Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury

• Cell death after spinal cord injury (SCI) contributes to resulting functional deficits.
• We assayed the cytoprotective activity of acute administration of ucf-101 in a mouse model of SCI.
• Ucf-101 treatment preserves neural tissue and improves functional recovery from SCI.
• Ucf-101 increases XIAP expression and protects neurons from apoptosis in vitro and in vivo.
• Ucf-101 also activates prosurvival pathways mediated by ERK1/2 phosphorylation.

Secondary death of neural cells plays a key role in the physiopathology and the functional consequences of traumatic spinal cord injury (SCI). Pharmacological manipulation of cell death pathways leading to the preservation of neural cells is acknowledged as a main therapeutic goal in SCI. In the present work, we hypothesize that administration of the neuroprotective cell-permeable compound ucf-101 will reduce neural cell death during the secondary damage of SCI, increasing tissue preservation and reducing the functional deficits. To test this hypothesis, we treated mice with ucf-101 during the first week after a moderate contusive SCI. Our results reveal that ucf-101 administration protects neural cells from the deleterious secondary mechanisms triggered by the trauma, reducing the extension of tissue damage and improving motor function recovery. Our studies also suggest that the effects of ucf-101 may be mediated through the inhibition of HtrA2/OMI and the concomitant increase of inhibitor of apoptosis protein XIAP, as well as the induction of ERK1/2 activation and/or expression. In vitro assays confirm the effects of ucf-101 on both pathways as well as on the reduction of caspase cascade activation and apoptotic cell death in a neuroblastoma cell line. These results suggest that ucf-101 can be a promising therapeutic tool for SCI that deserves more detailed analyses.

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