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Rene C. Renteria, Asta Vasalauskaite, Nikolay P. Akimov, Songqing Lu; Chronic Rapamycin Treatment Causes a Deficit in Optokinetic Tracking in Male Mice and Does Not Prevent Tracking Deficits in the Ins2Akita Mouse Model of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3290.
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Diabetic retinopathy (DR) is a complex, multifactorial disease that affects both neuronal and vascular function. Mechanistic links between the pathologies are not clearly understood, but the retinal injury in DR includes vessel hyper-permeability resulting from high vascular endothelial growth factor (VEGF) expression. Endothelial cells, pericytes, and retinal neurons are progressively lost. The Ins2Akita model of diabetes (Akita) recapitulates these aspects of DR, and Akita mice have deficits in optokinetic tracking (OKT; Akimov & Rentería, 2011). Because VEGF-induced hyper-permeability is known to be suppressed by the mTOR inhibitor rapamycin, here we tested the hypothesis that chronic rapamycin treatment ("Rapa") would improve OKT visual performance of the Akita mouse.
Diabetic Akita mice were fed control chow or chow containing micro-encapsulated rapamycin from 1 until 7 months (mos) of age. Two groups of non-diabetic mice were fed the control or Rapa diet from 3 until 18 mos. Spatial frequency threshold at maximum contrast (SPFT) and contrast sensitivity (CS) at 0.103 cyc/deg of OKT were determined (OptoMotry; Cerebral Mechanics, Inc.). A third group of non-diabetic mice was fed from 4 until 25 mos. Retinas were stained with cell type-specific markers in order to count neuron numbers.
Rapa neither protected against nor worsened OKT decline in diabetic male Akita mice. Rapa, however, was detrimental to OKT performance in normal mice, causing decreased SPFT in male, but not female, mice at 18 mos (male Ctrl: 0.379 cyc/deg ctrl; 0.344 cyc/deg Rapa.; p<0.0001). Rapa did not slow normal, age-related OKT decline. Non-diabetic, 25 mos, Rapa-fed male mice had decreased inner plexiform layer (IPL) thickness in the retinal periphery, but we detected no change in numbers of retinal ganglion cells, dopaminergic amacrine cells, and cholinergic amacrine cells compared to age- and sex-matched, control-fed mice.
Rapa does not prevent either diabetes-induced or age-related declines in OKT visual function and retinal neuron number. Rapa was detrimental, causing an OKT SPFT deficit in non-diabetic male mice. Rapa, which increases lifespan in mice, may thus decrease vision healthspan during normal male aging.
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