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The dietary supplement CDP-choline, is sold as a brain-boosting agent. It is now under study for stroke and traumatic brain injury as it may block skull and brain damage resulting from alcohol consumption early in pregnancy. (ABOVE) Medical College of Georgia: Drs. Erhard Bieberich and Guanghu Wang report.

Supplement may prevent alcohol-related defects

CDP-choline, sold as a brain-boosting agent and under study for stroke and traumatic brain injury, may block skull and brain damage that can result from alcohol consumption early in pregnancy.

Medical College of Georgia researchers report that alcohol consumption in early pregnancy increases levels of a little-known lipid called ceramide, significantly increasing suicide among cells critical to skull and brain formation. Dr. Erhard Bieberich, biochemist in the MCG Schools of Graduate Studies and Medicine, reported his results in Cell Death and Disease.

Resulting neural crest damage that the research observed included injury to the brain's "skin" — the multi-layered meninges that surrounds the brain providing protection and nourishment. Damage included producing less TGF-β1, a growth factor critical to brain and bone development. Their finding helps explain cranial bone and cognitive defects seen as a result of fetal alcohol syndrome.

Added Bieberich: "There is just a little window," about four weeks after conception when neural crest cells emerge for a few days before morphing into cell types for numerous organs. This four week period is often before a woman knows she is pregnant.

The research indicated there is potential for lasting damage to the fetus if a woman drinks, for example, several glasses of wine within one hour during that four week window.

MCG researchers suspected ceramide as cause of the damage because it is known to induce cell death after activation by alcohol. Ceramide was found at high levels in cells of pregnant mice exposed to alcohol along with a five-fold increase in apoptotic, or dying cells. "There is a clear correlation," says Bieberich.

Researchers thought neural crest cell function could be replaced if any happened to get injured. Instead they found that 25 percent of mouse embryos exposed to alcohol during that four week critical period, had defects in the fibrous joints that connect the skull.

"You get a snowball effect. The neural crest is damaged, the meninges doesn't develop properly and tissue like bone and brain that are regulated by the meninges don't develop properly either."

Erhard Bieberich, biochemist in the Medical College of Georgia, Schools of Graduate Studies and Medicine

When researchers added ceramide-neutralizing CDP-choline to their mouse cell colonies, cell death and ceramide levels were reduced. Alcohol prompts the body to produce more ceramide from the brain lipid sphingomyelin, a major component of cell membranes. They found that CDP-choline produces less ceramide, thus preventing damage if the drinking stops.

"Ceramide can be bad or good," notes Bieberich, who has shown, for example, ceramide's role in helping early stem cells evolved into embryonic tissue. But alcohol upsets the natural balance.

Follow up studies, funded by the March of Dimes, include determining whether CDP-choline can rescue cells after the fact or whether it or a similar supplement would need to be taken preventively.

"Hopefully we can rescue some of the cells by triggering or signaling the back reaction," says Bieberich, who also wants to see if CDP-choline affords the same protection to pregnant mice that it does in laboratory cells.

Abstract
Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy. The reason why specific embryonic tissues are sensitive toward ethanol is not understood. We found that in neural crest-derived cell (NCC) cultures from the first branchial arch of E10 mouse embryos, incubation with ethanol increases the number of apoptotic cells by fivefold. Apoptotic cells stain intensely for ceramide, suggesting that ceramide-induced apoptosis mediates ethanol damage to NCCs. Apoptosis is reduced by incubation with CDP-choline (citicoline), a precursor for the conversion of ceramide to sphingomyelin. Consistent with NCC cultures, ethanol intubation of pregnant mice results in ceramide elevation and increased apoptosis of NCCs in vivo. Ethanol also increases the protein level of prostate apoptosis response 4 (PAR-4), a sensitizer to ceramide-induced apoptosis. Prenatal ethanol exposure is concurrent with malformation of parietal bones in 20% of embryos at day E18. Meninges, a tissue complex derived from NCCs, is disrupted and generates reduced levels of TGF-β1, a growth factor critical for bone and brain development. Ethanol-induced apoptosis of NCCs leading to defects in the meninges may explain the simultaneous presence of cranial bone malformation and cognitive retardation in FAS. In addition, our data suggest that treatment with CDP-choline may alleviate the tissue damage caused by alcohol.

Dr. Guanghu Wang, MCG research scientist, is the study's co-author.

A related article presents a potentially negative affect of ceramide to adult brains - pregnant or not :
Surprising finding provides more support for Alzheimer’s being an autoimmune disease

10 March 2015

“We thought, we can immunize the mouse against its own ceramide; it develops antibodies, which neutralize the ceramide; and we get a similar affect as blocking its production, like a vaccination against it,” Bieberich said. It should also block the subsequent chain of events that contribute to brain cell loss.

Instead they found female Alzheimer’s mice treated with more ceramide experienced about a 33 percent increase in amyloid formation and that serum exosome levels increased 2.4 times.

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