Rapamycin could make an epilepsy drug much safer during pregnancy

The drug rapamycin could prevent the epilepsy medication sodium valproate from causing developmental problems during pregnancy.

Sodium valproate is used to treat epilepsy, bipolar disorder and sometimes migraines. Although effective, it isn’t recommended during pregnancy because it can cause congenital conditions such as spina bifida, as well as lifelong learning difficulties.

Giovanni Pietrogrande at the University of Queensland in Australia and his colleagues wanted to understand why sodium valproate can have such effects. So they used stem cells to create mini spinal cords, called organoids, in the laboratory. These mimic the spines of fetuses in the early weeks of pregnancy.

When the organoids were exposed to sodium valproate, their cells changed in ways that can be linked to the risk of a congenital condition.

Searching for why this might be, the team found that activity in one of the cells’ signalling pathways, called mTOR, indicated that they were going through senescence. This is a process where cells stop multiplying but don’t die off, and instead continue to release chemicals that can cause inflammation.

Rapamycin, which was first developed as an immune suppressant but is showing some promise for its anti-ageing effects, also targets the mTOR pathway.

In another experiment, the researchers exposed a new set of spinal organoids to a combination of sodium valproate and rapamycin, finding that senescence didn’t occur. They then replicated the tests in zebra fish larvae, and similarly found that the cells didn’t go into senescence and showed no signs of the changes that occurred when cells were exposed to sodium valproate alone.

Rather than doctors taking people with epilepsy off sodium valproate if they are, or might become, pregnant, we could one day prevent its negative effects by combining it with rapamycin, says Pietrogrande. Studies in people are required before this can be recommended.

Frank Vajda at the University of Melbourne says sodium valproate is a “terribly important drug and the single most effective treatment for generalised seizures”, when abnormal electrical activity begins in both halves of the brain at the same time.

“I think this is a very important paper that may lead to this drug being restored to its level of importance prior to the discovery of its adverse effects,” he says.