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LETTERS TO THE EDITOR

The Inhibition of Central Nicotinic nAch Receptors Is the Possible Cause of Prolonged Cognitive Impairment After Anesthesia

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

1. Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg 2003; 96: 1004–9.[Abstract/Free Full Text]
2. Belluardo N, Mudo G, Blum M, Fuxe K. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 2000: 113: 21–34.[Web of Science][Medline]
3. Belluardo N, Mudo G, Blum M, et al. Neurotrophic effects of central nicotinic receptor activation. J Neural Transm Suppl 2000; 60: 227–45.
4. Levin ED, Bradley A, Addy N, Sigurani N. Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory. Neuroscience 2002; 109: 757–65.[Web of Science][Medline]
5. Tassonyi E, Charpantier E, Muller D, et al. The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia. Brain Res Bull 2002; 57: 133–50.[Web of Science][Medline]
6. Narahashi T. Neuroreceptors and ion channels as the basis for drug action: past, present, and future. J Pharmacol Exp Ther 2000; 294: 1–26.[Abstract/Free Full Text]
7. Rasmussen LS, Johnson T, Kuipers HM, et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anesthesia in 438 elderly patients. Acta Anaethesiol Scand 2003; 47: 260–6.[Web of Science][Medline]
8. Fodale V, Santamaria LB. Laudanosine, an atracurium and cisatracurium metabolite. Eur J Anaesth 2002: 19: 466–73.[Web of Science][Medline]
9. Tassonyi E, Fathi M, Hughes J, et al. Cerebrospinal fluid concentrations of atracurium, laudanosine and vecuronium following clinical subarachnoid hemorrhage. Acta Anaesthesiol Scand 2002: 46: 1236–41.[Web of Science][Medline]

Response

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

1. Culley DJ, Yukhananov RY, Baxter MG, Crosby G. Memory effects of general anesthesia persist for weeks in young and aged rats. Anesth.Analg 2003; 96: 1004–9.
2. Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol.Life Sci 1999; 55: 1278–303.
3. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J.Neurosci 2003; 23: 876–82.[Abstract/Free Full Text]

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