Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome.

Marco Emili, Fiorenza Stagni, Maria Elisa Salvalai, Beatrice Uguagliati, Andrea Giacomini, Christelle Albac, Marie-Claude Potier, Mariagrazia Grilli, Renata Bartesaghi, Sandra Guidi

Neurobiology of disease 2020 Jul

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Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drug screening campaign showed that the β2-adrenergic receptor (β2-AR) agonists clenbuterol hydrochloride (CLEN) and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dn model of DS. The goal of the current study was to establish their efficacy in vivo, in the Ts65Dn model. We found that, at variance with the in vitro experiments, treatment with CLEN or SALM did not restore neurogenesis in the hippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLEN or SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells were restored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALM are used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study suggests that treatment with these β2-AR agonists may be a therapy of choice in order to correct dendritic development in DS but is not suitable to rescue neurogenesis. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Marco Emili, Fiorenza Stagni, Maria Elisa Salvalai, Beatrice Uguagliati, Andrea Giacomini, Christelle Albac, Marie-Claude Potier, Mariagrazia Grilli, Renata Bartesaghi, Sandra Guidi. Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome. Neurobiology of disease. 2020 Jul;140:104874