OxyBaby · The Inflammasome: a novel therapeutic target for the treatment of Hypoxic Brain Injury in Neonates

The Inflammasome: a novel therapeutic target for the treatment of Hypoxic Brain Injury in Neonates

OxyBaby is focussed on understanding the mechanisms of inflammation in the young brain after injury caused by a lack of oxygen, hypoxic injury. It is particularly focussed on an inflammatory complex called the inflammasome and a small molecule called microRNA-155, which can regulate gene expression. Anti-inflammatory therapies are being trialled in adult neurological diseases but very little is known about how targeting inflammation in the young brain can improve outcomes for newborns with hypoxic injuries. Approximately 25% of newborns affected by hypoxic injury develop neurological disorders including cerebral palsy and epilepsy. The only effective care used at the moment is cooling of babies in a treatment called ‘therapeutic hypothermia’, but it is not always successful. OxyBaby will investigate inflammatory pathways involving the inflammasome and microRNA-155 using models of hypoxic injury in the newborn brain. We will then try to treat the injuries by targeting these inflammatory pathways. The first model in Oxybaby is very similar to hypoxic injuries that leads to the development of cerebral palsy and the second model is similar to hypoxic injuries that lead to epilepsy. Both of these disorders are costly disabilities because of their persistence over the course of a patient’s life. There are also a number of comorbidities associated with hypoxic injuries, for example, people who suffer from epilepsy or cerebral palsy are more likely to experience anxiety and depression. Excitingly, recent studies have shown that inhibiting the inflammasome complex and inflammatory pathways is a favourable target for the treatment of adult neurological disorders including stroke, Parkinson’s and Alzheimer’s. The overall objectives of this project are to explore the role of the inflammasome complex and microRNA-155 in the young hypoxic injured brain and to test targeting these pathways for treatment of the injuries. We hope to identify the exact timing and activation of these pathways following hypoxic injury and to then target components of the pathways to attempt to block the development of cerebral palsy/epilepsy using our preclinical models. Conclusion of the action: Transgenic mouse models are critical for molecular interrogation of microRNA function in the injured brain. The work in Oxybaby has resulted in the development of novel transgenic mouse model that allows us to analyse the role of the inflammatory microRNA-155 in a discrete immune cell population of the brain called microglia. This was invaluable in understanding the role of inflammation after hypoxic brain injury in the newborn brain. Deletion of microRNA-155 in the microglia of our transgenic mouse model reduced inflammation and improved motor function after hypoxic injury. Additionally, these transgenic mice had a reduction in the number and severity of seizures. This work will be continued in preclinical projects testing microRNA-155 inhibitors that are delivered shortly after injury for the treatment of hypoxic brain damage and neuroinflammation that can lead to epilepsy. Oxybaby results also demonstrated that inflammasome inhibitors can have a significant effect on inflammation in the brain up to at least three days after injury in our preclinical model. This is a critical time point when perpetual inflammation is highly detrimental to newborn brain health and function. Ongoing work is confirming the beneficial effects of inflammasome inhibition on negative outcomes of hypoxic injury including poor motor function during development.

Data: CORDIS, © European Union