The Road to Low-Dose Aspirin Therapy for the Prevention of Preeclampsia Began with the Placenta

The road to low-dose aspirin therapy for the prevention of preeclampsia began in the 1980s with the discovery that there was increased thromboxane and decreased prostacyclin production in placentas of preeclamptic women. At the time, low-dose aspirin therapy was being used to prevent recurrent myocardial infarction and other thrombotic events based on its ability to selectively inhibit thromboxane synthesis without affecting prostacyclin synthesis. With the discovery that thromboxane was increased in preeclamptic women, it was reasonable to evaluate whether low-dose aspirin would be effective for preeclampsia prevention. The first clinical trials were very promising, but then two large multi-center trials dampened enthusiasm until meta-analysis studies showed aspirin was effective, but with caveats. Low-dose aspirin was most effective when started <16 weeks of gestation and at doses >100 mg/day. It was effective in reducing preterm preeclampsia, but not term preeclampsia, and patient compliance and patient weight were important variables. Despite the effectiveness of low-dose aspirin therapy in correcting the placental imbalance between thromboxane and prostacyclin and reducing oxidative stress, some aspirin-treated women still develop preeclampsia. Alterations in placental sphingolipids and hydroxyeicosatetraenoic acids not affected by aspirin, but with biologic actions that could cause preeclampsia, may explain treatment failures. Consideration should be given to aspirin’s effect on neutrophils and pregnancy-specific expression of protease-activated receptor 1, as well as additional mechanisms of action to prevent preeclampsia.

CHARACTERISTICS AND THERAPEUTIC EFFECTS OF THE NOVEL FREE RADICAL SCAVENGER – EDARAVONE

Edaravone is the first free radical scavenger which approved clinically and has an ability to decrease the level of free radicals in cells. Edaravone is a strong antioxidant, which can protect different cells (e.g. endothelial cells) against damage by ROS by inhibiting the lipoxygenase metabolism of arachidonic acid, by trapping hydroxyl radicals, by increasing prostacyclin production, by inhibiting alloxan-induced lipid peroxidation, etc. Because of that, Edaravone is used in treatment of diseases which are associated with oxidative stress. Key words: edaravone, free radical, antioxidant, neuroprotective agent, oxidative stress

Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox

Rationale: Endothelial cells (ECs) and platelets, which respectively produce antithrombotic prostacyclin and prothrombotic thromboxane A 2 , both express COX1 (cyclooxygenase1). Consequently, there has been no way to delineate any antithrombotic role for COX1-derived prostacyclin from the prothrombotic effects of platelet COX1. By contrast, an antithrombotic role for COX2, which is absent in platelets, is straightforward to demonstrate. This has resulted in an incomplete understanding of the relative importance of COX1 versus COX2 in prostacyclin production and antithrombotic protection in vivo. Objective: We sought to identify the role, if any, of COX1-derived prostacyclin in antithrombotic protection in vivo and compare this to the established protective role of COX2. Methods and Results: We developed vascular-specific COX1 knockout mice and studied them alongside endothelial-specific COX2 knockout mice. COX1 immunoreactivity and prostacyclin production were primarily associated with the endothelial layer of aortae; freshly isolated aortic ECs released >10-fold more prostacyclin than smooth muscle cells. Moreover, aortic prostacyclin production, the ability of aortic rings to inhibit platelet aggregation and plasma prostacyclin levels were reduced when COX1 was knocked out in ECs but not in smooth muscle cells. When thrombosis was measured in vivo after FeCl 3 carotid artery injury, endothelial COX1 deletion accelerated thrombosis to a similar extent as prostacyclin receptor blockade. However, this effect was lost when COX1 was deleted from both ECs and platelets. Deletion of COX2 from ECs also resulted in a prothrombotic phenotype that was independent of local vascular prostacyclin production. Conclusions: These data demonstrate for the first time that, in healthy animals, endothelial COX1 provides an essential antithrombotic tone, which is masked when COX1 activity is lost in both ECs and platelets. These results help us define a new 2-component paradigm wherein thrombotic tone is regulated by both COX1 and COX2 through complementary but mechanistically distinct pathways.

Role of Cyclooxygenase Pathway and Risk Associated with Non-Steroidal Anti-inflammatory Drugs Therapy in Cardiovascular Diseases

<p>Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase enzyme activity through different<br />mechanisms and prevent inflammation. But they all have different risks associated with them. Some are associated with<br />gastrointestinal bleeding and some are strongly allied with the cardiovascular risks. Cyclooxygenase enzyme regulates<br />prostaglandin synthesis by converting arachidonic acid present at the sn-2 position of membrane phospholipids to<br />prostaglandin H2. Prostaglandin H2 is the precursor of all prostaglandins. There are two isoforms of cyclooxygenase<br />enzyme, cyclooxygenase-1 and cyclooxygenase-2 which differ in their active site due to an isoleucine to valine<br />substitution at amino acid 523 in cyclooxygenase-2. Cyclooxygenase-1 is constitutively expressed in platelets<br />where it helps in the formation of thromboxane whereas cyclooxygenase-2 is inductive form and is expressed in<br />the endothelial cells due to shear stress and forms prostacyclins. Both thromboxanes and prostacyclins maintain<br />the homeostasis of the vascular wall. During vascular injury prostacyclin production decreases as a result of which<br />thromboxane synthesis increases in the platelets which leads to platelet aggregation. Although, being strongly<br />associated with cardiovascular risks, NSAIDs are still prescribed to the patients to prevent pain according to their<br />condition. So this review aims to summarise the mechanism of cyclooxygenase pathway, possible mechanism of<br />action of NSAIDs and the risks of cardiovascular events associated with the use of NSAIDs.</p>