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

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.

ILB® Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis

“…Previous clinical studies have demonstrated that brain levels of NAA in patients with ALS are significantly lower than those of healthy subjects [ 26 , 27 , 28 ] and correlates negatively with time of patients’ survival [ 29 ]. Furthermore, in a mouse model of selective motoneuronal loss, mimicking the primary pathology associated with ALS, we have very recently found a dramatic depletion of NAA in spinal cord extracts [ 30 ]. It has been shown that changes in cerebral NAA levels under pathological conditions are not simply due to neuronal loss but may also occur under conditions of mitochondrial dysfunction with consequent energy penalty [ 31 , 32 , 33 , 34 , 35 ].…”

“…These compounds, particularly uric acid, represent the end products of the adenine nucleotide degradation pathway occurring at a high rate under conditions of impaired energy metabolism, i.e., when imbalance between ATP production and consumption takes place [ 36 , 37 ]. Increased oxypurines have been observed during coronary bypass surgery [ 38 ], following traumatic brain injury [ 39 ], in patients affected by multiple sclerosis (correlating with disease progression, clinical subtype and neuroradiological findings) [ 40 , 41 ], as well as under various experimental conditions of cellular energy penalty [ 42 , 43 , 44 ] including those found in muscle tissue in an ALS-like murine model of motoneuron ablation [ 30 ]. Recently, using 31 P-magnetic resonance spectroscopy for the quantification of energy-related metabolites in vivo, it has been found that patients with ALS have evident mitochondrial dysfunction in both brain and muscle tissues [ 45 ].…”

Mu and Delta Opioid Receptor Targeting Reduces Connexin 43-Based Heterocellular Coupling during Neuropathic Pain

“…Nuclei were counterstained with Mayer’s hematoxylin (Bio-Optica, Milan, Italy), dehydrated with increasing concentrations of ethanol (50%, 70%, 95%, 100%) and xylene, and cover-slipped with Entellan (Merck Millipore, Cat.No. 1.079.600.500) [ 48 ]. Digital images were acquired using the Nexcope NIB600 biological microscope.…”

GSK-3β suppression upregulates Gli1 to alleviate osteogenesis inhibition in titanium nanoparticle-induced osteolysis

“…2 E). In order to more intuitively evaluate the Gli1 nuclear translocation, cell immunofluorescence staining of Gli1 was performed as previous studies [ 35 , 36 ]. The results indicated that Gli1 expression was obviously upregulated in the 0 µg/cm 2 group in both cytoplasm and nucleus.…”