Cargando…

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease

Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora 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 neuroprote...

Descripción completa

Detalles Bibliográficos
Autores principales: Gan, Ping, Ding, Lidong, Hang, Guihua, Xia, Qiaofang, Huang, Zhimei, Ye, Xing, Qian, Xiaojuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264119/
https://www.ncbi.nlm.nih.gov/pubmed/32528295
http://dx.doi.org/10.3389/fphar.2020.00776
_version_ 1783540905931702272
author Gan, Ping
Ding, Lidong
Hang, Guihua
Xia, Qiaofang
Huang, Zhimei
Ye, Xing
Qian, Xiaojuan
author_facet Gan, Ping
Ding, Lidong
Hang, Guihua
Xia, Qiaofang
Huang, Zhimei
Ye, Xing
Qian, Xiaojuan
author_sort Gan, Ping
collection PubMed
description Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora 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-κB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-κB 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-κB 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.
format Online
Article
Text
id pubmed-7264119
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-72641192020-06-10 Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease Gan, Ping Ding, Lidong Hang, Guihua Xia, Qiaofang Huang, Zhimei Ye, Xing Qian, Xiaojuan Front Pharmacol Pharmacology Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora 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-κB both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-κB 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-κB 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. Frontiers Media S.A. 2020-05-26 /pmc/articles/PMC7264119/ /pubmed/32528295 http://dx.doi.org/10.3389/fphar.2020.00776 Text en Copyright © 2020 Gan, Ding, Hang, Xia, Huang, Ye and Qian http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Gan, Ping
Ding, Lidong
Hang, Guihua
Xia, Qiaofang
Huang, Zhimei
Ye, Xing
Qian, Xiaojuan
Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title_full Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title_fullStr Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title_full_unstemmed Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title_short Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-κB Pathway in Parkinson’s Disease
title_sort oxymatrine attenuates dopaminergic neuronal damage and microglia-mediated neuroinflammation through cathepsin d-dependent hmgb1/tlr4/nf-κb pathway in parkinson’s disease
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264119/
https://www.ncbi.nlm.nih.gov/pubmed/32528295
http://dx.doi.org/10.3389/fphar.2020.00776
work_keys_str_mv AT ganping oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT dinglidong oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT hangguihua oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT xiaqiaofang oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT huangzhimei oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT yexing oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease
AT qianxiaojuan oxymatrineattenuatesdopaminergicneuronaldamageandmicrogliamediatedneuroinflammationthroughcathepsinddependenthmgb1tlr4nfkbpathwayinparkinsonsdisease