The anti-platelet drug cilostazol enhances interrenal steroidogenesis and exerts a scant effect on innate immune responses in zebrafish

Abstract

Rationale: Cilostazol, an anti-platelet phosphodiesterase-3 inhibitor used for the treatment of intermittent claudication, is known for its pleiotropic effects on platelets, endothelial cells and smooth muscle cells. However, how cilostazol impacts the endocrine system and the injury-induced inflammatory processes remains unclear. Methods: We used the zebrafish, a simple transparent model that demonstrates rapid development and a strong regenerative ability, to test whether cilostazol influences steroidogenesis, and the temporal and dosage effects of cilostazol on innate immune cells during tissue damage and repair. Results: While dosages of cilostazol from 10 to 100 uM did not induce any noticeable morphological abnormality in the embryonic and larval zebrafish, the heart rate and adrenal/interrenal steroidogenesis in larval zebrafish was increased in a dose-dependent manner. During larval fin amputation and regeneration, cilostazol treatments did not affect the immediate injury-induced recruitment of either neutrophils or macrophages, followed by a subtle yet significant effect on reducing the neutrophil retention at the lesion site. Conclusions: Our results indicate that cilostazol has a significant effect on the growth and endocrine function of steroidogenic tissue; and a limited effect on the neutrophil retention without affecting neutrophil and macrophage recruitment during tissue damage and repair.