This project studied the role of reactive oxygen species (ROS) and oxidative stress in the mechanism of neuronal cell death induced by carbon monoxide.
In agreement with previous work in this area, it found that:
- CO induces the inhibition of mitochondrial respiration and a decrease in mitochondrial membrane potential in primary neurons and astrocytes.
- CO triggers calcium signalling in these cells.
- CO stimulates production of Nitric oxide (NO).
- Exposure of neurons and astrocytes to CO induces:
- A fast and significant increase in ROS production which is generated by various intracellular sources.
Uniquely, researchers have found a novel system, that:
Although CO inhibits mitochondrial respiration and ATP production, the death of neurons and astrocytes during CO exposure/ reoxygenation is not induced by ATP depleting and energy deprivation.
Importantly, the removal of CO and the reintroduction of oxygen to these cells (so mimicking current treatment options of CO poisoning), induced even higher rates of ROS production.
- The project identified the main producers of ROS during CO exposure and reoxygenation.
- As well as inhibitors which successfully reduced CO-induced oxidative stress (so decreasing the level of endogenous antioxidant glutathione and an increase in lipid peroxidation).
- These inhibitors and antioxidants also protected neurons against CO-induced neuronal cell death, specifically the inhibitor of NADPH oxidase AEBSF.
The project therefore confirmed that CO-induced ROS production and oxidative stress play an important role in the mechanism of carbon monoxide neurotoxicity. It has established that inhibition of this process can be used for development of a neuroprotective therapeutic strategy.
It has identified inhibitors: mitochondrially targeted antioxidants, inhibitors of xanthine oxidase and a general antioxidant that have the potential to work with the greatest effect, either singularly or in combination in conjunction with the provision of O2, that will prevent the production of harmful ROS associated with both CO poisoning, current treatment methods, and neurological injury.
