Photosynthesising cyanobacteria breathed life into what was, until ∼1500 million years ago (Mya), a planet virtually devoid of oxygen (O2), splitting water to obtain the hydrogen required to drive metabolic reactions (2H2O → 4H + O2↑). The inexorable rise in atmospheric O2 during the Proterozoic aeon of the Precambrian period ∼2500–540 Mya saw the emergence of aerobic respiration following a symbiotic merger with the once free‐living α‐proteobacteria that subsequently gave way to the more sophisticated energy powerhouse, the mitochondrion. Chemical reduction by the mitochondrial electron transport chain favoured O2 as the (ideal) terminal electron acceptor, reducing it to water, providing more efficient, regulated metabolic support that signalled the development of more complex structures including the early brain in bilateri. Today's ‘modern’ brain exemplifies our reliance on O2 because, unlike most other organs, an evolutionary ‘drive for size’ has meant that it is now committed to a continually active state, demanding a disproportionate 20–25% of the body's basal O2 budget, more than 10 times that expected from its mass alone (Bailey, 2019). Simply put, O2 is the molecule that made our world, our brains and us; without it, we wouldn't be here!
However, our basic need for O2 obscures a fascinating paradox; it is a toxic, mutagenic gas that is deadly to the CNS when in excess! So how can too much of a good thing be so bad? Delving deep into O2’s molecular orbital structure reveals that the triplet ground state (most stable) diatomic O2 molecule exists in air as a free radical since it has two unpaired electrons with parallel spins in opposing orbitals. Thankfully for the brain, which is peculiarly susceptible to the ravages of free radical‐induced membrane peroxidation (Bailey et al. 2018), this configuration means that O2 is ‘spin‐restricted’, forcing it to accept electrons one at a time to yield the superoxide anion (O2 •−), which means that, despite its powerful oxidising nature (it is highly explosive rocket fuel after all!), O2 at normal concentrations reacts sluggishly with the brain's organic biomolecules, protecting them from spontaneous combustion! But at higher values, the story is quite different, with univalent formation of O2 •− increasing, catalysing downstream formation of hydrogen peroxide (yet another rocket fuel!) and the hydroxyl radical, infamous for its unrivalled ability to cause indiscriminate membrane damage that lies at the very heart (and brain!) of O2 toxicity.
Rising atmospheric O2 levels probably signalled a death sentence to anaerobes, favouring the survival of organisms that could cope with free radical‐mediated O2 toxicity and control oxidative processes to harness energy, including cellular protection through evolution of antioxidant defence that even the Last Universal Common Ancestor was equipped with (Weiss et al. 2016). However, emerging evidence suggests that over billions of years of evolution, life has changed from simply eliminating free radicals and associated reactive oxygen species (ROS) to utilising them for selective advantage; indeed rather than being simply labelled as toxic, mutagenic ‘accidents’ of in vivo chemistry constrained to cellular oxidative damage and pathophysiology, it is becoming increasingly clear that at physiological, albeit undefined, concentrations, free radicals and ROS can equally serve as important signal transductants regulating gene expression and vasomotor tone that collectively serve to defend cerebral O2 homeostasis (Bailey, 2019).
The findings published in this issue of The Journal of Physiology by Mattos et al. (2019) speak to these potentially neuroprotective mechanisms providing much‐needed human insight into the redox‐regulation of ‘cerebral O2‐sensing’. By combining paired sampling of arterial and jugular venous blood to assess trans‐cerebral metabolic exchange with regional assessment of CBF, the authors demonstrated that acute isocapnic hyperoxia decreased CBF and cerebral metabolic rate of O2 (CMRO2) subsequent to increased systemic and cerebral oxidative‐nitrosative stress confirmed by a free radical‐mediated reduction in nitric oxide (NO) bioavailability. These changes were restored following intravenous infusion of vitamin C, the primary water‐soluble chain‐breaking antioxidant, at supraphysiological concentrations sufficient to outcompete O2 •−‐mediated NO inactivation, thereby conserving its vasoactive function.
Importantly, albeit contrary to the original working hypothesis, hyperoxia failed to cause structural neuronal‐parenchymal damage as indicated by stable exchange of neuron‐specific enolase. Interestingly and quite unlike skeletal muscle, the observed increase in arterial O2 content would typically be associated with a reciprocal reduction in CBF to ‘maintain’ CMRO2 at its normoxic baseline value. Yet CMRO2 in the present study was shown to decrease, similar in magnitude to reductions observed in hypoxaemic‐hypercapneic freedivers during prolonged apnoea, which was taken to reflect cerebral O2‐conservation (Bain et al. 2016). Thus, could it simply be that oxidative‐nitrosative stress signals (cerebral) arterial vasoconstriction and associated cerebral hypoperfusion helping titrate the delivery of excess O2 (and ROS) to protect the cerebrovasculature from potential damage? Antioxidant supplementation clearly upset this equilibrium, exposing the brain to additional, arguably needless O2. Why there isn't a negative feedback system triggering a compensatory reduction in O2 extraction to offset increased delivery is puzzling.
Given that the brain's O2 supply is so delicate, walking the tightrope between too much or too little of this rocket fuel, it would seem intuitive for evolution to favour feedback mechanisms capable of sensing subtle changes in blood O2 concentration and transmitting signals to the cerebrovasculature coupling local cerebral O2 delivery to tissue metabolic demand. The new information presented by Mattos et al. (2019) adds to an emerging, albeit limited, body of human evidence, indicating that free radicals may well fulfil such a role in preserving cellular O2 homeostasis.
Additional information
Competing interests
None declared.
Author contributions
Sole author.
Funding
Royal Society Wolfson Research Fellowship‐WM 170007.
Edited by: Michael Hogan & Caroline Rickards
Linked articles: This Perspective highlights an article by Mattos et al. To read this article, visit https://doi.org/10.1113/JP277122.
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