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Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-?B Pathway in Parkinson's Disease.

ABSTRACT: Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of Sophora ?avescens, 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-in?ammatory 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-?B both in vivo and in vitro. It is worth noting that overexpression of CathD reversed OMT-targeted inhibition of HMGB1/TLR4/NF-?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-?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.

SUBMITTER: Gan P

PROVIDER: S-EPMC7264119 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Gan Ping P Ding Lidong L Hang Guihua G Xia Qiaofang Q Huang Zhimei Z Ye Xing X Qian Xiaojuan X

Frontiers in pharmacology 20200526

Oxymatrine (OMT), a natural quinoxaline alkaloid extracted from the root of <i>Sophora ﬂavescens</i>, 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-pheny ...[more]

PMID: 32528295

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Project description:BackgroundAfter traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood-brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway.MethodsC57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated.ResultsHCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ.ConclusionsHCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

Project description:Ma Xing Shi Gan Decoction (MXD), a classical traditional Chinese medicine prescription, is widely used for the treatment of upper respiratory tract infection. However, the effect of MXD against particulate matters with diameter of less than 2.5 ?m (PM2.5) induced lung injury remains to be elucidated. In this study, rats were stimulated with PM2.5 to induce lung injury. MXD was given orally once daily for five days. Lung tissues were harvested to assess pathological changes and edema. Myeloperoxidase (MPO) activity and malonaldehyde (MDA) content in lung were determined to evaluate the degree of injury. To assess the barrier disruption, the bronchoalveolar lavage fluid (BALF) was collected to determine the total protein content and count the number of neutrophils and macrophages. For evaluating the activation of macrophage in lung tissue, CD68 was detected using immunohistochemistry (IHC). The levels of inflammatory factors including tumor necrosis factor-alpha (TNF-?), interleukin-1beta (IL-1?), and interleukin-6 (IL-6) in BALF and serum were measured. In vitro, a PM2.5-activated RAW 264.7 macrophages inflammatory model was introduced. To evaluate the protective effect of MXD-medicated serum, the cell viability and the release of inflammatory factors were measured. The effects of MXD on the High mobility group box-1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF?B) pathway in lung tissue and RAW 264.7 cells were assessed by Western blot. For further confirming the protective effect of MXD was mediated by inhibiting the HMGB1/TLR4/NF?B pathway, RAW 264.7 cells were incubated with MXD-medicated serum alone or MXD-medicated serum plus recombinant HMGB1 (rHMGB1). MXD significantly ameliorated the lung injury in rats, as evidenced by decreases in the pathological score, lung edema, MPO activity, MDA content, CD68 positive macrophages number, disruption of alveolar capillary barrier and the levels of inflammatory factors. In vitro, MXD-medicated serum increased cell viability and inhibited the release of inflammatory cytokines. Furthermore, MXD treatment was found to inhibit HMGB1/TLR4/NF?B signal pathway both in vivo and in vitro. Moreover, the protection of MXD could be reversed by rHMGB1 in RAW 264.7. Taken together, these results suggest MXD protects rats from PM2.5 induced acute lung injury, possibly through the modulation of HMGB1/TLR4/NF?B pathway and inflammatory responses.

Dataset Information

Oxymatrine Attenuates Dopaminergic Neuronal Damage and Microglia-Mediated Neuroinflammation Through Cathepsin D-Dependent HMGB1/TLR4/NF-?B Pathway in Parkinson's Disease.

Publications

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

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