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T. C. MacPherson, K. C. Leonard, K. A. Hill, C. M. L. Hutnik; In vivo Model for Drug Delivery Testing: Memantine Treated Mouse Model of Retinal Degeneration Followed With Electroretinography. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5918.
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Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world with its prevalence increasing greatly in the elderly. While AMD pathogenesis remains poorly understood, current scientific literature has provided strong evidence for a role of oxidative stress in the development of AMD. The harlequin mutant mouse is a genetic model of oxidative stress-mediated retinal degeneration, and thus is relevant to certain aspects of AMD. This model has a drastic reduction in expression of the AIF gene, a gene typically involved in the programmed cell death pathway and also aiding in antioxidant defence. With a reduction in expression levels, a resulting deregulation of apoptosis and weakened antioxidant defence result. Progressive retinal degeneration is first observed in the ganglion cell layer at three months of age.
An appropriate protocol was designed for testing retinal function in mice using electroretinography (ERG). Harlequin mice were then compared to age-matched wild type mice of the same inbred background through ERG testing to illustrate the dramatic effect of progressive age-related retinal degeneration on visual acuity. Also, the feasibility of early intervention with chronic drug delivery to harlequin mice was assessed using the neuroprotective agent memantine dissolved in drinking water and delivered orally at a dose of 30 mg/kg/day. Treatment began prior to disease onset at one month of age with early ERG testing performed after one month of treatment.
In untreated harlequin and wild type animals, significant differences in retinal function were detected (p=0.0167; Fisher’s Exact Test). Harlequin mice at the age of 6 months had a 3.3 fold decrease in retinal function when compared to 8 month old wild type mice. Early and chronic memantine delivery showed no taste aversion based on body weight and daily treated water consumption. Early electroretinography after one month of drug delivery shows no significant difference in ERG test results in sentinels from each of the two experimental cohorts.
Results confirm feasibility of ERG testing prior to disease onset, late in disease progression, and with chronic drug delivery in a transgenic mouse model of oxidative stress-mediated progressive retinal degeneration. Our results establish an in vivo model for drug testing in a mammalian model of human retinal degeneration related to aging.
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