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Evening primrose oil and celecoxib inhibited pathological angiogenesis, inflammation, and oxidative stress in adjuvant-induced arthritis: novel role of angiopoietin-1

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Abstract

Rheumatoid arthritis is a chronic inflammatory disease characterized by overproduction of inflammatory mediators along with undermined oxidative defensive mechanisms. Pathological angiogenesis was found to play a critical role in the progression of this disease. The current study was carried out to evaluate the anti-angiogenic, anti-inflammatory, and anti-oxidant effects of evening primrose oil (EPO), rich in gamma linolenic acid (GLA), either alone or in combination with aspirin or celecoxib, on adjuvant-induced arthritis. Arthritis was induced by subcutaneous injection of complete Freund’s adjuvant (CFA) in the right hind paw of male albino rats. All treatments were administered orally from day 0 (EPO, 5 g/kg b.w.) or day 4 (celecoxib, 5 mg/kg; aspirin, 150 mg/kg) till day 27 after CFA injection. In the arthritic group, the results revealed significant decrease in the body weight and increase in ankle circumference, plasma angiopoietin-1 (ANG-1) and tumor necrosis factor-alpha (TNF-α) levels. Anti-oxidant status was suppressed as manifested by significant decline in reduced glutathione content along with decreased enzymatic activity of superoxide dismutase and increased lipid peroxidation. Oral administration of EPO exerted normalization of body weight, ANG-1, and TNF-α levels with restoration of activity as shown by reduced malondialdehyde levels. Moreover, histopathological examination demonstrated that EPO significantly reduced the synovial hyperplasia and inflammatory cells invasion in joint tissues, an effect that was enhanced by combination with aspirin or celecoxib. The joint use of GLA-rich natural oils, which possess anti-angiogenic, anti-inflammatory, and anti-oxidant activities, with traditional analgesics represents a promising strategy to restrain the progression of rheumatoid arthritis.

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Acknowledgments

The authors express gratitude to Dr. Hend M. Tag, Assistant Professor of Physiology, Faculty of Science, Suez Canal University, Ismailia, Egypt, for her valuable assistance with photomicrography and histopathology scoring. They also would like to thank Mr. Mohamed I. El-Assaal for his great efforts in keeping the animals under uniform experimental conditions. Celecoxib and aspirin were kindly provided by Pfizer Co. for Pharm. & Chemical Ind. and Sigma Pharmaceutical Co., Egypt, respectively.

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Correspondence to M. F. El-Azab.

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Supplemental Fig. 1. Correlation between plasma levels of TNF-α (upper panel) or body weight (lower panel) and ankle circumference in adjuvant induced arthritic rats. Analyses were done on day 27. r denotes the Pearson’s correlation coefficient obtained for the linear regression line.

Supplemental Fig. 2. Photomicrographs represent changes of mononuclear cell infiltration in the hind limb of adjuvant induced arthritic rats. (A) Score 0, no infiltration; (B) Score 1, mild infiltration; (C) Score 2, moderate infiltration; (D) Score 3, severe infiltration. Histological examination using H&E staining of the foot joint (X100) (n = 6).

Supplemental Fig. 3. Photomicrographs represent scores changes of cartilage and bone destruction by pannus formation in the hind limb of adjuvant induced arthritic rats. (A) Score 0, no change; (B) Score 1, mild change [pannus invasion within cartilage]; (C) Score 2, moderate change [pannus invasion into cartilage/subchondral bone]; (D) Score 3, severe change [pannus invasion into the subchondral bone]. Histological examination using H&E staining of the foot joint (X100) (n = 6).

Supplemental Fig. 4. Photomicrographs represent scores changes of vascularity in the hind limb of adjuvant induced arthritic rats. (A) Score 0, almost no blood vessels; (B) Score 1, a few blood vessels; (C) Score 2, some blood vessels; (D) Score 3, many blood vessels. Histological examination using H&E staining of the foot joint (X100) (n = 6).

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El-Sayed, R.M., Moustafa, Y.M. & El-Azab, M.F. Evening primrose oil and celecoxib inhibited pathological angiogenesis, inflammation, and oxidative stress in adjuvant-induced arthritis: novel role of angiopoietin-1. Inflammopharmacol 22, 305–317 (2014). https://doi.org/10.1007/s10787-014-0200-5

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