Abstract
1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum® which is being mainly used for the maintenance of sinus and respiratory health. Due to its clinically valuable properties, 1,8-cineole has gained significant scientific interest over the recent years specifically to investigate its anti-inflammatory and antioxidant effects. However, the impact of 1,8-cineole on the modulation of platelet activation, thrombosis and haemostasis was not fully established. Therefore, in this study, we demonstrate the effects of 1,8-cineole on agonists-induced platelet activation, thrombus formation under arterial flow conditions and haemostasis in mice. 1,8-cineole largely inhibits platelet activation stimulated by glycoprotein VI (GPVI) agonists such as collagen and cross-linked collagen-related peptide (CRP-XL), while it displays minimal inhibitory effects on thrombin or ADP-induced platelet aggregation. It inhibited inside-out signalling to integrin αIIbβ3 and outside-in signalling triggered by the same integrin as well as granule secretion and intracellular calcium mobilisation in platelets. 1,8-cineole affected thrombus formation on collagen-coated surface under arterial flow conditions and displayed a minimal effect on haemostasis of mice at a lower concentration of 6.25 µM. Notably, 1,8-cineole was found to be non-toxic to platelets up to 50 µM concentration. The investigation on the molecular mechanisms through which 1,8-cineole inhibits platelet function suggests that this compound affects signalling mediated by various molecules such as AKT, Syk, LAT, and cAMP in platelets. Based on these results, we conclude that 1,8-cineole may act as a potential therapeutic agent to control unwarranted platelet reactivity under various pathophysiological settings.
Highlights
Cardiovascular diseases (CVD) thrombotic conditions such as ischemic stroke and heart attacks are the leading cause of death around the modern world.Platelets are small anucleated circulating blood cells and they play an essential role in the maintenance of haemostasis through blood clotting upon vascular injury [1].the inappropriate activation of platelets during pathological conditions such as upon the rupture of atherosclerotic plaque results in the formation blood clots within the vasculature leading to reduced/blocked blood supply to vital organs such as the heart and brain
Intrigued by the broad range of beneficial effects of 1,8-cineole, here, we demonstrate its effects in the modulation of platelet activation, thrombus formation and haemostasis
platelet-rich plasma (PRP)) were used as agonists, 1,8-cineole inhibited fibrinogen binding only at a higher concentration (50 μM). These results demonstrate that 1,8-cineole is able to affect the insideout signalling to integrin αIIbβ3, and thereby controls the level of fibrinogen binding on the platelet surface and subsequent platelet aggregation
Summary
Platelets are small anucleated circulating blood cells and they play an essential role in the maintenance of haemostasis through blood clotting upon vascular injury [1]. The inappropriate activation of platelets during pathological conditions such as upon the rupture of atherosclerotic plaque results in the formation blood clots (thrombi) within the vasculature leading to reduced/blocked blood supply to vital organs such as the heart and brain. Platelets act as a powerful therapeutic target to prevent/treat thrombotic diseases and anti-platelet drugs such as aspirin and clopidogrel play predominant roles in the treatment, management, and prevention of these conditions. There is an unmet clinical need for more effective and safer anti-platelet drugs to prevent and treat thrombotic diseases [2]
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