scholarly journals Osteoporosis and Dietary Inflammatory Index

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.

In Inflamation Dietary Inflammatory Index and the Role of Different Diet Types

2020 ◽  
pp. 169-201
Author(s):  
Ramazan Mert Atan ◽  
Uğur Günşen
Keyword(s):  
Chronic Diseases ◽  
Inflammatory Cytokines ◽  
Scientific Evidence ◽  
Inflammatory Biomarkers ◽  
Dietary Inflammatory Index ◽  
Food Groups ◽  
Negative Effects ◽  
Inflammatory Index ◽  
Anti Inflammatory

Inflammation usually occurs as a result of imbalances between pro-inflammatory and anti-inflammatory cytokines. Diet is one of the factors that play a role in their development and prevent them from developing. Therefore, it is important to determine the pro- and anti-inflammatory properties of foods. Diet is an important and modifiable determinant of chronic diseases. There is a lot of scientific evidence to support the fact that foods consumed have positive and negative effects on individuals' health. In addition to being effective whole of diet, it is seen that the food groups contained in the diet affect the inflammatory biomarkers separately. This section provides information about dietary inflammatory index (DII) and diets that are effective on inflammation.

Primary Radiation Stress, Inflammatory Reaction and the Mechanism of Early Postradiation Reparative Processes in Irradiated Tissues

2018 ◽  
Vol 63 (6) ◽  
pp. 71-81 ◽  
Author(s):  
М. Васин ◽  
M. Vasin ◽  
В. Соловьев ◽  
V. Solov'ev ◽  
В. Мальцев ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Cathepsin G ◽  
Inflammatory Factors ◽  
Hemopoietic Tissue ◽  
Post Radiation ◽  
Apoptotic Proteins ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The products of radiolysis released from cellular compartment under the influence of ionizing radiation: highly mobile groups of proteins, damaged nuclear and mitochondrial DNA, extracellular ATP and oxidized low density lipoproteins, cause stress activation in irradiated tissues through a pattern of the receptors with start of the cascade r53 and NF-κB of pro-inflammatory ways conducting to an expression of pro-inflammatory genes stimulating synthesis of cytokines of the IL-1 family. Excessive activation of pro-inflammatory way under the influence of a radioactive stress is limited to synthesis, anti-inflammatory cytokines: IL-4, IL-10, IL-11, IL-13 and also antagonists of IL-1 receptor and TGF-β. G-CSF and MG-CSF induced by action of pro-inflammatory cytokines have anti-inflammatory and anti-apoptotic properties decreasing level of pro-inflammatory cytokines IL-6 and TNF. Glucocorticoids participate in regulation of primary radioactive stress, suppressing an excessive expression of genes of pro-inflammatory cytokines. Increased IL-1 level stimulates secretion of corticosteroids through mechanism of feedback. Adrenergic stimulation is capable to raise a gene IL-1β expression. The mechanism of radiation apoptosis of stem cells is implemented through p53-Puma way which blocks interaction anti-apoptotic proteins of Bcl-2 with pro-apoptotic proteins of Bax and Bak. After release from mitochondrion of cytochrome C and apoptosis-inducing factor there is an activation of effector caspases: caspases 3, 6 and 7 through caspase 9, and final cell destruction. Wnt way is crucial for post-radiation repair. Potential of the regenerative response of hemopoietic tissue to radiation injury depends on catenin and ability of Wnt way to stimulate post-radiation bone marrow reparation. Mesenchymal stem cells of bone marrow play a large role in post-radiation regeneration of hemopoietic tissue. Their main action is carried out through TLR2 and TLR4 receptors. Mobilization of hemopoietic stem cells is bound to release proteases from bone marrow, including neutrophil elastase and cathepsin G, and a matrix metalproteinase-9. Radioprotective properties of exogenous IL-1 aren’t limited only by induction of raised G-CSF and GM-CSF production. The larger role in radiation protection is played by the reaction induced by IL-1 in the form of feedback with production anti-apoptotic and anti-inflammatory factors. Primary radioactive stress limits time of radiomitigable effect of IL-1 by 1-2 h after its application after radiation.

Na+/K+-ATPase dependent regulation of astrocyte Ca2+ signalling: A novel mechanism for modulation of long-term pain?

2012 ◽  
Vol 3 (3) ◽  
pp. 185-185 ◽  
Author(s):  
Elisabeth Hansson ◽  
Linda Block ◽  
Johan Forshammar ◽  
Christopher Lundborg ◽  
Björn Biber
Keyword(s):  
Chronic Pain ◽  
Inflammatory Cytokines ◽  
Pharmacological Treatment ◽  
Primary Cultures ◽  
Physiological Role ◽  
Major Health Problem ◽  
Analgesic Drugs ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Background Long-term or chronic pain represents a major health problem and is associated with significant socio-economic costs. During injury, pain can be dissociated from its normal physiological role. It can persist for a longer period of time, even after the primary noxious stimulus has more or less subsided. Analgesic drugs, with predominant neuronal sites of actions, seem to be relatively ineffective. Chronic pain is probably partly a consequence of ongoing neuroinflammation. The mechanisms behind these phenomena, and how the neuronal and non-neuronal activities evoked by painful stimuli and inflammation are processed in the brain and throughout the CNS, are not well understood. Methods Primary cultures, calcium imaging, immunocyto-chemistry, Western blotting, cytokine release. Results Following pain stimuli increased activity of inflammatory receptors and shifts in intra- and extracellular ion concentrations occur within the CNS. One signalling pathway in astrocytes propagates Ca2+ waves, which initially decrease and then increase in form of oscillations in the astrocyte networks. This causes dysfunction in the astrocytic Ca2+ signalling resulting in down-regulation of Na+ transporters, and increased release of pro-inflammatory cytokines. The neurons will then increase their excitability and, hypothetically, also increase the sensitivity for development or potentiation of neuropathic pain states. Low-dose of potential anti-inflammatory and analgesic drugs restore the disturbed astrocytic Ca2+ signalling, and modulate the activity of inflammatory receptors and Na+/K+-ATPase. We recently report, in patients with long-term pain, changes in neurotrophic factors and pro-inflammatory cytokines in blood and CSF. Conclusions Dysfunction in downregulation of Na+ transporters, changed Ca2+ signalling in the astrocyte networks and release of cytokines from glial cells can lead to pathogenic chronic neuroinflammation. Modulation of the Na+/K+-ATPase activity and restoration with anti-inflammatory substances will lead to a balance between inflammatory and anti-inflammatory mediators in inflammatory reactive cells. The pharmacological treatment of today is directed towards neuronal over-excitability, unfortunately with less success. A novel pharmacological treatment strategy would thus be directed towards the activated astrocytes and microglial cells, being the source of the neuroinflammation. This will be an important knowledge for treatment in clinical therapy.

scholarly journals Anti-Inflammatory Effects of 6,7-Dihydroxy-4-Methylcoumarin on LPS-Stimulated Macrophage Phosphorylation in MAPK Signaling Pathways

2021 ◽  
Vol 16 (5) ◽  
pp. 1934578X2110209
Author(s):  
Yun Sil Kang ◽  
You Chul Chung ◽  
Jung No Lee ◽  
Bong Seok Kim ◽  
Chang-Gu Hyun
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Mapk Signaling ◽  
Raw 264.7 Cells ◽  
Inflammatory Factors ◽  
Raw 264.7 ◽  
Dependent Manner ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Coumarin derivatives, such as esculetin, have various physiological functions, including antioxidant, anti-inflammatory, antibacterial, antiviral, and anti-cancer. 6,7-Dihydroxy-4-methylcoumarin (6,7-DH-4MC) is a derivative of esculetin, and its anti-inflammatory effect and mechanism in macrophages have not been studied. In this study, the anti-inflammatory activity of 6,7-DH-4MC was evaluated by measuring the expression of inflammatory factors (NO and PGE2) and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in LPS-stimulated RAW 264.7 macrophages. The results revealed that 6,7-DH-4MC significantly reduced NO levels and PGE2 expression without inducing cytotoxicity; it was confirmed that the inhibition of NO and PGE2 expression was related to iNOS and COX-2 downregulation in response to 6,7-DH-4MC treatment. Moreover, 6,7-DH-4MC decreased the levels of pro-inflammatory cytokines, such as IL-1β and IL-6, in a dose-dependent manner. Mechanistic studies revealed reduced phosphorylation of ERK and p38-MAPK upon 6,7-DH-4MC treatment. Furthermore, the degradation of IκB-α and phosphorylation of NF-κB in cells treated with LPS were interrupted by 6,7-DH-4MC treatment. These results suggest that 6,7-DH-4MC is a potential therapeutic agent for inflammatory diseases. To the best of our knowledge, this is the first report demonstrating the anti-inflammatory effects of 6,7-DH-4MC in RAW 264.7 cells via MAPK and NF-κB signaling pathways.

scholarly journals Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jeonghyeon Moon ◽  
Seon-yeong Lee ◽  
Jeong Won Choi ◽  
A Ram Lee ◽  
Jin Hee Yoo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Th17 Cells ◽  
Skin Fibroblasts ◽  
Inflammatory Factors ◽  
Metformin Treatment ◽  
Protective Effects ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

AbstractScleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

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

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.

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

2020 ◽  
Vol 17 (1) ◽  
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.

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

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

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.

Metformin Ameliorates Scleroderma Via Inhibiting Th17 Cells and Reducing mTOR-STAT3 Signaling in Skin Fibroblasts

2021 ◽  
Author(s):  
Jeonghyeon Moon ◽  
Seon-yeong Lee ◽  
Jeong Won Choi ◽  
Aram Lee ◽  
Jin Hee Yoo ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Th17 Cells ◽  
Skin Fibroblasts ◽  
Inflammatory Factors ◽  
Metformin Treatment ◽  
Protective Effects ◽  
Stat3 Signaling ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that mTOR and STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.

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

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

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.

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