Neuroprotective effects of natural cordycepin on LPS-induced Parkinson’s disease through suppressing TLR4/NF-κB/NLRP3-mediated pyroptosis

Abstract

• LPS resulted in TLR4-mediated NF-κB activation and NLRP3-dependent pyroptosis both in vivo and in vitro. • Cordycepin treatment ameliorated locomotor impairments and reversed DA degeneration. • Treatment with cordycepin inhibited the activation of NLRP3 inflammasome through TLR4/NF-κB signaling pathways. • Cordycepin administration suppressed LPS-induced NLRP3-depedent pyroptosis and inflammatory cascades. Cordycepin extracted from Cordyceps militaris , an edible and rare caterpillar fungus, possess neuroprotective and anti-inflammatory activity. Neuroinflammation has been implicated in the onset and development of Parkinson’s disease (PD). Notably, pyroptosis is a new form of programmed cell death which plays an important role in inflammation. However, the roles of pyroptosis and cordycepin on anti-pyroptosis in PD remain unclear. This study was designed to investigate neuroprotective effects of cordycepin in LPS-treated C57BL/6J mice and LPS- treated BV2. The results showed that cordycepin ameliorated LPS-induced PD symptoms and suppressed TLR4/NF-κB-mediated NLRP3 inflammasome activation and GSDMD-related pyroptosis. Additionally, cordycepin remarkably inhibited pore formation in the plasma membrane and reduced the release of proinflammatory mediators in vitro , which is associated with the inhibition of NLRP3-dependent pyroptosis. Collectively, cordycepin exerts neuroprotective activity by regulating TLR4/NF-κB/NLRP3-dependent pyroptosis, which should be developed as healthcare food or natural medicine for the treatment of PD in the future.