Clobetasol promotes remyelination in a mouse model of neuromyelitis optica.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can produce marked neurological deficit. Current NMO therapies include immunosuppressants, plasma exchange and B-cell depletion. Here, we evaluated 14 potential remyelinating drugs emerging from prior small molecule screens done to identify drugs for repurposing in multiple sclerosis and other demyelinating neurological diseases. Compounds were initially evaluated in oligodendrocyte precursor cell (OPC) and cerebellar slice cultures, and then in a mouse model of NMO produced by intracerebral injection of anti-AQP4 autoantibody (AQP4-IgG) and human complement characterized by demyelination with minimal axonal damage. The FDA-approved drug clobetasol promoted differentiation in OPC cultures and remyelination in cerebellar slice cultures and in mice. Intraperitoneal administration of 2 mg/kg/day clobetasol reduced myelin loss by ~60 %, even when clobetasol was administered after demyelination occurred. Clobetasol increased the number of mature oligodendrocytes within lesions without significantly altering initial astrocyte damage or inflammation. These results provide proof-of-concept for the potential utility of a remyelinating approach in the treatment of NMO.
Departments of Medicine and Physiology, University of California San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA.
Xiaoming
X
Yao
Departments of Medicine and Physiology, University of California San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA.
Tao
T
Su
Departments of Medicine and Physiology, University of California San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA. alan.verkman@ucsf.edu.
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Verkman
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002990:Clobetasol / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009471:Neuromyelitis Optica / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D046509:Tissue Culture Techniques
D018696:Neuroprotective Agents; D002990:Clobetasol
Clobetasol; Demyelination; Mouse models; NMO; Oligodendrocyte