Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson's Disease
Open Access
- 26 May 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Pharmacology
- Vol. 11, 776
- https://doi.org/10.3389/fphar.2020.00776
Abstract
Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root ofSophora flavescens, presents amounts of pharmacological properties including immunomodulation, anti-inflammation, anti-oxidation, and anti-virus. Recent studies tend to focus on its effects on neuroinflammation and neuroprotection in Parkinson's disease (PD) due to its profound anti-inflammatory effect. In this study, the neuroprotective and anti-neuroinflammatory effects of OMT were investigated in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-stimulated mice and 1-methyl-4-phenylpyridinium (MPP+)-induced mice primary microglia. Additionally, mice primary neuron-microglia co-cultures and primary microglia infected with Cathepsin D (CathD)-overexpressed lentivirus were used to clarify whether the neuroprotective effect of OMT was through a CathD-dependent pathway. Results showed that OMT dose-dependently alleviated MPTP-induced motor deficits and conferred significant dopamine (DA) neuroprotection against MPTP/MPP+-induced neurotoxicity. In addition, OMT inhibited MPTP/MPP+-induced microglia activation and the pro-inflammatory cytokines release. Further, OMT down-regulated the expression of CathD, and inhibited the activation of the HMGB1/TLR4 signaling pathway as well as the nuclear translocation of NF-kappa B bothin vivoandin vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-kappa B signaling and OMT-produced neuroprotection in reconstituted neuron-microglia co-cultures. Our findings indicated that OMT conferred DA neuroprotection and attenuated microglial-mediated neuroinflammation through CathD-dependent inhibition of HMGB1/TLR4/NF-kappa B signaling pathway. Our study supports a potential role for OMT in ameliorating PD, and proposes that OMT may be useful in the treatment of PD.This publication has 48 references indexed in Scilit:
- Oxymatrine Prevents NF-κB Nuclear Translocation And Ameliorates Acute Intestinal InflammationScientific Reports, 2013
- Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptorsPhytomedicine, 2013
- Upregulation of cathepsin D in the caudate nucleus of primates with experimental parkinsonismMolecular Neurodegeneration, 2011
- The activation of P2X7 receptor induces cathepsin D-dependent production of a 20-kDa form of IL-1β under acidic extracellular pH in LPS-primed microglial cellsJournal of Neurochemistry, 2011
- HMGB1 Acts on Microglia Mac1 to Mediate Chronic Neuroinflammation That Drives Progressive NeurodegenerationJournal of Neuroscience, 2011
- Mechanisms Underlying Inflammation in NeurodegenerationCell, 2010
- Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic NeuronsPLOS ONE, 2008
- Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's diseaseProceedings of the National Academy of Sciences of the United States of America, 2007
- Chronic microglial activation and progressive dopaminergic neurotoxicityBiochemical Society Transactions, 2007
- Functional changes in cocultures of mesencephalon and striatal neurons from embryonic C57/BL6 mice due to low concentrations of 1-Methyl-4-Phenylpyridinium (MPP+)Journal of Neural Transmission, 1993