Common Anesthetic Causes Changes in Mouse Brains

Neuroscience has a long and sordid history with anesthetic chemicals. Take curare (d-Tubocurarine) for example. Better known as a South American "dart poison," curare causes paralysis but not loss of consciousness. However, this chemical was used during the early 1900s as a surgical anesthetic for women and children until the 1940s when it was recognized as merely a paralytic. Its quite chilling to think of the numerous surgeries which were performed on completely conscious individuals who were paralyzed but unanestisized. Later procedures mixed muscle relaxants with an anesthetic, and monitored conscious-state brain activity with EEG.

Before that, there was ether (delivery apparatus to the left).

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Discovered in the middle ages, it was introduced as a potent anesthetic by Dr. Crawford Long in 1842 in Boston, MA, when he removed two tumors from the neck of an unconscious patient. However ether (and close on its heels, chloroform) could sometimes result in death, due to a rather narrow window that existed between the dose to anesthetize and the dose to kill. Ether was also consumed recreationally, often mixed with ethanol.

"A dose of a little more than [a teaspoonful] of ether will produce a condition of inebriation lasting from one half to one hour, but the dose must soon be greatly increased. The after effects are, if anything, rather pleasant, and the habit of ether-drinking is certainly not so injurious as alcoholism."

Artist's rendition of the first demonstration of ether anesthesia.

Now, an interesting study reported yesterday at Nature News might compound our anesthetic-related worries: exposure to the common inhaled anesthetic halothane increases the production of a protein thought to be implicated in Alzheimer's disease. Which prompts the questions: does the repeated and prevalent use of anesthesia contribute to the incidence of Alzheimer's disease?

Inhaled doses of halothane, one of a class of drugs called volatile anesthetics, increase the amount of a protein called amyloid beta in mouse brains, researchers at the University of Pennsylvania in Philadelphia have found. Some 60 million people worldwide are given volatile anesthetics each year. The drugs are known to cause 'post-operative cognitive decline' in many cases, which can last for days, weeks or years.

However, the relationship between anesthesia and Alzheimer's isn't a straightforward one. The group used mice engineered to have high levels of amyloid beta, and exposed them to halothane. These mice ended up having more amyloid beta, although they seemed cognitively normal. On the other hand, wildtype mice exposed to isoflurane (another common anesthetic) showed cognitive impairment but no increase in amyloid beta. During the process of normal aging, people accumulate amyloid beta plaques (Alzheimer's is this pathology in the extreme) but mice don't. Hence why transgenic mice are used to mimic old-age plaque load.

Many people possess mutations that predispose them to Alzheimer's disease, although there is currently no screening for such mutations before surgery. People who are not elderly and don't have a predisposing mutation should be fine to undergo surgery, he says. "But if you had one of these mutations, even as a 20-year-old, I would be concerned," he says.

Last month, another research group reported that exposure to isoflurane increases amyloid beta levels in cultured brain cells. The researchers think that volatile anesthetics stabilize the enzymes that underpin amyloid beta production, causing the molecule to accumulate.

The authors suggest that hospitals should collect samples during brain operations to test whether similar effects are observed in humans following inhaled anesthetic. But tentatively, they suggest that the inhalant desflurane is safer than halothane or isoflurane.

Reference:
Bianchi et al. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiology of Aging, In Press, 7 March 2007. doi:10.1016/j.neurobiolaging.2007.02.009