Argon as a potential strategy against the neurotoxicity of nitrous oxide and perinatal hypoxia/ischemia induced brain injury

Abstract

Perinatal hypoxia is the cause of a large proportion of deaths in newborn infants globally, and accounts for up to 20% of cerebral palsy cases clinically. While clinical trials are currently under way to include the noble gas xenon alongside hypothermia as a treatment, there are still disadvantages, hence the search for a novel method to administer neuroprotective agents. By focusing on the noble gas argon, which is available at a fraction of the cost of xenon, and administer this gas before any hypoxic insult, we seek to improve outcomes after perinatal hypoxia. This study used four model systems to assess the neuroprotective benefits of argon against both N2O neurotoxicity and hypoxic brain injury. It was found that in primary cortical neurons, 50% N2O administered for four hours could induce apoptosis, which argon could attenuate. However, this did not prove to also be the case in either immortalised cell lines or naïve pups in the first week of life. In an in vivo model of perinatal hypoxia, pre-treatment with 50% N2O was associated with similar or worse outcomes than hypoxia alone for most outcome measures, including hippocampal cell damage and mortality, while the addition of argon to N2O pre-treatment could reverse these neurotoxic effects. This thesis presents the first data regarding the preconditioning effects of argon gas against both anaesthetic and hypoxic neurotoxicity. As well as this, it provides evidence in a perinatal hypoxia model that just 20% argon can have neuroprotective benefits. This expands the field of work surrounding argon significantly and paves the way to begin experiments in higher model systems and eventually clinical trials. Argon has many distinct advantages so its use clinically would be an excellent addition to medicine.