Abstract
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-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1G86R 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-HT2BR agonist : BW723C86 (BW), in the Sod1G86R 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.
Highlights
Degeneration of brainstem serotonin neurons has been demonstrated in Amyotrophic lateral sclerosis (ALS) patients and mouse models and was found responsible for the development of spasticity
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the joint involvement of lower motor neurons (LMNs), in the brainstem and spinal cord, and upper motor neurons (UMNs), in the motor cortex, leading to loss of body weight, progressive muscle paralysis and spasticity, and death within 2–5 years after onset
We previously observed that the 5-HT2B receptor (5-HT2BR) was upregulated at disease onset in the spinal cord of ALS mice[9] and that deletion of Htr2b, encoding the 5-HT2BR, worsened disease outcome in the Sod1G86R mouse model
Summary
Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. 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. To evaluate the effect of 5-HT2BR stimulation in ALS, BW was selected due to two reasons: (1) its described selectivity for 5-HT2 receptors over the other serotonergic receptor families[10] and (2) its non-amphetaminic chemical structure, since amphetaminic molecules such as fenfluramines, are anorexigens and loss of body weight is correlated to poor survival in A LS11 To this aim, we characterized the pharmacological profile of this compound, optimized its mode of delivery for diseases of the central nervous system, and characterized its Scientific Reports | (2021) 11:23582. 7.87 NC 100.21 74.42 0.97 0.78 No Yes efficacy and target engagement in Sod1G86R mice, a model with fast progression of disease in which ablation of Htr2b accelerated d isease[9]
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