Evaluation of a 5-HT(2B) receptor agonist in a murine model of amyotrophic lateral sclerosis

Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT(2B) receptor (5-HT(2B)R) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1(G86R) mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT(2B)R agonist : BW723C86 (BW), in the Sod1(G86R) mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.