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

Abstract

IntroductionSpinocerebellar 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-HT1A receptors may be a promising therapeutic strategy to attenuate ataxia symptoms. MethodsNLX-112, a highly selective 5-HT1A 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. ResultsBoth 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. ConclusionsThe 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/674027v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f0a8e1org.highwire.dtl.DTLVardef@1df4d49org.highwire.dtl.DTLVardef@14af6a2org.highwire.dtl.DTLVardef@86096b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISpinocerebellar ataxia type 3 (SCA3) is marked by progressive motor disturbances C_LIO_LITargeting the serotonergic system is a promising strategy to treat SCA3 C_LIO_LITransgenic SCA3 mice were treated with NLX-112, a selective 5-HT1A agonist C_LIO_LIChronic NLX-112 normalized performance of mice in the motor swimming test C_LIO_LINLX-112 could constitute a drug candidate for treatment of the ataxia disorders C_LI