Echinacoside protects dopaminergic neurons by inhibiting NLRP3/Caspase-1/IL-1β signaling pathway in MPTP-induced Parkinson’s disease model

Persistent microglia-mediated neuroinflammation contributes to the progressive loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Recently, NOD-like receptor protein 3 (NLRP3) inflammasome-mediated neuroinflammation is considered to influence the pathogenesis of PD profoundly. Promoting DA neuron survival and/or inhibiting neuroinflammation may offer neuroprotection for PD. In the present study, we found that echinacoside (ECH), a phenylethanoid glycoside derived from Cistanche Deserticola, ameliorated motor deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mouse PD model, characterized as decreased mobility distance in open field test and average time in rotarod test, as well as increased turn time and total time in pole test. ECH administration promoted the reduction of tyrosine hydroxylase (TH) expression and the number of TH-positive neurons in the substantia nigra (SN) under MPTP injury as the molecular docking simulation predicted that ECH would interact with TH. Moreover, ECH improved cell viability in MPP+-damaged SH-SY5Y cell, a cell line for DA neuron, in vitro. Furthermore, ECH administration alleviated MPTP-triggered microglial activation, thus downregulated the expression and activation of NLRP3 inflammasomes in mice SN, along with the involved proteins including Caspase (CASP)-1 and interleukin-1β (IL-1β). The inhibition of NLRP3/CASP-1/IL-1β neuroinflammatory signaling was further confirmed in murine N9 microglia activated by MPP+ insult after ECH treatment in vitro. Furthermore, MCC950, a selective inhibitor for NLRP3 activation, reduced the enhancive expression of NLRP3/CASP-1/IL-1β in MPP+-insulted N9, and also facilitated the inhibition of inflammation synergistically mediated by ECH treatment. All the collected data revealed that ECH ameliorated PD mice neuroethology through promoting DA neuron survival and inhibiting the activated microglia-mediated NLRP3/CASP-1/IL-1β inflammatory signaling. These findings highlight the crucial roles of NLRP3 inflammasome involved in PD neuropathology and ECH exertes neuroprotection for PD as double-targeting neuroinflammation and DA neuronal survival.