|
||||||||
|
NEUROLOGY Handhold Found for Alcohol's Grip on BrainFindings May Lead to Agents that Prevent the Damage Alcohol Inflicts It is estimated that one in 1,000 babies in the U.S. is born with fetal alcohol syndrome, characterized by mental and growth retardation, malformations of the brain and face, and behavioral disorders. Alcohol abuse can also lead to neurological disorders in adults, disrupting memory and learning. Yet for such a widely used drug, relatively little is known about how alcohol damages the brain. Until a decade ago, scientists thought that it dissolved into the lipids of nerve cell membranes and non-specifically disrupted protein function. However, an increasing amount of research is showing that alcohol, like more potent drugs such as Valium and morphine, reacts in very specific ways with cell receptors to cause intoxication, addiction, cell death, and abnormal development. Michael Wilkemeyer, HMS instructor in neurology, and Michael Charness, HMS associate professor of neurology, director of the Alcohol Research Laboratory, and chief of neurology at the VA Boston Healthcare System, are leading research into how alcohol's effects on cell adhesion may be responsible for disrupting brain development. A paper published in the March 21 Proceedings of the National Academy of Sciences shows that alcohols like ethanol have a surprisingly specific interaction with the cell adhesion molecule L1, an interaction that can actually be blocked by alcohols of a different size or shape. This discovery is a step toward finding alcohol antagonists that can be used to prevent some of its damaging effects.
Michael Charness, Anita Sebatian, and Michael Wilkemeyer(l to r) are studying how alcohol disrupts brain development by inhibiting cell adhesion in nerve cells. Telltale MutationsCharness's group became interested in studying alcohol and cell adhesion after noting that children with mutations in the gene for the cell adhesion molecule L1 exhibit similar brain malformations as those with severe cases of fetal alcohol syndrome. Brain malformations occur when neurons fail to migrate to their proper destinations in the developing brain. Cell adhesion molecules like L1 are critical to guiding growth and migration of neurons and helping them form nerve bundles. Charness's group showed previously that ethanol in fairly low concentrations can inhibit cell adhesion mediated by L1.Ethanol has a water-soluble hydroxyl group and a fat-soluble two-carbon group. Some other alcohols have longer carbon chains, and these larger molecules increasingly inhibit cell adhesion. But something interesting happens between the four-carbon butanol and the five-carbon pentanol: the inhibitory effect disappears. Butanol strongly interferes with L1, but pentanol and larger alcohols have no effect at all. "That led us to believe that there must be some kind of pocket or crevice that only the smaller alcohols can fit into," Charness says. The research team, which included research associates Sherri Smith and Anita Sebastian, showed that size was not the only factor regulating this interaction. They found that by adding a double bond between the third and fourth carbon of butanol, which limits its ability to rotate about its last carbon, the molecule is rendered inactive. "What we discovered is that, not the solubility of an alcohol and not the size of it, but the shape of it seems to be the most important determinant of whether or not it will inhibit cell adhesion," Wilkemeyer says. Awkward EmbraceAlthough the exact mechanism of the interaction is unknown, one possibility is that alcohol binds to two sites on the L1 molecule, a hydrophilic site and a hydrophobic one, and a particular structure is required for the molecule to align properly at both sites. Like a tricky game of Twister, the alcohol molecule must reach both sites at once, and the longer and bulkier ones are unable to align themselves correctly while the more inflexible ones cannot bend as well to reach their targets. According to this logic, a molecule that is structured to present multiple forms of a potent alcohol like butanol would also be more likely to align correctly with L1. The researchers found that molecules presenting two and three forms of butanol inhibited cell adhesion more potently than butanol alone, showing that proper alignment is necessary for the interaction.
Interaction with cell adhesion molecule L1 requires a highly specific structure. Two-carbon ethanol interacts with L1 to inhibit adhesion, but octanol, with eight carbons, is too large. Butanol also interacts with L1, but the addition of a double bond to the terminal carbon atoms of butanol (circled in red) reduces its flexibility and renders it inactive. Carbon atoms are represented by black balls, hydrogen atoms by gray balls, and oxygen atoms by red balls. "This degree of structural specificity wasn't anticipated—we were quite surprised," Charness says. Such a specific lock-and-key interaction between a molecule and a receptor is exciting because it suggests the possibility of discovering an antagonist that will also fit in the lock. No one has found an antagonist for alcohol that can block a specific interaction in the nervous system. Charness and his team wondered if the structurally similar molecules that were inactive could block the effects of ethanol on cell adhesion. They found that low concentrations of octanol completely prevented ethanol inhibition of cell adhesion. They also exposed nerve cells in culture to growth factor BMP-7, which causes cells to express L1 and clump into sheets. When exposed to ethanol for two days, the cells no longer clustered, but when exposed to both ethanol and octanol they clustered normally. The research, which was funded by the National Institute on Alcohol Abuse and Alcoholism and the Medical Research Service of the Department of Veterans Affairs, will continue to focus on octanol as an antagonist for ethanol in vivo. Because octanol has toxic effects, it would not make a likely candidate for a drug to prevent fetal alcohol syndrome. However, a structurally similar drug might prevent some of the damage caused by ethanol during brain development. Because L1 is also expressed in the mature brain and seems to have a role in learning and memory, these findings may also have implications for alcohol-related memory disorders in adults. —Courtney Humphries |
