June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Mouse retina is amenable to cholesterol lowering by a statin
Author Affiliations & Notes
  • Joseph B Lin
    Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States
  • Natalia Mast
    Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States
  • Marcin Golczak
    Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States
  • Irina A Pikuleva
    Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Joseph Lin, None; Natalia Mast, None; Marcin Golczak, None; Irina Pikuleva, None
  • Footnotes
    Support  NIH Grant R01 EY018383
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 222. doi:
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    • Get Citation

      Joseph B Lin, Natalia Mast, Marcin Golczak, Irina A Pikuleva; Mouse retina is amenable to cholesterol lowering by a statin. Invest. Ophthalmol. Vis. Sci. 2017;58(8):222.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To establish whether cholesterol-lowering drugs statins can cross the blood-retinal barrier in mice and lower retinal cholesterol.

Methods : In a pilot experiment, two lipophilic statins (simvastatin and atorvastatin) and two hydrophilic statins (pravastatin and rosuvastatin) were evaluated. Statin doses corresponded to ~40-50% reduction of low-density lipoprotein cholesterol in humans. Simvastatin (60 mg/kg bodyweight), pravastatin (80 mg/kg bodyweight), and rosuvastatin (15 mg/kg bodyweight) were injected intraperitoneally to C57BL/6J mice, whereas atorvastatin (30 mg/kg bodyweight) was given orally by gavage. At times specific for each statin (ranging from 2-6 hours post-administration), mice were anesthetized and either perfused or not perfused through the heart with phosphate-buffered saline prior to sacrifice. Retinas were isolated, extracted with 100% acetonitrile, and analyzed for the presence of statin and statin metabolites by liquid chromatography-mass spectrometry. In the next experiment, mice were put on a 0.3% cholesterol-containing diet for 2 weeks followed by simvastatin treatment for 4 weeks, which was delivered in the chow (60 mg/kg bodyweight). At the end of the treatment, mice were sacrificed, and total retinal cholesterol was quantified by gas chromatography-mass spectrometry.

Results : Only simvastatin along with its active metabolite simvastatin hydroxy acid was consistently detectable in the retinas of mice after intraperitoneal injection, and signal intensity was higher in non-perfused animals than perfused animals. Pravastatin was detectable in non-perfused mice only, while rosuvastatin and atorvastatin were not detectable in either perfused or non-perfused mice. Subsequent long-term treatment with simvastatin decreased retinal cholesterol from 48±1 to 28±1 nmol/mg protein (p<0.001).

Conclusions : Simvastatin, a lipophilic statin, can penetrate the blood-retinal barrier and lower retinal cholesterol in mice. It remains to be determined whether hydrophilic statins can reach the retina, as they may be present in the retina at concentrations lower than the limits of detection. Studies evaluating how local retinal cholesterol biosynthesis and retinal uptake of systemic cholesterol respond to simvastatin treatment are ongoing.

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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