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Department of Neuroscience, Psychiatric and Anesthesiological Sciences, Section of Anesthesiology and Intensive Care, Messina University School of Medicine., Messina, Italy
To the Editor:
The study of Culley et al. (1) demonstrated that isoflurane and nitrous oxide anesthesia produce a sustained learning impairment in aged rats with the conclusion that general anesthesia itself can cause prolonged cognitive alterations in aged subjects. Nevertheless they were unable to speculate about the causes of such impairment, therefore the etiology remains unknown.
A growing number of data have shown that compounds interacting with nicotinic acetylcholine (nAch) receptors, present in the central nervous system, modulate cognitive functions (2,3). Treatment with nAch receptors agonists elicits long-lasting improvement of cognitive performance in a variety of behavioral tests in animals and humans (2,3), while nicotinic receptor blockade can impair memory (4). In rats, nicotinic antagonists impaired memory performance tested on the 8-arm radial maze (4), the method used in the Culley et al. study (1).
Volatile anesthetics, such as isoflurane, are potent inhibitors of nicotinic nAch receptors with clinically relevant IC50 values (5,6).
Propofol also exerts an inhibitory effect on these nicotinic receptors, but only at concentrations higher than those necessary for anesthesia (5,6). It is consistent with a recent study (7) where the incidence of postoperative cognitive dysfunction in elderly patients who underwent regional anesthesia was not significantly different between patients sedated with propofol and those not sedated.
Other drugs used in anesthesia, as the neuromuscular blocking drugs atracurium, and the atracurium and cisatracurium metabolite laudanosine, activate nicotinic nAch receptors at concentrations comparable with those measured in the central nervous system during general anesthesia (8,9).
Given these considerations, in the study of Culley et al. (1) the causes of cognitive dysfunction could be consistent with the potent inhibition of isoflurane on nicotinic nAch receptors. Moreover, because the cognitive impairment in the general anesthesia suggests a negative effect of either the general anesthetic agents or the postoperative analgesic regimen (7), postoperative cognitive dysfunction must be related to drugs administered and not to the general anesthesia itself.
References
Harvard Medical School, Brigham & Women’s Hospital, Boston, MA
In Response:
We are aware of the literature cited by Fodale and Santamaria in their letter and agree that inhibition of nicotinic acetylcholine receptors by certain general anesthetics is a plausible explanation for the learning impairment we observed in rats after isoflurane-nitrous oxide anesthesia (1). However, we know of no study that demonstrates long-lasting effects of a single general anesthetic administration on this or any other neurotransmitter receptor system. Furthermore, most general anesthetic agents act on multiple receptors (e.g., GABA and NMDA receptors) that participate in learning (2) and there are other possible explanations for our observations (3). Therefore, although we have experiments underway to investigate the mechanisms involved, we stand by our assertion that the etiology of postanesthetic learning impairment is unknown.
References
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