EFFICACY OF CHRONIC 5-HT<SUB>1A</SUB> RECEPTOR AGONISM BY NLX-112 IN A MOUSE MODEL OF SPINOCEREBELLAR ATAXIA TYPE 3

Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by an elongated polyglutamine (polyQ) sequence in the ataxin-3 protein, which triggers neuropathological events that lead to progressive motor impairments. No effective treatment is currently available; however, selective targeting of the serotonergic system has revealed promising results. NLX-112 (a.k.a. befiradol/F13640), a highly selective 5-HT_1A receptor (5-HT_1AR) full agonist, ameliorated motor dysfunction and reduced mutant ATXN3 aggregation in a Caenorhabditis elegans model of SCA3. Here, we assessed the effects of NLX-112 in CMVMJD135 transgenic mice, using the 5-HT_1AR partial agonist tandospirone (TD) as a comparator.
NLX-112 (0.625 or 5 mg/kg/day) and TD (20 or 80 mg/kg/day) were administered chronically in drinking water for 34 weeks, before the onset of symptoms, or NLX-112 (1.25 or 5 mg/kg/day) was administered by twice-daily intraperitoneal injections for 14 weeks, starting after the onset of symptoms. Motor-related behavior tests and neuropathological analysis were executed.
Both drugs were well tolerated by WT and SCA3 mice. NLX-112 treatment, initiated both before and after symptom onset, induced significant improvements in motor performance and slowed the symptom deterioration as the disease progressed. These effects were not observed with TD. NLX-112 elicited neuroprotective effects, reducing dopaminergic (tyrosine hydroxylase-positive) cell loss and reactive astrocytes in the substantia nigra.
In summary, NLX-112 treatment enhanced motor function, slowed disease progression and revealed neuroprotective effects in SCA3 mice, supporting full agonist activation of 5-HT_1AR as a promising therapeutic strategy for SCA3 and other related movement disorders.