TAK-242 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TLR4/NF-κB pathway in rat experimental autoimmune neuritis

The inhibition of the TLR4 receptor has been shown to protect neural structure and improve neurological functions in peripheral nervous system (PNS) diseases. There is a scarcity of research regarding the effect of inflammasomes during the process of neuroinflammation in immune related PNS disorders, such as, Guillain-Barré syndrome (GBS), even though it is an essential part for pathophysiology from immunological diseases that impact central nervous system (CNS). In this investigation, we found that TLR4 expression and formation and activation of the NLRP3 inflammasome were increased in the sciatic nerve of experimental autoimmune neuritis (EAN). Further intraperitoneal injection of the selective TLR4 receptor inhibitor TAK-242 (Resatorvid) showed that TAK-242 not only stopped the advancement of EAN to a certain extent, but also alleviated peripheral nerve injury brought on by EAN, as evidenced by improvements in body weight loss, neurological function scores, and nerve conduction deficits. More importantly, TAK-242 effectively inhibited neuroinflammation in EAN rats, mitigated myelin loss and helped the regeneration and repair of EAN peripheral nerve injury, mainly through suppressing TLR4/NF-κB signaling pathway and decreasing NLRP3 inflammasome activation. Based on these findings, administration of TAK-242 can be used as a potential therapy approach for GBS.

Experimental autoimmune neuritis (EAN); Guillain-Barré syndrome (GBS); NLRP3-ASC inflammasome; Neuroinflammation; TAK-242; TLR4.