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Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate.

Osada M, Sakai T, Kuroyanagi K, Kohno H, Tsuneoka H - Mol. Vis. (2014)

Bottom Line: DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls).Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls.The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan.

ABSTRACT

Purpose: The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU).

Methods: EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was 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 with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes.

Results: Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls.

Conclusions: The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation.

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Related in: MedlinePlus

Histopathologic features of the retina and histological scores of rats with experimental autoimmune uveoretinitis. The average histological score of five histological sections from each animal (n=5) was examined. Representative photographs of the groups treated with vehicle (A), low-dose fenofibrate (FF (20); 20 mg/kg) (B), and high-dose fenofibrate (FF (100); 100 mg/kg) (C) on day 28 post-immunization are shown. The vehicle-treated rats had severe posterior uveoretinitis with destruction of the photoreceptor cell layer with inflammatory cell infiltration in the retina. Rats treated with low-dose fenofibrate exhibited mild inflammatory cell infiltration. Rats treated with high-dose fenofibrate exhibited suppression of inflammation and preservation of the photoreceptor layer. INL; inner nuclear layer, ONL; outer nuclear layer (original magnification, ×100). The mean experimental autoimmune uveoretinitis (EAU) histological severity grades of the rats treated with vehicle, low-dose fenofibrate, and high-dose fenofibrate were 4.32±1.65 (n=5), 4.32±1.65 (n=5), and 4.32±1.65 (n=5), respectively. The scores of the rats treated with high-dose fenofibrate (FF(100)) were significantly lower than that of vehicle- or low-dose fenofibrate-treated rats (D). The results are presented as the mean ± standard deviation (SD) * p<0.0001 versus vehicle-treated group, ** p<0.0001 versus the low-dose fenofibrate-treated group.
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f2: Histopathologic features of the retina and histological scores of rats with experimental autoimmune uveoretinitis. The average histological score of five histological sections from each animal (n=5) was examined. Representative photographs of the groups treated with vehicle (A), low-dose fenofibrate (FF (20); 20 mg/kg) (B), and high-dose fenofibrate (FF (100); 100 mg/kg) (C) on day 28 post-immunization are shown. The vehicle-treated rats had severe posterior uveoretinitis with destruction of the photoreceptor cell layer with inflammatory cell infiltration in the retina. Rats treated with low-dose fenofibrate exhibited mild inflammatory cell infiltration. Rats treated with high-dose fenofibrate exhibited suppression of inflammation and preservation of the photoreceptor layer. INL; inner nuclear layer, ONL; outer nuclear layer (original magnification, ×100). The mean experimental autoimmune uveoretinitis (EAU) histological severity grades of the rats treated with vehicle, low-dose fenofibrate, and high-dose fenofibrate were 4.32±1.65 (n=5), 4.32±1.65 (n=5), and 4.32±1.65 (n=5), respectively. The scores of the rats treated with high-dose fenofibrate (FF(100)) were significantly lower than that of vehicle- or low-dose fenofibrate-treated rats (D). The results are presented as the mean ± standard deviation (SD) * p<0.0001 versus vehicle-treated group, ** p<0.0001 versus the low-dose fenofibrate-treated group.

Mentions: Following induction of EAU, animals were monitored every other day for clinical signs of disease. Clinical scores of day 17 and day 21 post-immunization are shown (Figure 1A,B). The high dose of fenofibrate (100 mg/kg) significantly decreased the clinical score compared with the vehicle-treated group, but the low-dose fenofibrate (20 mg/kg) did not significantly decrease the clinical score on day 17 or 21 post-immunization (Figure 1A,B). The fenofibrate-treated rats exhibited low-grade histological severity (Figure 2A–D). The mean EAU histological severity grade of the high-dose fenofibrate-treated rats was significantly low compared with the control rats and the low-dose fenofibrate-treated rats (Figure 2D). Control rats exhibited severe posterior uveitis with infiltration of inflammatory cells in the retina and destruction of the photoreceptor cell layer (Figure 2A). Rats treated with high-dose fenofibrate (100 mg/kg) exhibited suppression of inflammation and preservation of the photoreceptor cell layer, the target of the immune response. Meanwhile, photoreceptor destruction was not prevented completely by oral fenofibrate at 20 mg/kg or 100 mg/kg, since the treatment was started when the first sign of clinical onset was seen.


Treatment of experimental autoimmune uveoretinitis with peroxisome proliferator-activated receptor α agonist fenofibrate.

Osada M, Sakai T, Kuroyanagi K, Kohno H, Tsuneoka H - Mol. Vis. (2014)

Histopathologic features of the retina and histological scores of rats with experimental autoimmune uveoretinitis. The average histological score of five histological sections from each animal (n=5) was examined. Representative photographs of the groups treated with vehicle (A), low-dose fenofibrate (FF (20); 20 mg/kg) (B), and high-dose fenofibrate (FF (100); 100 mg/kg) (C) on day 28 post-immunization are shown. The vehicle-treated rats had severe posterior uveoretinitis with destruction of the photoreceptor cell layer with inflammatory cell infiltration in the retina. Rats treated with low-dose fenofibrate exhibited mild inflammatory cell infiltration. Rats treated with high-dose fenofibrate exhibited suppression of inflammation and preservation of the photoreceptor layer. INL; inner nuclear layer, ONL; outer nuclear layer (original magnification, ×100). The mean experimental autoimmune uveoretinitis (EAU) histological severity grades of the rats treated with vehicle, low-dose fenofibrate, and high-dose fenofibrate were 4.32±1.65 (n=5), 4.32±1.65 (n=5), and 4.32±1.65 (n=5), respectively. The scores of the rats treated with high-dose fenofibrate (FF(100)) were significantly lower than that of vehicle- or low-dose fenofibrate-treated rats (D). The results are presented as the mean ± standard deviation (SD) * p<0.0001 versus vehicle-treated group, ** p<0.0001 versus the low-dose fenofibrate-treated group.
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Related In: Results  -  Collection

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f2: Histopathologic features of the retina and histological scores of rats with experimental autoimmune uveoretinitis. The average histological score of five histological sections from each animal (n=5) was examined. Representative photographs of the groups treated with vehicle (A), low-dose fenofibrate (FF (20); 20 mg/kg) (B), and high-dose fenofibrate (FF (100); 100 mg/kg) (C) on day 28 post-immunization are shown. The vehicle-treated rats had severe posterior uveoretinitis with destruction of the photoreceptor cell layer with inflammatory cell infiltration in the retina. Rats treated with low-dose fenofibrate exhibited mild inflammatory cell infiltration. Rats treated with high-dose fenofibrate exhibited suppression of inflammation and preservation of the photoreceptor layer. INL; inner nuclear layer, ONL; outer nuclear layer (original magnification, ×100). The mean experimental autoimmune uveoretinitis (EAU) histological severity grades of the rats treated with vehicle, low-dose fenofibrate, and high-dose fenofibrate were 4.32±1.65 (n=5), 4.32±1.65 (n=5), and 4.32±1.65 (n=5), respectively. The scores of the rats treated with high-dose fenofibrate (FF(100)) were significantly lower than that of vehicle- or low-dose fenofibrate-treated rats (D). The results are presented as the mean ± standard deviation (SD) * p<0.0001 versus vehicle-treated group, ** p<0.0001 versus the low-dose fenofibrate-treated group.
Mentions: Following induction of EAU, animals were monitored every other day for clinical signs of disease. Clinical scores of day 17 and day 21 post-immunization are shown (Figure 1A,B). The high dose of fenofibrate (100 mg/kg) significantly decreased the clinical score compared with the vehicle-treated group, but the low-dose fenofibrate (20 mg/kg) did not significantly decrease the clinical score on day 17 or 21 post-immunization (Figure 1A,B). The fenofibrate-treated rats exhibited low-grade histological severity (Figure 2A–D). The mean EAU histological severity grade of the high-dose fenofibrate-treated rats was significantly low compared with the control rats and the low-dose fenofibrate-treated rats (Figure 2D). Control rats exhibited severe posterior uveitis with infiltration of inflammatory cells in the retina and destruction of the photoreceptor cell layer (Figure 2A). Rats treated with high-dose fenofibrate (100 mg/kg) exhibited suppression of inflammation and preservation of the photoreceptor cell layer, the target of the immune response. Meanwhile, photoreceptor destruction was not prevented completely by oral fenofibrate at 20 mg/kg or 100 mg/kg, since the treatment was started when the first sign of clinical onset was seen.

Bottom Line: DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls).Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls.The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan.

ABSTRACT

Purpose: The peroxisome proliferator-activated receptor α (PPARα) agonist has been approved for treating hypercholesterolemia and lipid abnormalities. Researchers have recently discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. This study aims to investigate the therapeutic effects of fenofibrate on experimental autoimmune uveoretinitis (EAU).

Methods: EAU was induced in Lewis rats using bovine S-antigen (S-Ag) peptide. Fenofibrate was suspended in 3% arabic gum and administered orally at a high dose of 100 mg/kg and at a low dose of 20 mg/kg every day. Fenofibrate treatment was 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 with [3H] thymidine incorporation into antigen-stimulated T cells from inguinal lymph nodes.

Results: Clinical and histological scores of EAU were decreased in the fenofibrate-treated groups. The expression of inflammatory cytokines and Müller cell proliferation were inhibited in the fenofibrate-treated groups. DTH was significantly inhibited in the fenofibrate-treated groups, compared with the vehicle-treated groups (controls). Lymphocyte proliferation assay demonstrated decreased proliferation in the presence of 25 mg/ml S-Ag peptide in the fenofibrate-treated groups compared with controls.

Conclusions: The current results indicate that fenofibrate administered orally following clinical onset has therapeutic effect in EAU. Fenofibrate may be useful for treating intraocular inflammation.

Show MeSH
Related in: MedlinePlus