Medications that block the harmful effects of ethanol on the nervous system could be on the horizon based on research reported in the March 28 Proceedings of the National Academy of Sciences. Such drugs hold the promise of preventing some of the damage found in fetal alcohol syndrome (FAS) and the cognitive impairment associated with alcohol abuse.

Michael F. Wilkemeyer, Ph.D., and his colleagues at the West Roxbury Veterans Affairs Boston Healthcare System and Harvard Medical School report the latest results from their research into the neural L1 cell adhesion molecule. Cell-cell adhesion molecules such as L1 are critical to the development of the nervous system. They stimulate and guide axonal growth, synapse information, and other events in the developing nervous system. L1 not only mediates neural development, it also is also thought to play a role in learning and memory.

In 1996 the Massachusetts scientists found that ethanol disrupts cell-cell adhesion mediated by the L1 cell adhesion molecule. In the new study they took the next step and found a means of blocking these disruptions.

The investigators note that cell-cell adhesion is inhibited with increasing potency by methanol, ethanol, 1-propanol, and 1-butanol. That disruption stops abruptly with the five-carbon pentanol. These and other observations suggest that the target site is highly selective, which in turn predicts the existence of antagonists, according to Wilkemeyer and his colleagues.

The aim of the new study was to identify such antagonists. The research team found that pentanol does not inhibit cell-cell adhesion and completely reverses these effects of ethanol and other short-chain alcohols. Proving to be an even more potent antagonist is 1-octanol, which like pentanol is normally inactive.

Just how long-chain alcohols antagonize cell-cell inhibition remains unclear, although Wilkemeyer and his colleagues explored alternative mechanisms. One possibility is that the long-chain alcohol antagonists compete with the short-chain alcohols for access to the target site on the cell membrane. An alternative model is that the binding of the antagonists may induce a conformational change that moves the site out of range without disrupting adhesion of the cells.

In the new study, the investigators also found that the structure of the molecule may be more important than the molecular volume or number of carbons in the inhibition of cell-cell adhesion. They altered the shape of butanol, the most potent of the short-chain alcohols in inhibiting cell-cell adhesion. Even slight modifications in structure abolished such inhibition.

"Our structure activity analysis indicates that the alcohol target discriminates among alcohols of equivalent molecular volume and is exquisitely sensitive to molecular shape," the researchers noted.

In their 1996 study, the investigators found the disruptions in cell-cell adhesion produced by ethanol in both mouse fibroblasts and in cerebellar granule cells from rat neonates. They used an ethanol concentration equivalent to that produced by one drink in a human being.

The researchers speculate that ethanol’s effects on L1 could play a role in the pathophysiology of fetal alcohol syndrome. Their hypothesis is based, in part, on the similarity of the brain lesions found in children with FAS and those with mutations in the gene for L1.