Efficacy of chronic 5-HT 1A receptor agonism by NLX-112 in a mouse model of Spinocerebellar Ataxia type 3

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Abstract Background Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an elongated polyglutamine (polyQ) sequence in the ataxin-3 protein. This expansion triggers neuropathological events, leading to progressive motor disturbances. Currently, no approved therapy exists for this debilitating condition, but compelling evidence suggests that targeting the serotonergic system can significantly attenuate SCA3 disease progression in animal models. Objective This study aimed to assess the effects of NLX-112, a highly selective serotonin 1A receptor (5-HT 1A R) full agonist, in the CMVMJD135 transgenic mouse model of SCA3. Methods NLX-112 (0.625 and 5 mg/kg/day) and tandospirone (a 5-HT 1A R partial agonist used as a comparator; 20 and 80 mg/kg/day) were administered chronically in drinking water for 34 weeks, starting prior to symptom onset. To evaluate the effects of the drugs on SCA3 mice, motor-related behavioral tests and neuropathological techniques were employed. Results Treatment with the higher dose of NLX-112 led to improvements in motor coordination and balance, and slowing of symptom deterioration as the disease progressed. These beneficial effects were not achieved with tandospirone. NLX-112 treatment also elicited neuroprotective effects, reducing dopaminergic (tyrosine hydroxylase-positive) cell loss and astrocyte reactivity in the substantia nigra. Conclusions NLX-112 treatment, started pre-symptomatically, enhanced motor function, slowed disease progression and elicited neuroprotective effects in SCA3 mice, supporting its further development as a drug candidate for treatment of ataxia and related movement disorders. Graphical Abstract Key findings NLX-112 attenuated motor deficits of SCA3 mice, when administered chronically prior to disease onset. NLX-112 reduced neuropathological biomarkers in SCA3 mice, namely by restoring dopaminergic neuron loss and decreasing astrocyte reactivity. NLX-112 is a potential candidate for addressing ataxia-related deficits in SCA3 patients.

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