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Senkyunolide I attenuates oxygen-glucose deprivation/reoxygenation-induced inflammation in microglial cells
Yang-Ye Hu1, Yuan Wang2, Shuang Liang2
1Engineering Research Center of Modern Preparation of TCM, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; TCM syndrome and System Biology Research Center, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract:
Over-activated microglia during stroke has been documented to aggravate brain damage. Our previous studies showed that senkyunolide I (SEI) exerted anti-inflammatory effects against endotoxin insult in vitro and ameliorative effects on cerebral ischemia/reperfusion (I/R) injury in vivo. Using oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic stroke, we here investigated the anti-inflammatory effect of SEI on microglial cells and explored the underlying mechanisms. OGD for 3h followed by reoxygenation for 12h significantly enhanced the release of pro-inflammatory cytokines and expressions of inflammation-related enzymes in BV-2 cells, which was inhibited by pretreatment with SEI. To elucidate the mechanisms, we studied its effect on upstream signaling pathways. It was found that SEI suppressed the activation of NF-κB pathway induced by OGD/R and the MAPK pathway was shown not to be involved. Furthermore, SEI significantly down-regulated TLR4/MyD88 pathway with specifically improving inducible Hsp70 level through increasing HSF-1/DNA binding activity, and these regulations responsive to SEI were attenuated by transfecting Hsp70 siRNA and HSF-1 decoy ODNs. Additionally, SEI exerted similar influence on Hsp70/TLR4/NF-κB pathway in rat primary microglial cells. The results suggested that SEI had a potent effect against stroke-induced neuroinflammation through suppressing the TLR4/NF-κB pathway by up-regulating Hsp70 dependent on HSF-1.
Insights
Senkyunolide I (SEI) reduces brain damage from stroke by inhibiting neuroinflammation in microglial cells. SEI suppresses the TLR4/NF-κB pathway, offering a potential therapeutic strategy for stroke recovery.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Over-activated microglia exacerbate brain damage following stroke.
- Senkyunolide I (SEI) has demonstrated anti-inflammatory and neuroprotective effects in previous studies.
- Microglial activation plays a critical role in stroke-induced neuroinflammation.
Purpose of the Study:
- To investigate the anti-inflammatory effects of SEI on microglial cells under stroke-like conditions (oxygen-glucose deprivation/reoxygenation - OGD/R).
- To elucidate the underlying molecular mechanisms by which SEI exerts its anti-inflammatory action.
- To explore the role of specific signaling pathways, including NF-κB, MAPK, and TLR4/MyD88, in SEI's effects.
Main Methods:
- Utilized oxygen-glucose deprivation/reoxygenation (OGD/R) in BV-2 microglial cells to mimic stroke conditions.
- Assessed the release of pro-inflammatory cytokines and expression of inflammation-related enzymes.
- Investigated the involvement of NF-κB, MAPK, TLR4/MyD88, HSF-1, and Hsp70 signaling pathways.
- Employed techniques such as siRNA and decoy oligonucleotides to validate pathway involvement.
- Confirmed findings in primary rat microglial cells.
Main Results:
- OGD/R significantly increased pro-inflammatory mediators in BV-2 cells, an effect inhibited by SEI pretreatment.
- SEI suppressed OGD/R-induced activation of the NF-κB pathway.
- The MAPK pathway was not found to be involved in SEI's effects.
- SEI down-regulated the TLR4/MyD88 pathway by up-regulating inducible Hsp70 levels via increased HSF-1/DNA binding activity.
- These SEI-mediated regulations were confirmed in primary rat microglial cells.
Conclusions:
- SEI exhibits potent anti-neuroinflammatory effects against stroke-induced damage in microglial cells.
- SEI primarily acts by suppressing the TLR4/NF-κB signaling pathway.
- The mechanism involves the up-regulation of Hsp70, dependent on HSF-1 activation, leading to reduced neuroinflammation.
