Carbon monoxide (CO) exposure induces alterations in brain function. Around 67 % of survivors of acute CO poisoning incidents develop neurological problems, including problems with cognition and movement.
This is induced by an effect of CO on the brain cells that leads to a loss of neurons and glia in different brain areas.
The previous grant from CO Research Trust helped to investigate the mechanisms by which CO induces neuronal death. We have found (paper published 2023) that brain cell loss is induced by oxidative damage of the cells at the time of CO exposure and, most importantly, during the reintroduction of oxygen to the tissue (i.e. when the patient is being treated at the scene of exposure by paramedics and in hospital with standard oxygen therapy).
Several enzymes responsible for this oxidative stress have been identified and have shown that the pharmacological inhibition of these enzymes (by using treatments that temporarily prevent these enzymes from working) protected brain cells against CO-induced cell death.
In considering that major oxidative damage and brain cell death occur when oxygen is reintroduced, a means of suppressing the oxidative stress could be used as a therapeutic strategy to prevent neuronal damage and associated outcomes that can occur with current oxygen therapy, for people affected by CO.
The main objective of this research project is to investigate the inhibition of the specific enzyme which produces oxidative stress at the time of re-oxygenation (i.e. by stopping this enzyme from working temporarily) as a neuroprotective against CO toxicity (i.e. safeguards the brain cells from the damage caused by the influence CO has on this enzyme) with respect to the age and underlying neurological conditions of the neurons.
This will provide an understanding as to whether the provision of oxygen after or alongside that of an easily administered drug, already marketed for human use, will protect neurons of different ‘ages’.
The study will be undertaken in two parts:
1) Study on human neurons (produced by a modern technique from adult human skin fibroblasts (reprogramming). Experiments with human neurons will help to identify the inhibition of oxidative stress at the time of and shortly after CO exposure could protect the brain.
Additionally, it will also answer the question of whether a future neuron replacement strategy (i.e. by replacing those brain cells lost to damage during CO exposure) for recovery of brain function (using stem cells or iPSC* – from adult tissue) would be affected by CO and the post CO toxicity brain environment. This aspect would develop work towards the impact of CO on these cells and to improve the recovery prospects of those exposed to CO that sustain brain damage, and the potential to prevent neurological disease e.g. dementias triggered by brain damage, following exposure to CO.
2) Essential study in rats.
Studies in rats will show if the application of drugs which inhibit (prevent) oxidative damage before CO exposure or at the time of reintroducing oxygen could be neuroprotective.
The brain of the treated rats will be extracted and studied for the identification of brain damage, and oxidative stress, and for the functional characteristics of the neurons and glia cells as part of our assessment of damage and protection.
Thus, this study is a further step forward in the development of a therapeutic strategy for the protection of people affected by CO against the initiation of future neurological issues, that can range from mild cognitive impacts to debilitating dementias.
*Pluripotent stem cell – cells generated from adult human tissue that are being used in the development of personalised therapeutics
