In a project funded by Ataxia UK, Dr Andreia Teixeira-Castro and her team at the University of Minho have investigated the therapeutic potential of the anti-depressant vortioxetine to treat SCA3.
Spinocerebellar ataxia type-3 (SCA3) is caused by a change in the ATXN3 gene which codes for the Ataxin-3 protein, leading to a build-up of a toxic form of the protein. There is currently no disease-modifying therapy available to treat SCA3.
Dr Teixeira-Castro’s group have previously shown that targeting the serotonin signalling pathway with a drug called citalopram suppressed the build up of the ataxin-3 protein in animal models of SCA3. They also saw that the drug was able to suppress neuronal dysfunction. Citalopram works by increasing serotonin levels in the brain.
In this project, the researchers targeted a number of serotonin receptors with another antidepressant that targets serotonin pathways, vortioxetine, in a SCA3 mouse model. They selected this drug as it has some benefits over citalopram, such as having an effect for longer periods and increased safety and tolerability. They looked at the effects of the drug at a dose of 10mg/kg of body weight on ataxin-3 levels and markers of disease progression in SCA3 mice, and compared this with the effects of citalopram.
They observed a number of motor functions in the mice treated with vortioxetine compared to mice without vortioxetine, and found that at 16 weeks of age, the female mice treated with vortioxetine showed some improvement in their ability to cross a balance beam. But this was not sustained, and on a larger balance beam there was no significant difference in the time to cross between treated and untreated SCA3 mice. In a swimming test, the researchers saw no major alteration in motor coordination between the treated and untreated SCA3 mice.
Whilst the researchers showed only a mild effect from treatment of SCA3 mice with vortioxetine, they continued to study the SCA3 mice and found alterations in ATXN3 aggregation in different brain regions affected in SCA3, and a neuroprotective effect in the nigrostriatal dopaminergic system (a major pathway in the brain for controlling movement) were observed upon treatment.
Dr Teixeira-Castro and her team presented research from this project at ICAR 2024.
