Anticonvulsant Shows Promise at Treating Fragile X in Mouse Model

The anticonvulsant carbamazepine can normalize behavior and memory in a mouse model of fragile X syndrome (FXS), suggesting that this medication might be re-purposed to treat people with this disorder, according to a study.

The study, “Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome,” was published in the International Journal of Molecular Sciences and was conducted by scientists in the U.S.

Fragile X is caused by lack of properly working FMRP protein. Although the exact molecular mechanisms by which missing FMRP causes the disease are incompletely understood, it is known that FMRP normally lowers the levels of another protein called ADCY1. Consistently, research has indicated that ADCY1 levels are higher than normal in a mouse model of fragile X, which has been tied to abnormally high activity in two molecular pathways — ERK1/2 and Akt — that are also dysregulated in fragile X.

Carbamazepine, sold under the brand names Equetro and Tegretol, among others, is used to treat certain types of seizures, nerve pain, and bipolar disorder. Notably, previous research has shown that carbamazepine can inhibit ADCY1.

“Because carbamazepine shows pharmacological activity against ADCY1, we reason that it may elicit therapeutic effects on FXS-associated [manifestations],” the scientists wrote.

These researchers first confirmed that, in an adult mouse model of fragile X, ADCY1 levels were increased in a specific area of the hippocampus — a key brain region involved in memory and learning — relative to wild-type mice serving as healthy controls. ADCY1 expression was mostly found in nerve cells.

They then tested the effects of carbamazepine treatment. Mice engineered to mimic fragile X symptoms exhibit learning and memory problems, are hyperactive, and are less likely to engage in social behavior with other mice than are wild-type animals.

Through a variety of tests, the researchers showed that carbamazepine’s use normalized many of these problems in the mouse model: carbamazepine-treated mice performed better on memory tests, were less hyperactive, and engaged in more social behavior with other mice. Notably, repeated daily treatment carbamazepine over eight days provided greater benefits in social interaction and memory.

At the molecular level, carbamazepine’s use reduced the abnormal activation of the ERK1/2 and Akt pathways in mouse neurons. In a dose-dependent manner, the treatment also lowered the elevated protein production seen in the mouse model, which is another molecular hallmark of fragile X.

“Treatment with carbamazepine, which has inhibitory action against ADCY1, is sufficient to correct certain aspects of FXS-associated [processes] in a mouse model during adulthood,” the scientists wrote.

“As carbamazepine is an FDA [U.S. Food and Drug Administration]-approved drug, it may offer a practical approach and be clinically repurposed for FXS therapy,” they added.

The investigators also noted that carbamazepine and other anticonvulsants have been used to control seizures in children with fragile X, without severe side effects.

“Our results advocate future tests of clinical efficacy with adult human FXS patients, beyond the anticonvulsant effects in children,” they wrote.