Abstract

Microcystin-LR (MC-LR) is a potent neurotoxin released by cyanobacterial blooms, posing significant threats to aquatic ecosystems and human health. However, the molecular mechanisms driving its dopaminergic neurodegeneration remain elusive. Herein, we demonstrated that chronic MC-LR exposure (60 days, 10 μg/L) to zebrafish exhibited motor deficits and anxiety-like behaviors. MC-LR also disrupted Nissl body integrity, reduced dopamine (DA) and its metabolites (HVA, DOPA), and suppressed key dopaminergic markers (TH, DAT and DRD1). These changes collectively impaired DA synthesis, transport and signaling cascades. Pathologically, MC-LR triggered robust neuroinflammation, evidenced by neuronal phagocytosis, microglial proliferation and elevated pro-inflammatory cytokines (TNF-α and IL-1β). Transcriptomic profiling, combined with computer simulation and CESTA, identified MyD88 as a master regulator of MC-LR-induced neuroinflammation. This finding was validated using both in vitro co-culture models (HMC3 microglia/SH-SY5Y neurons) and in vivo myd88 knockdown experiments. Notably, MC-LR promoted microglial M1 polarization via the MyD88/NFκB pathway, directly damaging dopaminergic neurons. Crucially, echinacoside (ECH) exerted potent neuroprotection by suppressing microglia activation, inhibiting MyD88/NFκB signaling, and restoring DA levels to controls. Together, these findings unveil a previously unrecognized pathway linking MC-LR exposure to inflammation-driven neurodegeneration, positioning MyD88 as a novel therapeutic target and ECH as a promising candidate against cyanotoxin-induced neurotoxicity.