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.

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

Vicario N.
Primo
;
Spitale F. M.;Tibullo D.;Giallongo C.;Amorini A. M.;Scandura G.;Spoto G.;Saab M. W.;D'Aprile S.;Alberghina C.;Botta C.;Gulisano M.;Leanza G.;Vecchio M.;Di Rosa M.;Li Volti G.;Lazzarino G.;Parenti R.
Penultimo
;
Gulino R.
Ultimo
2021-01-01

Abstract

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.
Amyotrophic Lateral Sclerosis
Animals
Case-Control Studies
Cholera Toxin
Clobetasol
Databases, Genetic
Disease Models, Animal
Energy Metabolism
Glucocorticoids
Hedgehog Proteins
Humans
Inflammation Mediators
Male
Mice, 129 Strain
Mitochondria, Muscle
Motor Activity
Motor Neurons
Muscle, Skeletal
Neuronal Plasticity
Neuroprotective Agents
Open Field Test
Saporins
Signal Transduction
Smoothened Receptor
Spine
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/519462
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