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

Aug 27, 2020Brain research bulletin

Echinacoside protects dopamine-producing brain cells by blocking inflammation signals in a Parkinson's disease model

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Abstract

Echinacoside (ECH) improved motor deficits in a mouse model of Parkinson's disease.

Motor deficits were assessed through decreased mobility in the open field test and average time in the rotarod test, along with increased turn time in the pole test.
ECH administration led to a reduction in the expression of tyrosine hydroxylase and the number of tyrosine hydroxylase-positive neurons in the substantia nigra.
Cell viability in MPP-damaged dopamine neuron-like SH-SY5Y cells improved after ECH treatment in vitro.
ECH reduced microglial activation and downregulated the expression of NLRP3 inflammasomes, along with associated proteins like Caspase-1 and interleukin-1β.
MCC950, an NLRP3 inhibitor, also contributed to the reduction of NLRP3/Caspase-1/interleukin-1β expression in MPP-insulted microglia, enhancing the anti-inflammatory effects of ECH.

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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 MPPinsult 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. + + +

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

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