Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing

Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported...

Full description

Saved in:

Bibliographic Details
Published in:	Cell death & disease Vol. 12; no. 7; pp. 625 - 13
Main Authors:	Vicario, Nunzio, Spitale, Federica M., Tibullo, Daniele, Giallongo, Cesarina, Amorini, Angela M., Scandura, Grazia, Spoto, Graziana, Saab, Miriam W., D’Aprile, Simona, Alberghina, Cristiana, Mangione, Renata, Bernstock, Joshua D., Botta, Cirino, Gulisano, Massimo, Buratti, Emanuele, Leanza, Giampiero, Zorec, Robert, Vecchio, Michele, Di Rosa, Michelino, Li Volti, Giovanni, Lazzarino, Giuseppe, Parenti, Rosalba, Gulino, Rosario
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-06-2021 Springer Nature B.V Nature Publishing Group
Subjects:	13/1 13/31 14/1 631/378/1689 631/378/2596 631/443 631/45 64/60 82/51 82/80 96/2 96/31 Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - chemically induced Amyotrophic Lateral Sclerosis - drug therapy Amyotrophic Lateral Sclerosis - immunology Amyotrophic Lateral Sclerosis - metabolism Animals Antibodies Atrophy Biochemistry Biomedical and Life Sciences Case-Control Studies Cell Biology Cell Culture Cholera Toxin Clobetasol - pharmacology Databases, Genetic Denervation Disease Models, Animal Energy Metabolism - drug effects Gliosis Glucocorticoids Glucocorticoids - pharmacology Hedgehog protein Hedgehog Proteins - metabolism Humans Immunology Immunomodulation Inflammation Inflammation Mediators - metabolism Life Sciences Male Metabolism Mice Mice, 129 Strain Microglia Mitochondria Mitochondria, Muscle - drug effects Mitochondria, Muscle - metabolism Mitochondria, Muscle - pathology Motor Activity - drug effects Motor Neurons - drug effects Motor Neurons - immunology Motor Neurons - metabolism Muscle, Skeletal - innervation Neurodegenerative diseases Neuronal Plasticity - drug effects Neuroprotection Neuroprotective Agents - pharmacology Neurotoxicity Open Field Test Regeneration Saporins Signal Transduction Smoothened Receptor - agonists Smoothened Receptor - metabolism Spinal plasticity Spine - drug effects Spine - immunology Spine - metabolism Spine - physiopathology
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-021-03907-1