Cerebral hypoxia–ischemia increases toll-like receptor 2 and 4 expression in the hippocampus of neonatal rats

Zhang, Peng; Cheng, Guoqiang; Chen, Long-Xia; Zhou, Wenhao; Sun, Jinqiao

doi:10.1016/j.braindev.2014.12.001

Cited by 13 publications

(15 citation statements)

References 20 publications

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“…Also, TLR2 mRNA expression gradually increased over the first 4 days in the ischemic brain (Lehnardt et al, 2007; Ziegler et al, 2007). This increase is also observed in the hippocampus of neonatal rats following artery ligature (Zhang et al, 2015). When TLR2 expression levels were compared to TLR4 and TLR9 expression levels, it was found that ishemic insult increases TLR2 mRNA level more than the others (Ziegler et al, 2007).…”

Section: Toll-like Receptorsmentioning

confidence: 69%

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Anttila

Whitaker

Wires

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Stroke is the leading cause of disability in adults. Drug treatments that target stroke-induced pathological mechanisms and promote recovery are desperately needed. In the brain, an ischemic event triggers major inflammatory responses that are mediated by the resident microglial cells. In this review, we focus on the microglia activation after ischemic brain injury as a target of immunomodulatory therapeutics. We divide the microglia-mediated events following ischemic stroke into three categories: acute, subacute, and long-term events. This division encompasses the spatial and temporal dynamics of microglia as they participate in the pathophysiological changes that contribute to the symptoms and sequela of a stroke. The importance of Toll-like receptor (TLR) signaling in the outcomes of these pathophysiological changes is highlighted. Increasing evidence shows that microglia have a complex role in stroke pathophysiology and they mediate both detrimental and beneficial effects on stroke outcome. So far, most of the pharmacological studies in experimental models of stroke have focused on neuroprotective strategies which are impractical for clinical applications. Post-ischemic inflammation is long lasting and thus, could provide a therapeutic target for novel delayed drug treatment. However, more studies are needed to elucidate the role of microglia in the recovery process from an ischemic stroke and to evaluate the therapeutic potential of modulating post-ischemic inflammation to promote functional recovery.

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Section: Toll-like Receptorsmentioning

confidence: 69%

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Anttila

Whitaker

Wires

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…TLR4 is an innate and adaptive immune cell receptor, which is well known as a mediator of inflammatory reaction involved in neonatal hypoxia brain injury [ 10 ]. TLR4 up-regulation has been found in the animal models of neonatal brain injury after HI and in primary microglia exposed to hypoxic treatment in vitro [ 9 , 10 ]. Mice deficient in TLR4 have reduced brain damage and improved neurological and behavioral outcomes after ischemia/reperfusion [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among all TLRs, Toll-like receptor4 (TLR4) has been shown to widely express on microglia, and mediates neuroinflammatory diseases through activation of innate immunity [ 8 ]. Recent studies have shown that the expression of TLR4 is up-regulated in a neonatal rat model of hypoxic-ischemic brain injury [ 9 ] and in microglia exposed to hypoxic treatment in vitro [ 10 ]. Furthermore, activated microglial TLR4 expression can promote nuclear translocation of the nuclear factor-κB (NF-κB) and subsequent production of pro-inflammtory cytokines involved in neurotoxicity [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats

Fang

Jiang

et al. 2017

Oncotarget

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Neonatal hypoxic-ischemic (HI) brain injury is a devastating disease that often leads to death and detrimental neurological deficits. The present study was designed to evaluate the ability of metformin to provide neuroprotection in a model of neonatal hypoxic-ischemic brain injury and to study the associated molecular mechanisms behind these protective effects. Here, we found that metformin treatment remarkably attenuated brain infarct volumes and brain edema at 24 h after HI injury, and the neuroprotection of metformin was associated with inhibition of neuronal apoptosis, suppression of the neuroinflammation and amelioration of the blood brain barrier breakdown. Additionally, metformin treatment conferred long-term protective against brain damage at 7 d after HI injury. Our study indicates that metformin treatment protects against neonatal hypoxic-ischemic brain injury and thus has potential as a therapy for this disease.

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“…IVH is associated with neuronal degeneration and cognitive dys-function (Georgiadis et al, 2008; Lewis and Bendersky, 1989). Because of its function in learning and memory, the hippocampus has been previously investigated as a target of injury-induced neuronal degeneration in the CA-1 through CA-4 and dentate gyrus regions (Ramani et al, 2013; Song et al, 2007; Zhang et al, 2015; Zlotnik et al, 2012). However, studies performed examining the effects of specific blood components in neonatal IVH-induced brain injury have been limited.…”

Section: Introductionmentioning

confidence: 99%

Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage

Garton

et al. 2016

Brain Research

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Neuronal degeneration following neonatal intraventricular hemorrhage (IVH) is incompletely understood. Understanding the mechanisms of degeneration and cell loss may point toward specific treatments to limit injury. We evaluated the role of hemoglobin (Hb) in cell death after intraventricular injection in neonatal rats. Hb was injected into the right lateral ventricle of post-natal day 7 rats. Rats exposed to anesthesia were used for controls. The CA-1 region of the hippocampus was analyzed via immunohistochemistry, hematoxylin and eosin (H&E) staining, Fluoro-Jade C staining, Western blots, and double-labeling stains. Compared to controls, intraventricular injection of Hb decreased hippocampal volume (27% decrease; p<0.05), induced neuronal loss (31% loss; p<0.01), and increased neuronal degeneration (2.7 fold increase; p<0.01), which were all significantly reduced with the iron chelator, deferoxamine. Hb upregulated p-JNK (1.8 fold increase; p<0.05) and increased expression of the Hb/haptoglobin endocytotic receptor CD163 in neurons in vivo and in vitro (cultured cortical neurons). Hb induced expression of the CD163 receptor, which co-localized with p-JNK in hippocampal neurons, suggesting a potential pathway by which Hb enters the neuron to result in cell death. There were no differences in neuronal loss or degenerating neurons in Hb-injected animals that developed hydrocephalus versus those that did not. Intraventricular injection of Hb causes hippocampal neuronal degeneration and cell loss and increases brain p-JNK levels. p-JNK co-localized with the Hb/haptoglobin receptor CD163, suggesting a novel pathway by which Hb enters the neuron after IVH to result in cell death.

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Cerebral hypoxia–ischemia increases toll-like receptor 2 and 4 expression in the hippocampus of neonatal rats

Cited by 13 publications

References 20 publications

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Metformin treatment after the hypoxia-ischemia attenuates brain injury in newborn rats

Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage

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