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Hideo Kohnoa, Tsutomu Sakaia, Saburo Saitob, Kiichiro Okanoa and Kenji
Kitaharaa
Jikei University School of Medicine
Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors, are approved for cholesterol reduction and
are commonly used to treat atherosclerosis and coronary artery
disease. Statins may also be potent immunomodulatory agents and
may be beneficial in the treatment of autoimmune diseases.
In this study, we investigated therapeutic effects of atorvastatin
and lovastatin on experimental autoimmune uveoretinitis (EAU).
EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide.
Atorvastatin was suspended in 0.5% aqueous methylcellulose and
was administered orally at a dose of 10 mg/kg and at a low-dose
of 1 mg/kg. Lovastatin was dissolved in DMSO:PBS (1:1) and was
administered by intraperitoneal (i.p.) injection at a dose of
2 mg/kg. Both statin treatments were initiated after the clinical
onset once daily for 14 days. The rats were examined every other
day for clinical signs of EAU. The histological scores and delayed-type
hypersensitivity (DTH) were evaluated on day 28 post-immunization.
Morphologic and immunohistochemical examinations were performed
with light and confocal microscopy, respectively. Lymphocyte proliferation
was measured by [3H]thymidine incorporation into antigen-stimulated
T cells from inguinal lymph nodes. After 72 h, supernatants were
collected and assayed for IFN-γ by ELISA.
Clinical and histological scores of EAU were decreased in both
the atorvastatin (10 mg/kg)- and lovastatin (2 mg/kg)-treated
groups. The invasion of T cells and macrophages, and Müller cell
proliferation, were inhibited in both atorvastatin- and lovastatin-treated
groups. DTH was significantly inhibited in both groups, compared
with vehicle-treated groups (controls). Lymphocyte proliferation
assay demonstrated decreased proliferation in the presence of
25 μg/ml S-Ag peptide in both groups, compared with controls.
In the supernatants of lymph node cells stimulated with S-Ag peptide
(5 μg/ml), 77 or 87% inhibition of IFN-γ production was observed
in rats treated with atorvastatin or lovastatin, respectively,
compared with controls. The current results indicate that atorvastatin
administrated orally following the clinical onset has therapeutic
effect in EAU as well as lovastatin administrated intraperitoneally.
Statins may be useful for treating intraocular inflammation.
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