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See Inside April/May 2007

Bigger Anesthetics May Be Better

Anesthetics may instigate the same molecular changes in the brain that have been implicated in Alzheimer's disease. After surgery or other procedures requiring anesthesia, some mentally sharp seniors suffer a steep cognitive decline, says Pravat K. Mandal of the University of Pittsburgh. “Nobody knows how it happens.” Now he is unraveling exactly how some anesthetics might interact with small proteins or peptides in the brain to cause cognitive problems.

Although Alzheimer's disease is still not entirely understood, it involves the formation of fibrous protein structures called amyloid plaques in the brain. These plaques occur when so-called amyloid beta peptides begin to clump together. Previous work has shown that mixing anesthetics in a test tube with amyloid beta peptides will result in the peptides sticking together more easily than they otherwise would.

Using a technique called nuclear magnetic resonance (NMR) spectroscopy, Mandal probed the interactions of different anesthetics with amyloid beta peptides. He found that each molecule of an inhaled anesthetic, halothane, binds into a small pocket of the peptide, thereby changing its shape and promoting its clumping with other peptide molecules. Halothane had the greatest clumping effect, yet it is rarely used in North America and Europe. Two other anesthetics—isoflurane and propofol—also cause clumping, but their effect is not as severe. Another one, called thiopental, does not cause clumping at all because its molecule is too big to fit inside the peptide's pocket.

Mandal cautions that these anesthetics and peptides may behave very differently in the brain, so he next plans to look for the same effects in a mouse model of Alzheimer's. If peptide binding is the cause of the cognitive decline, he says, it should be possible to design an anesthetic that binds to the amyloid beta peptide in a way that prevents clumping and so would protect patients during surgery.

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