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R. Roberts, M. Gradianu, B. A. Berkowitz; Manganese-Enhanced MRI Studies of Diabetic Mice: Effect of Superoxide Dismutase Overexpression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4926.
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To determine first if manganese-enhanced MRI (MEMRI), a powerful non-invasive approach for the study of intraretinal ionic regulation in rats, is also applicable to mouse models. Application of MEMRI before the appearance of vascular histopathology in diabetic rats revealed subnormal intraretinal ionic regulation which could be corrected by α-lipoic acid treatment (IOVS 48:4753 (2007)). α-lipoic acid is an anti-oxidant although it can affect other pathways. In this study, we also tested the hypothesis that increased oxidative protection, via Cu/Zn superoxide dismutase (SOD1) overexpression, prevents the early ionic dysregulation in diabetic mice.
Four hours post 66 mg/Kg MnCl2 injection i.p., high resolution MEMRI data were collected from over-night dark-adapted male 5.5 mo wildtype (WT, n = 6) and 7 mo diabetic male C57BL/6 mice (n = 5), and 7 mo control (n = 5) and diabetic male SOD1 overexpressor mice (n = 5). For comparison to the dark adapted data, a different group of WT mice (n = 4) were studied after light adaption. In all cases, central retinal thickness and intraretinal ion activity were measured from MEMRI data. Glycated hemoglobin was determined spectrophotometrically.
Similar to results previously reported in rats, in WT mice, light adaptation produced a larger (P < 0.05) difference in inner and outer retinal manganese uptake (18%) than that measured in dark adapted mice (1%). As expected, glycated hemoglobin levels for diabetic control (12.6 + 0.7%, mean + SEM) and diabetic SOD1 (10.9 + 0.7%) mice were supernormal (P < 0.05) when compared to wildtype control (5.85 + 0.10%) and SOD1 control (5.08 + 0.21%) mice. Despite some differences (P < 0.05) in MEMRI-determined whole retinal thicknesses between groups (range 204 - 225 µm), all values were within 10% of the mean WT thickness (220.8 + 1.3 µm). Similar to previous data in rats, intraretinal manganese uptake in dark adapted diabetic C57BL6 mice was subnormal (P < 0.05). In contrast, intraretinal ionic activities were similar (P > 0.05) in both SOD1 overexpressor mice and diabetic overexpressors.
First time evidence is reported that MEMRI and a modest dose of systemically administered MnCl2 robustly measures layer specific ionic regulation in mice. These data also support our hypothesis that early diabetes-induced disruption in intraretinal ionic regulation and later vascular histopathology are modulated by increased oxidative stress. MEMRI is a powerful approach for the study of early changes in diabetes-induced ionic dysregulation and predicting treatment efficacy.
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