To the Editor:
Because anesthesia administration is a sure marker for supplemental oxygen use, the submolecular effects of any level of oxygen and the attendant oxidative stress that hyperoxia may cause should be accounted for in research. LeFreche et al.1 (and the accompanying editorial by Eckenhoff and Planel)2 reference studies where tau phosphorylation was detected but the degree of oxygen used was not well documented.3,4 Even studies that rely on established models to parse anesthesia-induced neurotoxic/neuromodulatory effects report oxygen levels of “approximately 24%” against controls exposed to 21% oxygen without addressing the fact that 24% oxygen is still a hyperoxic experimental condition, although much lower than 100%.5
Thus, even as Le Freche et al.1 produce tantalizing data using a senescent mouse model of postoperative cognitive dysfunction and other tauopathies in aged patients, they also perpetuate a bigger problem. Although they report a 100% oxygen/null sevoflurane control for their 100% oxygen/sevoflurane (1.5% and 2.5%) short-term effects cohorts, they do not report a corresponding 100% oxygen/null sevoflurane control for the serial 100% oxygen/sevoflurane (1.5% and 2.5%) exposures in their long-term effects cohorts; nor do they report any form of 21% oxygen/sevoflurane control for any of their experiments, short- or long-term. In brief, they inadequately report on controls for the most powerful “drug” used in their studies: oxygen.
Why should this matter? Oxygen, reactive oxygen species, and associated free radicals are potent beneficial and detrimental subcellular event modulators.6 The stoichiometric nature of mitohormetic effects related to reactive oxygen species actions, membrane potential changes, peroxidation reactions, DNA damage, protein folding actions, and calcium homeostasis are increasingly recognized.7,8 Indeed, mitochondria can interact in networks to propagate the effects of small bursts of reactive oxygen species, thereby altering mitochondrial permeability transition pore function, among other effects.9 That this mitochondrial outer membrane complex may interact with the peripheral benzodiazepine receptor found in the same membrane presents an intriguing possible link between oxidative stress and anesthetic effects10 —effects, which according to recent research cannot be ignored.11
How does this relate to increased tau phosphorylation noted after the hyperoxic anesthesia used by LeFreche et al.1? Among the multiple mechanisms purported to cause tau hyperphosphorylation, oxidative stress is considered both a possible indirect and direct cause of tauopathy.12 Specifically germane to LeFreche et al.’s study is the prior finding that oxidative stress without anesthesia can cause tau hyperphosphorylation.13 Because oxidative stress originates at the mitochondrial level, any factor that increases oxidative stress—such as hypoxia14 or hyperoxia15 —may potentially influence tau hyperphosphorylation. Oxygen, then, would seem to require the tightest level of control wherever its effects might be anticipated.
Suppose serial 100% oxygen exposures or serial normoxic sevoflurane exposures actually produce tau phosphorylation levels equal to or higher than 100% oxygen/sevoflurane exposures. The controls used in LeFreche et al.’s1 experiments do not sufficiently address this possibility. Given that “nonanesthesia induced” experimental tauopathy produced in an Alzheimer model is propagated over time from the entorhinal cortex toward the limbic system and associated cortices,16 the possibility that iatrogenic “anesthesia-induced” tauopathy can spread similarly, irrespective of cause, becomes a legitimate concern in postanesthesia cognitive dysfunction modeling. In this regard, the possible role of hyperoxia, with or without anesthesia, in tauopathy induction—as well as other neurotoxicity/neuromodulatory models—deserves meticulous control in future investigations.
