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Effect of AP39 or ATB346 treatment, a mitochondrial targetting- and hybrid-H2S donor, respectively, in experimental models of thrombosis: In vivo in cerebral blood vessels and in vitro assays.

Grant number: 23/05115-2
Support Opportunities:Regular Research Grants
Duration: October 01, 2023 - September 30, 2025
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Stephen Fernandes de Paula Rodrigues
Grantee:Stephen Fernandes de Paula Rodrigues
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Marcelo Nicolas Muscara

Abstract

Coagulation is a complex phenomenon involving extra and intravascular, and extra and intracellular events that normally lead to thrombus formation and subsequent hemostasis, avoiding blood lost and death. However, this process needs to be carefully balanced to avoid disseminated thrombus formation, hypoxia, and tissue death. Thrombosis is one of the main causes of morbidity and mortality in the world as it is related to frequent and fatal diseases such as thrombotic ischemic stroke and acute myocardial infarction (AMI). There are two types of thrombosis, arterial and venous. Antithrombotic and antiplatelet drugs are effective as preventive or therapeutical treatment for both thrombosis; however, a common side effect is hemorrhage, which can be fatal. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs), which are antiplatelet drugs largely used in the clinic, often lead to gastrointestinal side effects. Therefore, it is necessary to discover safer antithrombotic/antiplatelet drugs. Physiological hemostasis can be influenced by gasomediators, including hydrogen sulfide (H2S). Due to the extremely labile nature of H2S, donors with a longer half-life were created to act as potential therapeutic agents, including AP39 and ATB-346. AP39 is a rapid mitochondrial-targeted H2S release donor that has shown a cytoprotective effect on several cell types, including endothelial cells and platelets under oxidative stress condition. ATB-346 is a H2S donor coupled to naproxen that longer and rapidly reduces the activity of COX, an important pro-inflammatory enzyme, with no concomitant gastrointestinal side effects, which usually happens when naproxen is used alone. However, despite of inflammation, oxidative stress and coagulation share common activation steps, it is not known whether these H2S donors exert any vascular protective action on thrombus formation. Thus, we will use in vivo and in vitro assays, and molecular ones, to measure the antithrombotic and antiplatelet effects of AP39 and ATB-346. Pial cerebral blood vessels of male C57BL/6 mice will be used, in vivo, to measure thrombus formation. Cerebral blood vessels were chosen because they are critical for development of thrombotic stroke. Moreover, it will be assayed in brain: in vivo perivascular reactive oxygen species (ROS), the thromboxane B2 (TXB2), prostacyclin (PGI2) and H2S concentration, the cystathionine beta-synthase (CBS) - the main H2S-producing enzyme in the brain -, caspase 1 and interleukin 1 beta (IL-1²) expression. It was reported H2S can act, at least partially, through the caspase 1/IL-1² axis. In vitro, it will be measured prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen concentration using plasma poor in platelets, the ±IIb²III integrin and P-selectin expression in thrombin- or ADP-stimulated platelets, and the time for thrombus formation in thrombin- or ADP-stimulated plasma rich in platelets, and the TXB2 and H2S concentration in this supernatant. It will also be measured macroscopic injuries in stomach and counted circulating platelets. Thus, we hope to gather evidence pointing the use of AP39 and/or ATB-346 as potential therapies for thrombotic diseases. (AU)

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