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Ian M MacDonald, Amany Mohamed, Sarah Samuelson, Ioannis S. Dimopoulos, Monika Sharma, Yves Sauve, Elena Posse de Chaves; Impaired retinal signal transmission in simvastatin fed mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):223.
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Simvastatin reduces cholesterol levels and decreases isoprenoid production; isoprenoids play a role in the post-translational modification of small GTPases (prenylation). Since, many retinal diseases have been associated with impaired prenylation of small GTPases, we examined whether simvastatin-induced inhibition of protein prenylation would impact retinal function.
C57BL6 mice were tested with two simvastatin treatment protocols and compared to untreated controls: (i) a low-dose of 10mg/kg/day simvastatin for 6 months (n=16), and (ii) a high-dose of 50mg/kg/day simvastatin for 3 months (n=7). Intensity-series of dark- and light-adapted full field electroretinograms (ERGs) were recorded and Naka-Rushton functions fit to estimate rod photoreceptor Vmax and K-value parameters. Eyes were dissected and processed for RPE flat mount preparation and retina cryo-sections, with a subset used to perform biochemical analysis of the cholesterol mass (Amplex Red Cholesterol Assay Kit and gas-liquid chromatography). RT-PCR was used to measure the expression level of the HMG-CoA reductase gene and a Rab GDI capturing method to analyze protein prenylation.
Simvastatin treatment was not associated with a change in the amplitude of ERG responses in C57BL6 mice (p>0.24). However, the mean rod photoreceptor K-values were significantly higher (p<0.03) in both groups of simvastatin-treated mice. Cryo-sections and RPE flat mounts revealed bipolar cell sprouting and larger RPE cells in the treated animals. The levels of retinal cholesterol mass and Rab protein prenylation did not differ between treated and untreated mice.
These experiments suggest that simvastatin treatment may affect sensitivity of rod photoreceptor retinal function even at low-doses. This side effect may be common to all statins and particularly relevant to patients with retinal disorders with a pre-existing defect in prenylation, such as choroideremia.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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