Abstract
Bradykinin (BK) has been shown to induce matrix metalloproteinase (MMP)-9 expression and participate in neuroinflammation. The BK/MMP-9 axis can be a target for managing neuroinflammation. Our previous reports have indicated that reactive oxygen species (ROS)-mediated nuclear factor-kappaB (NF-κB) activity is involved in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1). Rhamnetin (RNT), a flavonoid compound, possesses antioxidant and anti-inflammatory effects. Thus, we proposed RNT could attenuate BK-induced response in RBA-1. This study aims to approach mechanisms underlying RNT regulating BK-stimulated MMP-9 expression, especially ROS and NF-κB. We used pharmacological inhibitors and siRNAs to dissect molecular mechanisms. Western blotting and gelatin zymography were used to evaluate protein and MMP-9 expression. Real-time PCR was used for gene expression. Wound healing assay was applied for cell migration. 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate (H2DCF-DA) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) were used for ROS generation and NOX activity, respectively. Promoter luciferase assay and chromatin immunoprecipitation (ChIP) assay were applied to detect gene transcription. Our results showed that RNT inhibits BK-induced MMP-9 protein and mRNA expression, promoter activity, and cell migration in RBA-1 cells. Besides, the levels of phospho-PKCδ, NOX activity, ROS, phospho-ERK1/2, phospho-p65, and NF-κB p65 binding to MMP-9 promoter were attenuated by RNT. In summary, RNT attenuates BK-enhanced MMP-9 upregulation through inhibiting PKCδ/NOX/ROS/ERK1/2-dependent NF-κB activity in RBA-1.
Highlights
In the central nervous system (CNS), astrocytes are a type of glial cell that play a pivotal role in brain homeostasis and the pathogenesis of brain diseases
We have discovered that the matrix metalloproteinase (MMP)-9 upregulation induced by BK contributes to the inflammatory state in astrocytes [8]
We revealed that RNT could attenuate BK-enhanced MMP-9 expression and cell migration through, at least partially, inhibition of PKCδ/NOX/reactive oxygen species (ROS)/ERK1/2-dependent NF-κB activation in RBA-1 cells (Figure 7)
Summary
In the central nervous system (CNS), astrocytes are a type of glial cell that play a pivotal role in brain homeostasis and the pathogenesis of brain diseases Our reports suggested that BK-stimulated astrocytes contribute inflammatory reaction leading to neuronal apoptosis via upregulation of MMP-9, heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis, and reactive oxygen species (ROS) [7–9,11]. In these studies, we have found that BK-induced MMP-9 expression was mediated through protein kinase C(PKC)δ-extracellular regulated kinase (ERK)1/2 and nuclear factor-kappaB (NF-κB) pathway in rat brain astrocytes (RBA-1) [7,8]. Exploration of compounds with the property of targeting BK/MMP-9 system could be new therapeutic candidates to manage neuroinflammation-related brain diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
