Abstract
Neuroinflammation following spinal cord injury (SCI) leads to extensive secondary damage in neural tissue adjacent to the primary lesion foci. 5-Methoxytryptophan (5MTP) is a metabolite of tryptophan and proven to play a protective role in several inflammation-related diseases. However, the specific efficacy and molecular mechanism of 5MTP in SCI remains unknown. Here, we aimed to investigate the anti-inflammatory role of 5MTP in microglia-induced neuroinflammation and its therapeutic effect in SCI. To assess the effect of 5MTP in neuroinflammation, we used lipopolysaccharide (LPS) to stimulate microglia in vitro and detected the microglial phenotype using immunofluorescence staining, the inflammatory-related pathway using western blotting, and pro-inflammatory cytokines using ELISA and immunofluorescence. To explore the therapeutic effect of 5MTP in SCI, we performed contusion of the spinal cord in mice and measured the levels of neuroinflammation, glial accumulation, histological and functional recovery using ELISA, immunofluorescence staining, immunohistochemical staining, hematoxylin-eosin staining, Nissl staining and the Basso Mouse Scale, respectively. We found that treatment with 5MTP contributed to decreased activation of pro-inflammatory microglia and reduced the generation of inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IL-18, by negative regulation of the p38-MAPK signaling pathway and NLRP3/caspase-1 expression. In vivo, administration of 5MTP showed mitigatory neuroinflammation levels associated with alleviated glial scar in SCI mice; hence, the neurological integrity and the neuronal survival, as well as locomotor function, were improved following 5MTP administration.5MTP, as a novel anti-neuroinflammatory reagent, can attenuate activated microglia-induced secondary injury following SCI, and therefore, shows promise as a potential compound for application in a clinical trial for SCI therapy.
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