Anaesthesia and Alzheimer's risk

Dementia News 70, February 2007

In the February issue of the Journal of Neuroscience, a paper based on laboratory findings casts some doubts about the possibility that an inhalation anaesthetic gas, isoflurane, may cause changes in the brain that promote Alzheimer's disease (Xie Z et al., 2007). It should be immediately stressed that the paper reports results obtained in vitro using cultured cells, not yet studied in vivo and in the human body and therefore the results cannot directly transferred to the clinical practice.

The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. Few years ago it was hypothesized that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization. Indeed a research group working in Philadelphia showed that halothane and isoflurane enhance amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro by binding small oligomeric species (Eckenhoff RG et al., 2004). This topic was then further explored by the Tanzi's group in 2006 and now extended in the Journal of Neuroscience paper. The new results show that the anesthetic isoflurane induces apoptosis, i.e. programmed cell death, and increase amyloid beta generation and aggregation. The effect appears to be due to a primary effect of isoflurane in inducing apoptosis which, in turn, increases the levels of the enzymes processing the precursor of amyloid protein and consequently Aß secretion. Isoflurane also promotes amyloid beta aggregation. Accumulation of aggregated can then promote apoptosis generating a vicious cycle ultimately leading to cell death.

At this moment it is premature to tell that isofluorane should be substituted with other non inhalation anaesthetic but in any case these results strongly suggest the need for a thorough epidemiological assessment of the risk of Alzheimer's disease associated with anaesthesia and the various anaesthetics, a clinically relevant question. From a more general point of view these results further support that concept that various drugs active on the CNS can modulate at least in vitro the beta amyloid system, whether this in turn may modify the risk of developing Alzheimer's disease has to be established. Moreover it is possible that the increasing knowledge on the pharmacological modulation of amyloid precursor protein processing by CNS drugs, emerging from these in vitro studies, will provide suggestions for epidemiological or observational studies aimed to better define the role of the amyloid system in Alzheimer's disease.

prof. Stefano Govoni
Department of Experimental and Applied Pharmacology, University of Pavia, Italy

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