The 5-HT1A receptor agonist NLX-112 rescues motor swimming deficits in Spinocerebellar Ataxia type 3 mice

Introduction Spinocerebellar ataxia 3 (SCA3) is a rare neurodegenerative disorder which causes progressive motor disturbances. There is no approved drug treatment but selective activation of serotonin 5-HT 1A receptors may be a promising therapeutic strategy to attenuate ataxia symptoms. Methods NLX-112, a highly selective 5-HT 1A full agonist, was tested in the CMVMJD135 transgenic mouse model of SCA3. NLX-112 (1.25 and 5 mg/kg/day) was administered BID intraperitoneally for 14 weeks starting when the mice were 12 weeks of age, i.e., after ataxia signs had become established. The motor swimming test (MST), where mice are required to swim to a raised platform, was used to evaluate the motor behavior of SCA3 mice and their performance was compared with that of wild-type (WT) mice. Results Both doses of NLX-112 were well tolerated by the SCA3 mice, as assessed by welfare parameters. In the MST, the latency of SCA3 mice to reach the platform was significantly longer than that of WT mice. However, when SCA3 mice were treated with either 1.25 or 5 mg/kg/day of NLX-112, they showed robust improvement of motor performance, with swimming latencies which were similar to those of WT mice. This effect of NLX-112 was maintained throughout the period of the study. Conclusions The improved motor function of SCA3 mice when treated with NLX-112 supports its investigation as a drug candidate for the treatment of ataxia and related movement disorders. Graphical Abstract Highlights Spinocerebellar ataxia type 3 (SCA3) is marked by progressive motor disturbances Targeting the serotonergic system is a promising strategy to treat SCA3 Transgenic SCA3 mice were treated with NLX-112, a selective 5-HT 1A agonist Chronic NLX-112 normalized performance of mice in the motor swimming test NLX-112 could constitute a drug candidate for treatment of the ataxia disorders