Topotecan Reduces Neuron Death after Spinal Cord Injury by Suppressing Caspase-1-Dependent Pyroptosis.

Abstract

Neuronal loss and excessive inflammatory response mediate the pathogenesis of spinal cord injury (SCI). Topotecan (TPT), a topoisomerase 1 (Top 1) inhibitor, is recently revealed to control lethal inflammation. Top 1 is an essential enzyme in mammalian cells and acts as a key role in the DNA replication, transcription, and repair. However, the effects and underlying mechanisms of TPT in SCI remain unclear. Here, we report that topotecan (TPT), a Top 1 inhibitor, led to a significant recovery of hindlimb locomotor function in mice. Moreover, TPT reduced Top 1 level, prevented nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation, reduced caspase-1 expression and pyroptosis, and decreased the levels of pro-inflammatory cytokines and the number of neutrophils in mice. Furthermore, TPT suppressed NLRP3 inflammasome activation, diminished caspase-1 expression and pyroptosis, and reduced pro-inflammatory cytokines levels in neurons. In addition, inhibition of caspase-1 by VX-765 inhibited pyroptosis and reduced proinflammatory cytokine levels in mice. Furthermore, administration of VX-765 suppressed pyroptosis and alleviated cell damage in primary cultured neurons. Our findings suggest that TPT with specific dose and duration reduces neuron death and improves functional recovery after SCI presumably depends on inhibition of caspase-1-dependent pyroptosis.