
Maternal and neonatal mortality is a global public health problem, that leads to about 295,000 maternal deaths every year during pregnancy and childbirth, and 5.2 million deaths among children under five years of age. It remains one of the few fatal complications of pregnancy in industrialised countries today. In contrast to other diseases, the field has not progressed significantly despite the massive global burden it represents.
Professor Rasmussen and his team have been looking at repurposing Beta3 Adrenergic receptor agonists, a drug already FDA-approved for the treatment of overactive bladders, as a treatment that could offer improved care of ‘high-risk’ pregnancies with pre-eclampsia and/or IUGR. It’s hoped that this will enhance future maternal cardiovascular health.
Oxidative damage occurs when there is an increase in the production of reactive oxygen species (ROS) within cells. ROS are highly reactive molecules that can cause damage to cells and tissues, contributing to various diseases, including pre-eclampsia which the team are specifically looking at in this project. They have discovered an abnormality that occurs on part of the Na+-K+ pump that is caused by ROS.
The team have established that when cells were exposed to low oxygen levels followed by reoxygenation (which is a change from low oxygen to normal oxygen levels), two important proteins involved in cell function, namely the β1 subunit of the Na+-K+ pump and eNOS, had a significant increase in glutathionylation, where they had a molecule called glutathione attached to them, causing an impairment to their function.
Additionally, the team observed that another protein called NADPH oxidase, which is responsible for generating reactive oxygen species (ROS), also became more active under these conditions, indicating an increase in ROS formation. Adding the β3AR agonist drug, CL, reduced the increase in glutathionylation of the β1 subunit of the Na+-K+ pump, as well as the activity of some important enzymes.
Professor Rasmussen and his team have found that β3AR agonists are able to counteract the damage that occurs due to oxidative damage which holds promise for potential therapeutic interventions. By targeting and activating the β3AR with drugs, the team aims to mitigate the effects of oxidative damage that are present in pre-eclampsia and potentially use this as a treatment – a hugely exciting discovery.
Lead Researchers: Professor Helge Rasmussen, Dr Chia-Chi Liu, Dr Elisha Hamilton
Project Title: Re-purposing of Beta3 Adrenergic Receptor Agonists as a Novel Treatment for Pre-Eclampsia.