Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing
Nunzio Vicario, Federica Maria Spitale, Daniele Tibullo, Cesarina Giallongo, Angela Maria Amorini, Grazia Scandura, Graziana Spoto, Miriam Wissam Saab, Simona D’Aprile, Cristiana Alberghina, Renata Mangione, Joshua D. Bernstock, Cirino Botta, Massimo Gulisano, Emanuele Buratti, Giampiero Leanza, Robert Zorec, Michele Vecchio, Michelino Di Rosa, Giovanni Li Volti, Giuseppe Lazzarino, Rosalba Parenti, Rosario Gulino
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.