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Topotecan Reduces Neuron Death after Spinal Cord Injury by Suppressing Caspase-1-Dependent Pyroptosis
Wu Jiang1,2, Fan He2, Guoming Ding2
1Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Shangcheng District, Hangzhou, 310003, Zhejiang, China.
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.
Insights
Topotecan (TPT) significantly improves hindlimb function after spinal cord injury (SCI) in mice. This recovery is linked to TPT
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Spinal cord injury (SCI) pathogenesis involves neuronal loss and excessive inflammation.
- Topotecan (TPT), a topoisomerase 1 (Top 1) inhibitor, shows potential in controlling inflammation.
- The precise mechanisms of TPT in SCI are not fully understood.
Purpose of the Study:
- To investigate the therapeutic effects of TPT on spinal cord injury.
- To elucidate the underlying molecular mechanisms of TPT action in SCI.
Main Methods:
- Administration of TPT to mice with SCI.
- Assessment of locomotor function recovery.
- Analysis of Top 1, NLRP3 inflammasome, caspase-1, pyroptosis, pro-inflammatory cytokines, and neutrophil levels.
- Inhibition of caspase-1 using VX-765 in vivo and in primary neuronal cultures.
Main Results:
- TPT treatment significantly improved hindlimb locomotor function in SCI mice.
- TPT reduced Top 1 levels, suppressed NLRP3 inflammasome activation, caspase-1 expression, pyroptosis, and pro-inflammatory cytokine release.
- TPT also decreased neutrophil infiltration in injured spinal cords.
- Inhibition of caspase-1 by VX-765 mimicked TPT's effects, reducing pyroptosis and cell damage.
Conclusions:
- TPT demonstrates therapeutic potential for spinal cord injury by reducing neuronal death and inflammation.
- The beneficial effects of TPT in SCI are likely mediated through the inhibition of caspase-1-dependent pyroptosis.
- Targeting Top 1 and caspase-1 pathways offers a promising strategy for SCI treatment.
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