Antipsychotic Medication Trifluoperazine Shows Promise for Fragile X, Study Finds

Trifluoperazine, an approved antipsychotic medication normally prescribed to treat schizophrenia and anxiety, may be a promising therapeutic candidate for people with fragile X syndrome, a new study suggests.

The study, “Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model,” was published in the journal Communications Biology.

Fragile X, the most frequent genetic cause of autism, is caused by mutations in the FMR1 gene, which provides instructions for making the fragile X mental retardation protein (FMRP).

Despite recent research advances in the molecular mechanisms underlying fragile X, there are no effective medications currently to treat the disorder.

Some studies have proposed that analyzing the transcriptomic signature of certain populations of nerve cells may be useful not only to understand the origin and processes underlying neurological disorders, but also to discover potential new therapeutic candidates. Transcriptomics refers to the study of all RNA molecules (transcripts) that serve as templates for the production of proteins.

To help identify new therapeutic targets for fragile X syndrome, researchers at Michigan State University and their colleagues used computational analyses to examine the transcriptomic signature of neurons from mice lacking a functional Fmr1 gene (the mouse equivalent to the human FMR1 gene).

They started by comparing these nerve cells to those found in the connectivity Map database — a database that contains more than 7,000 reference profiles representing transcriptome changes brought on by 1,309 compounds/therapies.

Computational analyses predicted that trifluoperazine, an antipsychotic medicine approved by the U.S. Food and Drug Administration, could be a promising candidate to treat fragile X.

To explore this further, investigators then treated mice engineered to mimic the symptoms of fragile X with trifluoperazine at a dose of 0.05 mg/kg, administered through an intraperitoneal (abdominal wall) injection.

Low-dose treatment lessened several autistic behaviors associated with fragile X, including social avoidance and repetitive behaviors. Treatment also seemed to have a positive effect on memory.

Subsequent analyses also suggested the beneficial effects of trifluoperazine could be due to its ability to block PI3K, an enzyme that controls several cellular functions, including growth, differentiation, and survival.

Additional experiments confirmed that trifluoperazine inhibited the activity of PI3K and many of its targets (other molecules normally activated by this enzyme), including Akt and S6K1, in nerve cells. Trifluoperazine also lowered the abnormally high activity of both Akt and S6K1 in the mouse model of fragile X.

“Together, our data demonstrate a promising value of transcriptome-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential treatment for [fragile X syndrome],” the researchers wrote.