Cilostazol exerts antiplatelet and anti‐inflammatory effects through AMPK activation and NF‐kB inhibition on hypercholesterolemic rats

Abstract

This work presents a model of rats fed a high-cholesterol diet, receiving a long-term oral administration of cilostazol, a PDE3-inhibitor. The aim of this study was to evaluate the molecular mechanisms by which cilostazol interferes with platelets signaling pathways to avoid atherosclerosis early development. Male Wistar rats were divided into 3 groups: Control group received standard rat chow (C), hypercholesterolemic group (HCD), and HCD+CIL (cilostazol group) received hypercholesterolemic diet for 45 days. HCD+CIL group received cilostazol (30 mg/kg/p.o.) once daily in the last 15 days. Platelet aggregation, lipid profile, lipid peroxidation, and cytokine serum levels were assessed. Expression of P-selectin, CD40L, PKC-α, IkB-α, and iNOS and activation of AMPK, NF-κB, and eNOS in the platelets were assessed using Western blot analysis. Cilostazol reduced the levels of total cholesterol (361.0 ± 12.8 vs. 111.5 ± 1.6 mg/dL), triglycerides (186.9 ± 17.7 vs. 55.4 ±3.1 mg/dL), cLDL (330.9 ± 9.7 vs. 61.5 ± 3.5 mg/dL), cVLDL (45.0 ± 4.6 vs. 11.1 ± 0.6 mg/dL), and malondialdehyde (9.4 ± 0.5 vs. 3.2 ± 0.3 nmol/mL) compared to the HCD group. Cilostazol presented antiplatelet properties and decreased inflammatory markers levels. These effects seem to be related to AMPK activation, NF-kB inhibition, and eNOS activation.

A pathophysiological role of PDE3 in allergic airway inflammation

“…However, clinical data suggest that PDE3 inhibition therapy given via infusion in heart failure, bypass operations, and enterovirus 71 infection did show antiinflammatory effects (37)(38)(39). During the last decade, a growing number of studies suggest that PDE3 inhibition might be involved in immunosuppression (40)(41)(42)(43)(44)(45)(46)(47)(48), although there is no definitive proof. There have been concerns that PDE3 inhibitors were associated with increased cardiovascular mortality in previous clinical trials (49,50).…”

Cilostazol Suppresses IL-23 Production in Human Dendritic Cells via an AMPK-Dependent Pathway

“…However whether cilostazol could be used as a potential drug to target DCs warrants further study. Some reports have shown that the effect of cilostazol is associated with the activation of the AMPK pathway, and this effect has been validated in various models [20,21,24,25]. Furthermore, AMPK has been suggested to play an important role in TLRs-induced IL-23 production [26].…”

“…3, IL23A promoter activity was * P < 0.05 vs. zymosan alone, ** P < 0.01 vs. zymosan alone, # P < 0.05 vs. cilostazol plus zymosan treatment. [20,21]. Thus, we aimed to clarify whether the inhibitory effect of cilostazol on IL-23 production by mo-DCs was mediated by AMPK by treating cells with an AMPK agonist (A-769662) and an AMPK antagonist (Compound C).…”

A Comparison of the Anti-Inflammatory Effects of Four Combined Statin and Antiplatelet Therapies on Tumor Necrosis Factor-Mediated Acute Inflammation <b><i>in vivo</i></b>

“…However, platelet activation and aggregation induced by membrane receptor P2Y 12 , adenosine diphosphate or platelet glycoprotein IIb/IIIA cause thrombosis, atherosclerosis, systemic inflammation, and cancer DOI: 10.1159/000499335 [2,3]; thus, the blockade of platelet activation is important for therapeutic field. Cilostazol, an inhibitor of platelet aggregation, has been used to treat patients with peripheral vascular disease and coronary interventions, due to its anti-inflammatory and anti-atherosclerotic properties [4,5]. Clopidogrel, a prodrug, is converted to its active form by the cytochrome P450 3A4 (CYP3A4) pathway in the liver, and the active metabolite exerts antiplatelet effect by inhibiting the P2Y 12 receptor [6].…”