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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motoneurons (MNs) [1]
Several data on the pathogenesis of ALS have defined a focal origin in the central nervous system (CNS), where multiple factors contribute to creating a toxic milieu [6, 7], but an active role of both muscle cells and axon terminals in causing retrograde degeneration of MNs has been proposed as a triggering mechanism [8,9,10]
sonic hedgehog (SHH) signaling has been shown to modulation into specific cell populations, we evaluated the Gli1 play a role in ALS pathogenesis
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motoneurons (MNs) [1]. Activating smoothened (SMO); this leads to the nuclear Sap-lesioned mice at 42 dpl, but near-normal levels were found in translocation of transcription factors Gli, inducing the expression CTB-Sap mice treated with clobetasol (Fig. 2e). To analyze such a of target genes [25]. The reduction of Gli nuclear translocation in NeuN (i.e. neurons), Gfap (i.e. astrocytes), and has been reported within the MNs of SOD1G93A mice and SHH has Iba (i.e. microglia) positive cells. Neither CTB-sap lesion nor clobetasol cancer (i.e., SMO antagonists), stroke, and demyelinating disorders treatment did affect nuclear translocation of Gli in microglia
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