structure based on OCT imaging and histology. Memantine-exposed hq mice have decreased retinal function compared to hq control mice at 2 mo (p=0.049) but a slower average rate of degeneration (49µV/mo). OCT imaging shows a thicker cornea in memantine-exposed hq mice and histology reveals epithelium thinning, stromal neovascularization, mineralization and neutrophil infiltration. Memantine-exposed WT mice have reduced retinal function by 8 mo (p=0.02) with corneal histopathology evident as early as 6 mo.
Systemic memantine delivery is associated with vision loss and corneal histopathology in both WT and hq mice with greater effect observed in hq mice. Although the hq mouse is an excellent in vivo model for drug delivery testing, earlier intervention with an alternate drug is recommended.
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