Moderate hypothermia inhibits microglial activation after traumatic brain injury by modulating autophagy/apoptosis and the MyD88-dependent TLR4 signaling pathway

The protective role of electroacupuncture (EA) treatment in diverse neurological diseases such as ischemic stroke is well acknowledged. However, whether and how EA act on hippocampal neurogenesis following traumatic brain injury (TBI) remains poorly understood. This study aims to investigate the effect of EA on hippocampal neurogenesis and neurological functions, as well as its underlying association with toll-like receptor 4 (TLR4) signaling in TBI mice. BrdU/NeuN immunofluorescence was performed to label newborn neurons in the hippocampus after EA treatment. Water maze test and neurological severity score were used to evaluate neurological function posttrauma. The hippocampal level of TLR4 and downstream molecules and inflammatory cytokines were, respectively, detected by Western blot and enzyme-linked immunosorbent assay. EA enhanced hippocampal neurogenesis and inhibited TLR4 expression at 21, 28, and 35 days after TBI, but the beneficial effects of EA on posttraumatic neurogenesis and neurological functions were attenuated by lipopolysaccharide-induced TLR4 activation. In addition, EA exerted an inhibitory effect on both TLR4/Myd88/NF-κB and TLR4/TRIF/NF-κB pathways, as well as the inflammatory cytokine expression in the hippocampus following TBI. In conclusion, EA promoted hippocampal neurogenesis and neurological recovery through inhibition of TLR4 signaling pathway posttrauma, which may be a potential approach to improve the outcome of TBI.

Download Full-text

The Absence of TLR4 Prevents Fetal Brain Injury in the Setting of Intrauterine Inflammation

Reproductive Sciences ◽

10.1177/1933719118805859 ◽

2018 ◽

Vol 26 (8) ◽

pp. 1082-1093 ◽

Cited By ~ 1

Author(s):

Natalia M. Tulina ◽

Amy G. Brown ◽

Guillermo O. Barila ◽

Michal A. Elovitz

Keyword(s):

Brain Injury ◽

Notch Signaling ◽

Signaling Pathway ◽

Quantitative Polymerase Chain Reaction ◽

Fetal Brain ◽

Notch Signaling Pathway ◽

Mouse Strains ◽

Enzyme Linked Immunosorbent Assay ◽

Tlr4 Signaling ◽

Tlr4 Signaling Pathway

Background: Exposure to intrauterine inflammation during pregnancy is linked to brain injury and neurobehavioral disorders in affected children. Innate immunity, specifically Toll-like receptor (TLR) signaling pathways are present throughout the reproductive tract as well as in the placenta, fetal membranes, and fetus. The TLR pathways are mechanistically involved in host responses to foreign pathogens and may lead to brain injury associated with prenatal inflammation. Objective: We aimed to determine whether the activation of the TLR4 signaling pathway, in the mother and fetus, is critical to fetal brain injury in the setting of intrauterine inflammation. Methods: A mini-laparotomy was performed on time pregnant C57B6 mice and 2 knockout mouse strains lacking the function of the Tlr4 and Myd88 genes on embryonic day 15. Intrauterine injections of Escherichia coli lipopolysaccharide or saline were administered as described previously. Dams were killed 6 hours postsurgery, and placental, amniotic fluid, and fetal brain tissue were collected. To assess brain injury, quantitative polymerase chain reaction (qPCR) analysis was performed on multiple components of the NOTCH signaling pathway, including Hes genes. Interleukin (IL) IL6, IL1β, and CCL5 expression was assessed using qPCR and enzyme-linked immunosorbent assay. Results: Using an established mouse model of intrauterine inflammation, we demonstrate that the abrogation of TLR4 signaling eliminates the cytokine response in mother and fetus and prevents brain injury associated with increased expression of transcriptional effectors of the NOTCH signaling pathway, Hes1 and Hes5. Conclusions: These data show that the activation of the TLR4 signaling pathway is necessary for the development of fetal brain injury in response to intrauterine inflammation.

Download Full-text

Hyperoxia-induced immature brain injury through the TLR4 signaling pathway in newborn mice

Brain Research ◽

10.1016/j.brainres.2015.03.021 ◽

2015 ◽

Vol 1610 ◽

pp. 51-60 ◽

Cited By ~ 9

Author(s):

Yang Liu ◽

Pu Jiang ◽

Min Du ◽

Kun Chen ◽

Amber Chen ◽

...

Keyword(s):

Brain Injury ◽

Signaling Pathway ◽

Immature Brain ◽

Tlr4 Signaling ◽

Newborn Mice ◽

Tlr4 Signaling Pathway

Download Full-text

Microglial Activation as a Compelling Target for Treating Acute Traumatic Brain Injury

Current Medicinal Chemistry ◽

10.2174/0929867321666141106124657 ◽

2015 ◽

Vol 22 (6) ◽

pp. 759-770 ◽

Cited By ~ 35

Author(s):

Chung-Ching Chio ◽

Mao-Tsun Lin ◽

Ching-Ping Chang

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Microglial Activation ◽

Acute Traumatic Brain Injury

Download Full-text

The Adverse Pial Arteriolar and Axonal Consequences of Traumatic Brain Injury Complicated by Hypoxia and Their Therapeutic Modulation with Hypothermia in Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.235 ◽

2009 ◽

Vol 30 (3) ◽

pp. 628-637 ◽

Cited By ~ 26

Author(s):

Guoyi Gao ◽

Yasutaka Oda ◽

Enoch P Wei ◽

John T Povlishock

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Amyloid Precursor Protein ◽

Vascular Reactivity ◽

Axonal Damage ◽

Precursor Protein ◽

Moderate Hypothermia ◽

Vascular Protection ◽

Impact Acceleration ◽

Cerebral Vascular

This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone, IAI and hypoxia, IAI and hypoxia before induction of moderate hypothermia (33°C), IAI and hypoxia induced during hypothermic intervention, and IAI and hypoxia initiated after hypothermia. Hypoxia alone had no impact on vascular reactivity or axonal damage. Acceleration injury and posttraumatic hypoxia resulted in dramatic axonal damage and altered vascular reactivity. When IAI and hypoxia were followed by hypothermic intervention, no axonal or vascular protection ensued. However, when IAI was followed by hypoxia induced during hypothermia, axonal and vascular protection followed. When this same hypoxic insult followed the use of hypothermia, no benefit ensued. These studies show that early hypoxia and delayed hypoxia exert damaging axonal and vascular consequences. Although this damage is attenuated by hypothermia, this follows only when hypoxia occurs during hypothermia, with no benefit found if the hypoxic insult proceeds or follows hypothermia.

Download Full-text

Heme oxygenase-1 induction mitigates burn-associated early acute kidney injury via the TLR4 signaling pathway

Burns ◽

10.1016/j.burns.2021.04.013 ◽

2021 ◽

Author(s):

Songxue Guo ◽

Meirong Yu ◽

Quan Fang ◽

Liping Zhang ◽

Chuangang You ◽

...

Keyword(s):

Acute Kidney Injury ◽

Signaling Pathway ◽

Heme Oxygenase ◽

Kidney Injury ◽

Heme Oxygenase 1 ◽

Tlr4 Signaling ◽

Tlr4 Signaling Pathway

Download Full-text

THE TLR4 SIGNALING PATHWAY LINKS INNATE AND ADAPTIVE IMMUNITY IN LIVER ISCHEMIA AND REPERFUSION INJURY

Transplantation Journal ◽

10.1097/00007890-200407271-00266 ◽

2004 ◽

Vol 78 ◽

pp. 98-99

Author(s):

Y Zhai ◽

X-D Shen ◽

F Gao ◽

R OConnell ◽

R W. Busuttil ◽

...

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Adaptive Immunity ◽

Ischemia And Reperfusion ◽

Liver Ischemia ◽

Ischemia And Reperfusion Injury ◽

Tlr4 Signaling ◽

Innate And Adaptive Immunity ◽

Tlr4 Signaling Pathway

Download Full-text

Remote ischemic per-conditioning protects against renal ischemia–reperfusion injury via suppressing gene expression of TLR4 and TNF-α in rat model

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0543 ◽

2019 ◽

Vol 97 (2) ◽

pp. 112-119 ◽

Cited By ~ 3

Author(s):

Firouzeh Gholampour ◽

Jamshid Roozbeh ◽

Sahar Janfeshan ◽

Zeinab Karimi

Keyword(s):

Reperfusion Injury ◽

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Antioxidant Systems ◽

Tlr4 Signaling ◽

Tnf Α ◽

Renal Ischemia Reperfusion Injury ◽

Tlr4 Signaling Pathway

The pathogenesis of renal ischemia–reperfusion injury (IRI) involves both inflammatory processes and oxidative stress in the kidney. This study determined whether remote ischemic per-conditioning (RIPerC) is mediated by toll-like receptor 4 (TLR4) signaling pathway in rats. Renal IR injury was induced by occluding renal arteries for 45 min followed by 24 h of reperfusion. RIPerC included 4 cycles of 2 min of ischemia of the left femoral artery followed by 3 min of reperfusion performed at the start of renal ischemia. Rats were divided into sham, IR, and RIPerC groups. At the end of the reperfusion period, urine, blood and tissue samples were gathered. IR created kidney dysfunction, as ascertained by a significant decrease in creatinine clearance and a significant increase in sodium fractional excretion. These changes occurred in concert with a decrease in the activities of glutathione peroxidase, catalase, and superoxide dismutase with an increment in malondialdehyde levels, mRNA expression levels of TLR4 and tumor necrosis factor α (TNF-α), and histological damage in renal tissues. RIPerC treatment diminished all these changes. This study demonstrates that RIPerC has protective effects on the kidney after renal IR, which might be related to the inhibition of the TLR4 signaling pathway and augmentation of antioxidant systems.

Download Full-text