Featured Research

from universities, journals, and other organizations

Common Anesthetic Induces Alzheimer's-associated Changes In Mouse Brains

Date:
November 14, 2008
Source:
Massachusetts General Hospital
Summary:
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. Scientists have shown how administration of the gas isoflurane can lead to generation of the toxic amyloid-beta protein in the brains of mice.

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.

Gregory Crosby, MD, of Brigham and Women's Hospital (BWH) is a co-corresponding author of the Annals of Neurology paper. Additional co-authors are Yuanlin Dong, Guohua Zhang, and Bin Zhang, MGH-MIND and MGH Anesthesia; Robert D. Moir, PhD, MGH-MIND; Matthew Frosch, MD, PhD, MGH Neurology, and Deborah Culley, MD, BWH.

The study was supported by grants from the National Institutes of Health, the American Geriatrics Society, the Alzheimer's Association, Harvard University and the Cure Alzheimer's Fund. Tanzi is a co-founder, consultant and holds equity in Prana Biotechnology, Ltd, the company conducting a clinical trial of clioquinol derivative PBT2. Xie is a consultant of Baxer Healthcare, the company that produces isoflurane. Neither company supported or had any other connection with the current study.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Cite This Page:

Massachusetts General Hospital. "Common Anesthetic Induces Alzheimer's-associated Changes In Mouse Brains." ScienceDaily. ScienceDaily, 14 November 2008. <www.sciencedaily.com/releases/2008/11/081112124410.htm>.
Massachusetts General Hospital. (2008, November 14). Common Anesthetic Induces Alzheimer's-associated Changes In Mouse Brains. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2008/11/081112124410.htm
Massachusetts General Hospital. "Common Anesthetic Induces Alzheimer's-associated Changes In Mouse Brains." ScienceDaily. www.sciencedaily.com/releases/2008/11/081112124410.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins