Common anesthetic induces Alzheimer's-associated changes in mouse brains

Nov 12, 2008

For the first time researchers have shown that a commonly used anesthetic can produce changes associated with Alzheimer's disease in the brains of living mammals, confirming previous laboratory studies. In their Annals of Neurology report, which has received early online release, a team of Massachusetts General Hospital (MGH) investigators shows how administration of the gas isoflurane can lead to generation of the toxic amyloid-beta (A-beta) protein in the brains of mice.

"These are the first in vivo results indicating that isoflurane can set off a time-dependent cascade inducing apoptosis [cell death] and enhanced levels of the Alzheimer's-associated proteins BACE and A-beta," says Zhongcong Xie, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) and the MGH Department of Anesthesia and Critical Care, the study's lead and corresponding author. "This work needs to be confirmed in human studies, but it's looking like isoflurane may not be the best anesthesia to use for patients who already have higher A-beta levels, such as the elderly and Alzheimer's patients."

Alzheimer's disease is characterized by deposition of A-beta plaques within the brain. The A-beta protein is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes – beta-secretase, also known as BACE, and gamma-secretase – to release the A-beta fragment. Normal processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.

Several studies have suggested that surgery and general anesthesia may increase the risk of developing Alzheimer's disease, and it is well known that a small but significant number of surgical patients experience a transient form of dementia in the postoperative period. Last year the MGH team showed that applying isoflurane to cultured neural cells increased activation of the cell-death protein caspase and raised levels of BACE and gamma-secretase as part of a pathway leading to the generation of A-beta. The current study was designed to see if the same process takes place in mice.

Neurologically normal mice received isoflurane for two hours at doses comparable to what would be administered to human patients. Their brains were examined 2, 6, 12 and 24 hours after they received the anesthesia and compared with the brains of control mice. Results at 6 hours showed that caspase levels were elevated and BACE had modestly increased in mice that received isoflurane. At 12 hours moderate caspase activation persisted, and BACE levels were even higher in the treated mice; and at 24 hours BACE levels were more than four times higher than in controls, and A-beta levels had also risen, while caspase activation had fallen off.

Another group of mice had been treated for seven days with the drug clioquinol before the two-hour isoflurane administration. Laboratory studies have found that clioquinol inhibits the aggregation of A-beta into neurotoxic deposits, and a clioquinol derivative is currently in clinical trials as an Alzheimer's treatment drug. Six hours after they received isoflurane, caspase levels in the clioquinol-treated mice were significantly less than in other animals that had received the anesthetic, suggesting both that A-beta aggregation contributes to a vicious cycle of further cell death – echoing a finding from the team's 2007 study – and that a drug like clioquinol might block isoflurane's neurotoxic effects.

"This study cannot tell us about the long-term effects of isoflurane administration; that's something we will examine in future investigations," notes Xie, who is an assistant professor of Anesthesia at Harvard Medical School (HMS) and director of the Geriatric Anesthesia Research Unit in the MGH Department of Anesthesia and Critical Care.

"Until we can directly assess the impact of isoflurane on biomarkers like A-beta levels in the plasma or cerebrospinal fluid of human patients, we cannot conclusively determine its role in increasing the risk for Alzheimer's or postoperative dementia," adds Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging Research Unit, senior author of the study, and the Joseph P. and Rose F. Kennedy Professor of Neurology at HMS.

Source: Massachusetts General Hospital

Explore further: Quality control for adult stem cell treatment

add to favorites email to friend print save as pdf

Related Stories

Huge spring tides draw crowds to French Atlantic coast

16 hours ago

France kicked off nearly a month of exceptionally large spring tides Saturday, as tourists flocked to coastal areas to witness spectacularly high water levels ahead of the so-called "tide of the century" ...

Water in Oregon pipeline is tapped for electricity

18 hours ago

Lucid Energy has developed a renewable energy system that makes use of water moving through pipelines. The company's LucidPipe Power System converts pressure in water pipelines into electricity. They have ...

Arctic oil drillers face tighter US rules to stop spills

20 hours ago

Royal Dutch Shell Plc and any oil drilling company that prospects in the Arctic Ocean must boost safety practices to prevent spills in the frigid and often hostile waters or mitigate the impact, U.S. regulators proposed Friday.

Recommended for you

Quality control for adult stem cell treatment

42 minutes ago

A team of European researchers has devised a strategy to ensure that adult epidermal stem cells are safe before they are used as treatments for patients. The approach involves a clonal strategy where stem cells are collected ...

A gene for brain size only found in humans

2 hours ago

About 99 percent of human genes are shared with chimpanzees. Only the small remainder sets us apart. However, we have one important difference: The brain of humans is three times as big as the chimpanzee ...

Experts warn of stem cell underuse

9 hours ago

Since the first experimental bone marrow transplant over 50 years ago, more than one million hematopoietic stem cell transplantations (HSCT) have been performed in 75 countries, according to new research charting the remarkable ...

Longer needles recommended for epinephrine autoinjectors

20 hours ago

(HealthDay)—Given the increasing epidemic of obesity, epinephrine autoinjectors (EAIs) for anaphylaxis require longer needles to ensure intramuscular injection, according to a study published online Feb. ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.