Parthenolide ameliorates neurological deficits and neuroinflammation in mice with traumatic brain injury by suppressing STAT3/NF-κB and inflammasome activation.

Traumatic brain injury (TBI) triggers a set of complex inflammation that results in secondary injury. Parthenolide (PTN) is a sesquiterpene lactone extracted from the herb Tanacetum parthenium (Feverfew) and has potent anti-inflammatory, anti-apoptosis and anti-oxidative stress effects in the central nervous system (CNS)-related diseases. This study focuses on investigating the potential neuroprotective effect of PTN on TBI and the related mechanism. Bv2 microglia, primary microglia were stimulated by LPS, and HT22 neuron cells were stimulated by OGD/R, and they were treated with different doses of PTN. The expression profiles of pro-inflammatory cytokines, proteins, oxidative stress mediators, STAT3/NF-κB pathway, inflammasomes were detected. Forty male/female C57BL/6 mice were randomly divided into the sham, PTN, TBI, and TBI + PTN groups (10 mice per group). A mouse TBI model was set up with a controlled cortical impact (CCI) device. The modified nerve severity score (mNSS) was implemented to check short-term neurological impairment in mice, and the mice's memory and learning were assessed by the Morris water maze test. The water content in the mice's brains was measured by the dry-wet method. Hematoxylin-eosin (H&E) staining, Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were applied for neuronal apoptosis. PTN dramatically alleviated LPS-induced inflammation in microglia, and OGD-mediated neuronal apoptosis and oxidative stress. In addition, PTN repressed LPS- or OGD-modulated STAT3/NF-κB and NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLR family CARD domain containing 4 (NLRC4) inflammasomes activation. Administering the STAT3 inhibitor Stattic or NF-κB inhibitor Bay 11-7082 attenuated PTN-mediated effects. In vivo, PTN treatment relieved neural function deficits, brain edema and neuron apoptosis and improved the memory and learning function of TBI mice. Additionally, PTN impeded microglial activation and reduced the production of pro-inflammatory cytokines in brain lesions of TBI mice. Furthermore, PTN hindered STAT3/NF-κB and inflammasome activation. PTN can curb microglial activation and neuron apoptosis by dampening the STAT3/NF-κB pathway, thus exerting neuroprotective effects in TBI mice.

Ding W ，Cai C ，Zhu X ，Wang J ，Jiang Q ... -  《-》

The AMPK-SIRT1-FoxO1-NF-κB signaling pathway participates in hesperetin-mediated neuroprotective effects against traumatic brain injury via the NLRP3 inflammasome.

Song H ，Ding Z ，Chen J ，Chen T ，Wang T ，Huang J ... -  《-》

Traumatic Brain Injury-Mediated Neuroinflammation and Neurological Deficits are Improved by 8-Methoxypsoralen Through Modulating PPARγ/NF-κB Pathway.

8-Methoxypsoralen (8-MOP) has anti-inflammatory, antioxidant and tissue-repairing abilities. Here, we probed the function and mechanism of 8-MOP in traumatic brain injury (TBI). The in-vivo TBI model was constructed in Sprague-Dawley (SD) rats using controlled cortical impact (CCI) surgery. In parallel, BV2 microglia and HT22 neurons were activated by lipopolysaccharide (LPS) to establish an in-vitro model. The modified neurological score (mNSS) and the Morris water maze experiment were employed to evaluate the rats' neurological functions. The rats' brain edema was assessed by the dry and wet method, and neuronal apoptosis in damaged brain tissues was monitored by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and Nissl's staining. Immunohistochemistry (IHC) was applied to verify Iba1-microglial activation in brain lesions of rats. The expression of inflammatory cytokines in BV2 microglia and HT22 neurons in the injured lesion of TBI rats was examined by the enzyme-linked immunosorbent assay (ELISA). The levels of iNOS, COX2, TLR4, PPARγ, STAT3, and NF-κB in brain lesions, BV2 microglia and HT22 neurons were compared by Western blot. As a result, 8-MOP administration reduced inflammation and LPS-induced neuronal damage in BV2 microglia. In vivo, 8-MOP treatment relieved neurological deficits in TBI rats, improved cognitive, learning and motor functions and mitigated brain edema and neuroinflammation induced by TBI. Furthermore, LPS or TBI activated the NF-κB and STAT3 pathways and repressed the PPARγ expression. However, 8-MOP treatment attenuated NF-κB and STAT3 phosphorylation and elevated PPARγ levels. Hence, 8-MOP exerts neuroprotective and anti-inflammatory effects in TBI rats by modulating the PPARγ/NF-κB pathway.

Hui Y ，Zhao H ，Shi L ，Zhang H ... -  《-》

ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway.

Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI. Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001. ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response. Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI. Video Abstract.

Cai L ，Gong Q ，Qi L ，Xu T ，Suo Q ，Li X ，Wang W ，Jing Y ，Yang D ，Xu Z ，Yuan F ，Tang Y ，Yang G ，Ding J ，Chen H ，Tian H ... -  《Cell Communication and Signaling》

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

Shao A ，Wu H ，Hong Y ，Tu S ，Sun X ，Wu Q ，Zhao Q ，Zhang J ，Sheng J ... -  《-》