NLRP3 inflammasome inhibition and M1-to-M2 microglial polarization shifting via scoparone-inhibited TLR4 axis in ovariectomy/D-galactose Alzheimer's disease rat model

Illustrating the role of inhibiting TLR4/MyD88/NF-κB/NLRP3 and driving microglia polarization towards M2 in the neuroprotective and memory-improving effects of scoparone in OVX/D-Gal rats. Scoparone reduces OVX/D-Gal-induced Aβ aggregation and tau hyperphosphorylation. It exerts its anti-inflammatory and neuroprotective effects via inhibiting TLR4/MyD88/TRAF-6/TAK-1 pathway and consequently inhibits the downstream effectors, NF-κB and JNK. Moreover, inhibition of NF-κB by scoparone abrogates the NLRP3 inflammasome activation and in turn mitigates caspase-1 production and IL-1β/18 secretion. Further, scoparone-induced inhibition of NLRP3 suppresses the neurotoxic M1 while enhances the neuroprotective M2 activated microglia markers. These effects contribute to scoparone’s ability to reduce neuro-inflammation, neuronal degeneration, Aβ aggregation, and tau hyperphosphorylation. D-Gal D-galactose, OVX ovariectomy, Aβ amyloid-β, TLR4 toll-like receptor 4, MyD88 myeloid differentiation factor 88, TRAF-6 tumor necrosis factor (TNF) receptor-associated factor-6, TAK-1 transforming growth factor-β (TGF-β)-activated kinase-1, NF-κB nuclear factor-κB, JNK c-Jun N-terminal Kinase, NLRP3 nucleotide-binding oligomerization domain (NOD)-like receptor protein 3, IL-18 interleukin-18, IL-1β interleukin-1β, CD cluster of differentiation.