Common drugs help reverse signs of fetal alcohol syndrome in rats

A common blood sugar medication or an extra dose of a thyroid hormone can reverse signs of cognitive damage in rats exposed in utero to alcohol. Both affect an enzyme that controls memory-related genes in the hippocampus, researchers report July 18 in Molecular Psychiatry.

That insight might someday help scientists find an effective human treatment for fetal alcohol spectrum disorders, which can cause lifelong problems with concentration, learning and memory. “At this moment, there’s really no pharmaceutical therapy,” says R. Thomas Zoeller, a neurobiologist at the University of Massachusetts Amherst.
Fetal alcohol syndrome disorders may affect up to 5 percent of U.S. kids, according to estimates from the U.S. Centers for Disease Control and Prevention. Scientists don’t know exactly why alcohol has such a strong effect on developing brains. But the lower thyroid hormone levels commonly induced by alcohol exposure might be one explanation, suggests study coauthor Eva Redei, a psychiatrist at Northwestern University Feinberg School of Medicine in Chicago.

“The mother has to supply the thyroid hormones for brain development,” says Redei. So, pregnant women who drink might not be providing their fetuses with enough hormones for normal brain development. That could disrupt the developing hippocampus, a brain region involved in learning and memory.

To counter alcohol’s effects, Redei and her colleagues gave doses of thyroxine, a thyroid hormone, to newborn rats that had been exposed to alcohol before birth. (That timing coincides developmentally with the third trimester of pregnancy in humans.) The amount of alcohol fed to the rat moms corresponded roughly to a woman drinking a glass or two of wine a day.

The treatment helped, the team found. Healthy rats will freeze in place when they’re put in a room where they’ve previously experienced a mild electrical shock. Adult rats exposed to alcohol during development freeze for a shorter period of time, suggesting that they might not learn the association between the shock and the room as effectively. Thyroxine treatment after birth made rats freeze about 30 percent longer than rats that didn’t get the treatment — almost on par with rats born to nondrinking moms.

Surprisingly, treatment with a blood sugar drug called metformin also had a similar effect. While seemingly unrelated, the two treatments work in similar ways, Redei says. Alcohol makes the hippocampus produce less of an enzyme called Dnmt1. That enzyme regulates the way key learning and memory-related genes turn on and off during development. Disruptions in that process can harm hippocampus function. “Both treatments normalize those enzyme levels,” Redei says.
Whether this treatment will work in people is far from a guarantee: Many promising treatments shown in rats don’t pan out in humans. Plus, fetal alcohol syndrome includes a complex suite of physical, cognitive and behavioral symptoms, which probably aren’t all controlled by thyroid hormone levels.

“Kids with fetal alcohol effects don’t look like kids with congenital hypothyroidism,” a condition resulting in low thyroid hormone levels, says Zoeller. Alcohol exposure during development affects other systems, too, like the immune system.

Still, Redei eventually hopes to test thyroxine and metformin in pregnant drinkers during their third trimester to see if the drugs might improve their kids’ outcomes. (Both are generally recognized as safe for pregnant women at standard doses.)

If treatment works, it might be particularly helpful for women who drank heavily in their first trimester before realizing they were pregnant, says Joanne Rovet, who studies fetal alcohol syndrome at the Hospital for Sick Children in Toronto.