Date Published: May 29, 2019
Publisher: Public Library of Science
Author(s): Caroline Holtkamp, Björn Koos, Matthias Unterberg, Tim Rahmel, Lars Bergmann, Zainab Bazzi, Maha Bazzi, Hassan Bukhari, Michael Adamzik, Katharina Rump, Israel Silman.
Propofol is a widely used anaesthetic drug with advantageous operating conditions and recovery profile. However, propofol could have long term effects on neuronal cells and is associated with post-operative delirium (POD). In this context, one of the contributing factors to the pathogenesis of POD is a reduction of cholinesterase activity. Accordingly, we investigated the effects of propofol on the methylation, expression and activity of cholinergic genes and proteins in an in-vitro model.
We found that propofol indeed reduced the activity of AChE / BChE in our in-vitro model, without affecting the protein levels. Furthermore, we could show that propofol reduced the methylation of a repressor region of the CHRNA7 gene without changing the secretion of pro–or anti-inflammatory cytokines. Lastly, propofol changed the expression patterns of genes responsible for maintaining the epigenetic status of the cell and accordingly reduced the tri-methylation of H3 K27.
In conclusion we found a possible functional link between propofol treatment and POD, due to a reduced cholinergic activity. In addition to this, propofol changed the expression of different maintenance genes of the epigenome that also affected histone methylation. Thus, propofol treatment may also induce strong, long lasting changes in the brain by potentially altering the epigenetic landscape.
Propofol is a widely used short-acting intravenous anaesthetic drug with advantageous operating conditions and recovery profile [1, 2]. However, there are several indications that anaesthetics might induce unwanted long-lasting side effects, affecting the central nervous system and cognitive abilities [3–5]. Potentially, this comes to pass by changing the epigenetic profile of the cells [6, 7], which could cause post-operative complications. One of these cerebral complications after surgery is postoperative delirium (POD), which is statistically associated with propofol anaesthesia [8, 9]. POD depicts an acute brain failure , which occurs in 15–53% of older patients after surgery and anaesthesia [11, 12] and is associated with an adverse outcome . In addition, delirium is also linked to an increased risk of long term cognitive defects that recover with high inter-individual differences from days to months . Currently, a pathogenesis, involving a reduced cholinergic activity , neuroinflammation [16, 17] or a decreased antiinflammation, is discussed in the field . How and if propofol might influence these factors is currently unknown. However, it seems appropriate to speculate that one possible mechanism is an alteration of the epigenetic profile of the cells. Especially the methylation of the promoter regions of the cholinergic genes ACHE (acetylcholinesterase), BCHE (buturylcholinesterase) and CHRNA7 (the subunit alpha 7 of the nicotinic acetylcholine receptor) are of importance. The protein AChE is the primary acetylcholineesterase, hydrolysing acetylcholine at an enormous rate into acetic acid and choline . BChE on the other hand is an unspecific cholinesterase, hydrolysing a range of different choline esters. The activities of both, AChE and BChE, are associated with POD [20, 21]. In addition, CHRNA7 is coding for an ion channel receptor capable of binding acetylcholine mediating acetylcholine signalling. It has special significance for higher cognitive functions and is linked to Alzheimer’s Disease’s progression . Furthermore, Chrna7 is linked to the so called cholinergic anti-inflammatory pathway .
The use of propofol in anaesthesia is statistically associated with postoperative delirium (POD) [8, 9]. Since a causal relationship is currently unknown, we conducted this study to evaluate a possible epigenetic mechanism of how this anaesthetic drug could contribute to POD. We focussed our efforts on cholinergic genes, since a reduction in cholinesterase activity is discussed as a major factor for POD .
In summary, we found that the anaesthetic drug propofol reduces the cholinergic activity, suggesting a mode of action for association of propofol anaesthesia with post-operative delirium. Furthermore, propofol treatment changed the expression of DNA and histone modifying genes on a global scale. We can speculate that this might result in a wide spread re-wiring of the epigenome in propofol treated neuronal cells and possibly impact cholinergic activity by influencing the post translational modifications of these proteins. We call for a systematic investigation of how and to which extent anaesthetics change the epigenome of cells and have potentially an effect far exceeding the time of anaesthesia.