NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

Abstract Background: Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family, and it interacts with the tyrosine kinase B (TrkB) receptor. It has been studied that NT-4 has neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4 and it’s high affinity receptor TrkB as well as its downstream mediator phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FoxO1) following GMH in neonatal rats, with a specific focus on inflammation. Methods: GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. A total of 163 seven-day-old pups were used in this study. The recombinant human NT-4 was administered intranasally at 1 hour after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002 and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 hours prior to NT-4 treatment to investigate the potential mechanism. Short-and-long-term neurobehavior assessments, immunofluorescence staining, Nissl’s staining and Western blot were performed. Results ： The expression of p-TrkB increased after GMH with a peak at day3. The TrkB receptor was expressed by neurons, microglia, and astrocytes. The administration of rh-NT-4 increased phosphorylation of TrkB, expression of PI3K, phosphorylation of Akt and decreased FoxO1, IL-1beta and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. The use of FoxO1 activation CRISPR increased the expression of IL-6, suggesting that FoxO1 might potentially induce pro-inflammatory factors. These results demonstrated that PI3K/Akt/FoxO1 may be the downstream pathway of TrkB phosphorylation. The rat pups treated with rh-NT-4 performed better than untreated animals both in short-and-long-term behavior test. Conclusion： These data showed that rh-NT-4 can reduce the expression of pro-inflammatory cytokines, improve neurological function, attenuate neuroinflammation and post-hemorrhagic hydrocephalus after GMH by promoting TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic target to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

Download Full-text

NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

10.21203/rs.2.18641/v1 ◽

2019 ◽

Author(s):

Tianyi Wang ◽

Junyi Zhang ◽

Peng Li ◽

Yan Ding ◽

Jiping Tang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Factors ◽

Neonatal Rats ◽

Germinal Matrix ◽

Germinal Matrix Hemorrhage ◽

Trkb Receptor ◽

Rat Pups ◽

Short And Long Term ◽

Pro Inflammatory Cytokines

Abstract Background: Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family, and it interacts with the tyrosine kinase B (TrkB) receptor. It has been studied that NT-4 has neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4 and it’s high affinity receptor TrkB as well as its downstream mediator phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/Forkhead box protein O1 (FoxO1) following GMH in neonatal rats, with a specific focus on inflammation. Methods: GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U) in P7 rat pups. A total of 163 seven-day-old pups were used in this study. The recombinant human NT-4 was administered intranasally at 1 hour after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002 and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 hours prior to NT-4 treatment to investigate the potential mechanism. Short-and-long-term neurobehavior assessments, immunofluorescence staining, Nissl’s staining and Western blot were performed. Results：The expression of p-TrkB increased after GMH with a peak at day3. The TrkB receptor was expressed by neurons, microglia, and astrocytes. The administration of rh-NT-4 increased phosphorylation of TrkB, expression of PI3K, phosphorylation of Akt and decreased FoxO1, IL-1beta and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. The use of FoxO1 activation CRISPR increased the expression of IL-6, suggesting that FoxO1 might potentially induce pro-inflammatory factors. These results demonstrated that PI3K/Akt/FoxO1 may be the downstream pathway of TrkB phosphorylation. The rat pups treated with rh-NT-4 performed better than untreated animals both in short-and-long-term behavior test. Conclusion：These data showed that rh-NT-4 can reduce the expression of pro-inflammatory cytokines, improve neurological function, attenuate neuroinflammation and post-hemorrhagic hydrocephalus after GMH by promoting TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic target to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

Download Full-text

NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

10.21203/rs.2.18641/v3 ◽

2020 ◽

Author(s):

Tianyi Wang ◽

Junyi Zhang ◽

Peng Li ◽

Yan Ding ◽

Jiping Tang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Factors ◽

Neonatal Rats ◽

Germinal Matrix ◽

Germinal Matrix Hemorrhage ◽

Trkb Receptor ◽

Rat Pups ◽

Short And Long Term ◽

Pro Inflammatory Cytokines

Download Full-text

NT-4 attenuates neuroinflammation via TrkB/PI3K/FoxO1 pathway after germinal matrix hemorrhage in neonatal rats

Journal of Neuroinflammation ◽

10.1186/s12974-020-01835-z ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Tianyi Wang ◽

Junyi Zhang ◽

Peng Li ◽

Yan Ding ◽

Jiping Tang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Factors ◽

Neonatal Rats ◽

Short Term ◽

Germinal Matrix ◽

Expression Levels ◽

Germinal Matrix Hemorrhage ◽

Rat Pups ◽

Pro Inflammatory Cytokines

Abstract Background Neuroinflammation plays an important role in pathogenesis of germinal matrix hemorrhage (GMH). Neurotrophin-4 (NT-4) is a member of the neurotrophin family and interacts with the tropomyosin receptor kinase B (TrkB). NT-4 has been shown to confer neuroprotective effects following cerebral ischemia. We aimed to investigate the neuroprotective function of NT-4-TrkB signaling, as well as its downstream signaling cascade phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt)/forkhead box protein O1 (FoxO1), following GMH in neonatal rats. Methods GMH was induced by intraparenchymal injection of bacterial collagenase (0.3 U) in P7 rat pups. A total of 163 pups were used in this study. Recombinant human NT-4 was administered intranasally at 1 h after the collagenase injection. The selective TrkB antagonist ANA-12, selective PI3K inhibitor LY294002, and FoxO1 activating CRISPR were administered intracerebroventricularly at 24 h prior to NT-4 treatment to investigate the underlying mechanism. Short-term and long-term neurobehavioral assessments, immunofluorescence staining, Nissl’s staining, and Western blot were performed. Results Expression of phosphorylated TrkB increased after GMH, reaching the peak level at day 3 after hemorrhage. TrkB receptors were observed on neurons, microglia, and astrocytes. The administration of rh-NT-4 induced phosphorylation of TrkB, expression of PI3K, and phosphorylation of Akt. Meanwhile, it decreased FoxO1 and IL-6 levels. Selective inhibition of TrkB/PI3K/Akt signaling in microglia increased the expression levels of FoxO1 and pro-inflammatory cytokines. FoxO1 activating CRISPR increased the expression of IL-6, suggesting that FoxO1 might be a potential inducer of pro-inflammatory factors. These results suggested that PI3K/Akt/FoxO1 signaling may be the downstream pathway of activation of TrkB. The rat pups treated with rh-NT-4 performed better than vehicle-treated animals in both short-term and long-term behavioral tests. Conclusion These data showed that rh-NT-4 reduced the expression levels of pro-inflammatory cytokines, improved neurological function, attenuated neuroinflammation, and thereby mitigated post-hemorrhagic hydrocephalus after GMH by TrkB/PI3K/Akt/FoxO1 pathway. These results indicated that rh-NT-4 could be a promising therapeutic strategy to ameliorate neuroinflammation and hydrocephalus after GMH or other similar brain injuries.

Download Full-text

PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats

Neurobiology of Disease ◽

10.1016/j.nbd.2015.12.015 ◽

2016 ◽

Vol 87 ◽

pp. 124-133 ◽

Cited By ~ 33

Author(s):

Jerry J. Flores ◽

Damon Klebe ◽

William B. Rolland ◽

Tim Lekic ◽

Paul R. Krafft ◽

...

Keyword(s):

Neurological Deficits ◽

Neonatal Rats ◽

Germinal Matrix ◽

Germinal Matrix Hemorrhage

Download Full-text

Osteoporosis and Dietary Inflammatory Index

10.5772/intechopen.96772 ◽

2021 ◽

Author(s):

Olga Cvijanović Peloza ◽

Sandra Pavičić Žeželj ◽

Gordana Kenđel Jovanović ◽

Ivana Pavičić ◽

Ana Terezija Jerbić Radetić ◽

...

Keyword(s):

Bone Loss ◽

Chronic Diseases ◽

Inflammatory Cytokines ◽

Eating Habits ◽

Inflammatory Factors ◽

Fat Tissue ◽

Inflammatory Index ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Healthy bones are constantly being renewed and proper nutrition is an important factor in this process. Anti-inflammatory diet is designed to improve health and prevent the occurrence and development of chronic diseases associated with inadequate diet. Proper nutrition is based on the anti-inflammatory pyramid and changes in poor eating habits are the long-term strategy for preventing inflammation and chronic diseases. Inflammatory factors from food may play a role in the development of osteoporosis and an anti-inflammatory diet may be a way to control and reduce long-term inflammation and prevent bone loss. Pro-inflammatory cytokines from the fat tissue, through activation of the RANKL/RANK/OPG system could intervene with bone metabolism in a way of increased bone loss. Therefore the special attention need to be given to obese patients due to twofold risk, one related to pro-inflammatory cytokines release and the other related to the deprivation of the vitamin D in the fat tissue.

Download Full-text

Acute and Delayed Deferoxamine Treatment Attenuates Long-Term Sequelae After Germinal Matrix Hemorrhage in Neonatal Rats

Stroke ◽

10.1161/strokeaha.114.005079 ◽

2014 ◽

Vol 45 (8) ◽

pp. 2475-2479 ◽

Cited By ~ 26

Author(s):

Damon Klebe ◽

Paul R. Krafft ◽

Clotilde Hoffmann ◽

Tim Lekic ◽

Jerry J. Flores ◽

...

Keyword(s):

Neonatal Rats ◽

Germinal Matrix ◽

Germinal Matrix Hemorrhage

Download Full-text

The influence of different calorie restriction protocols on serum pro-inflammatory cytokines, adipokines and IGF-I levels in female C57BL6 mice: Short term and long term diet effects

Meta Gene ◽

10.1016/j.mgene.2016.12.013 ◽

2017 ◽

Vol 12 ◽

pp. 22-32 ◽

Cited By ~ 16

Author(s):

Soner Dogan ◽

Amitabha Ray ◽

Margot P. Cleary

Keyword(s):

Inflammatory Cytokines ◽

Calorie Restriction ◽

Short Term ◽

Igf I ◽

Pro Inflammatory Cytokines

Download Full-text

Abstract 424: Phospholipid Transfer Protein Deficiency Promotes Inflammatory Factors' Expression via TLR4-TAK1-NFκB Pathway in Macrophage

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.424 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Yang Yu

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Factors ◽

Phospholipid Transfer Protein ◽

Wild Type ◽

Transfer Protein ◽

Phospholipid Transfer ◽

Nfκb Pathway ◽

Nuclear Levels ◽

Deficient Mice ◽

Pro Inflammatory Cytokines

Phospholipid transfer protein (PLTP) plays important roles in macrophage mediated inflammation. In the current study we observed that endogenous PLTP modulated pro-inflammatory pathways in macrophage. With the presence of LPS, peritoneal derived macrophage (PDM) or bone marrow derived macrophage (BMDM) from PLTP deficient mice (PLTP-/-) expressed significantly higher level of pro-inflammatory cytokines compared with PDM or BMDM from wild-type mice (WT), respectively. LPS induced TNFα expression in PLTP-/- BMDM or PLTP knockdown RAW264.7 were suppressed by (5Z)-7-Oxozeaenol, a TAK1 inhibitor, suggesting PLTP deficiency enhanced the expression of pro-inflammatory cytokines via TAK1-NFκB pathway in macrophage. Furthermore, abundance of TLR4 on the membrane was dramatically increased in BMDM from PLTP-/- compared with WT. In addition, inhibition of ABCA1 by chemical inhibitor, glyburide, did not reduce nuclear levels of active STAT3 of BMDM, which indicated that no autocrine PLTP triggered ABCA1-JAK2-STAT3 pathway in this study. In conclusion, PLTP deficiency or low expression may enhance LPS induced pro-inflammatory cytokines expression via TLR4-TAK1-NFκB pathway in macrophage.

Download Full-text