Short and Long-Term Analysis and Comparison of Neurodegeneration and Inflammatory Cell Response in the Ipsilateral and Contralateral Hemisphere of the Neonatal Mouse Brain after Hypoxia/Ischemia

Shrivastava, Kalpana; Chertoff, Mariela; Llovera, Gemma; Recasens, Mireia; Acarín, Laia

doi:10.1155/2012/781512

Cited by 28 publications

(37 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1a,b). Interestingly, S100A4 was also induced in the contralateral WM, most probably following the spreading astrocytic activation, which occurs in focal brain injuries 27,28 and was also observed in this model (glial acidic fibrillary protein (GFAP) staining, Supplementary Fig. S1c).…”

Section: S100a4 Is Upregulated In Brain Injury and Protects Neuronssupporting

confidence: 52%

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Dmytriyeva¹,

Pankratova²,

Owczarek³

et al. 2012

Nat Commun

117

View full text Add to dashboard Cite

Identification of novel pro-survival factors in the brain is paramount for developing neuroprotective therapies. The multifunctional S100 family proteins have important roles in many human diseases and are also upregulated by brain injury. However, S100 functions in the nervous system remain unclear. Here we show that the S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes. Genetic deletion of S100A4 exacerbates neuronal loss after brain trauma or excitotoxicity, increasing oxidative cell damage and downregulating the neuroprotective protein metallothionein I þ II. We identify two neurotrophic motifs in S100A4 and show that these motifs are neuroprotective in animal models of brain trauma. Finally, we find that S100A4 rescues neurons via the Janus kinase/STAT pathway and, partially, the interleukin-10 receptor. Our data introduce S100A4 as a therapeutic target in neurodegeneration, and raise the entire S100 family as a potentially important factor in central nervous system injury.

show abstract

Section: S100a4 Is Upregulated In Brain Injury and Protects Neuronssupporting

confidence: 52%

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Dmytriyeva¹,

Pankratova²,

Owczarek³

et al. 2012

Nat Commun

117

View full text Add to dashboard Cite

show abstract

“…HI brain damage was induced in P7 mice by permanent left carotid occlusion and exposure to hypoxia as described and standardized elsewhere [19,35]. Briefly, a midline ventral skin incision was made under isoflurane anesthesia (4.5% v/v for induction and 2.5% v/v for maintenance, and 0.6 l/min of O 2 ); the left carotid artery was exposed and sutured with an 8-0 silk surgical suture.…”

Section: Methodsmentioning

confidence: 99%

“…Slides for immunohistochemistry were selected according to the optimal injury score as defined in our previous study [19]. To characterize cells expressing pSTAT3, triple immunofluorescence was performed using astrocyte (glial intermediate filament protein, GFAP) and microglia/macrophage (F4/80) markers (table 1).…”

Section: Methodsmentioning

confidence: 99%

“…This is usually characterized by the involvement of damaged neurons, microglial cells, astrocytes, endothelial cells, recruited blood leukocytes and various cytokines [12,13,14,15,16]. Although the function of glial cells in the neonatal brain has been intensively studied during the last decade [17,18,19], the data on molecular mechanisms and the role of glial cells in a central nervous system injury in neonates are still inadequate.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Shrivastava¹,

Llovera²,

Recasens³

et al. 2013

Dev Neurosci

View full text Add to dashboard Cite

Hypoxia/ischemia (HI) is a prevalent reason for neonatal brain injury with inflammation being an inevitable phenomenon following such injury; but there is a scarcity of data regarding the signaling pathway involved and the effector molecules. The signal transducer and activator of transcription factor 3 (STAT3) is known to modulate injury following imbalance between pro- and anti-inflammatory cytokines in peripheral and central nervous system injury making it a potential molecule for study. The current study investigates the temporal expression of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, IL-1ra, IL-4, IL-10, IL-13 and phosphorylated STAT3 (pSTAT3) after carotid occlusion and hypoxia (8% O₂, 55 min) in postnatal day 7 C57BL/6 mice from 3 h to 21 days after hypoxia. Protein array illustrated notable changes in cytokines expressed in both hemispheres in a time-dependent manner. The major pro-inflammatory cytokines showing immediate changes between ipsi- and contralateral hemispheres were IL-6 and IL-1β. The anti-inflammatory cytokines IL-4 and IL-13 demonstrated a delayed augmentation with no prominent differences between hemispheres, while IL-1ra showed two distinct peaks of expression spread over time. We also illustrate for the first time the spatiotemporal activation of pSTAT3 (Y705 phosphorylation) after a neonatal HI in mice brain. The main regions expressing pSTAT3 were the hippocampus and the corpus callosum. pSTAT3+ cells were mostly a subpopulation of activated astrocytes (GFAP+) and microglia/macrophages (F4/80+) seen only in the ipsilateral hemisphere at most time points studied (till 7 days after hypoxia). The highest expression of pSTAT3+ cells was observed to be around 24-48 h, where the presence of pSTAT3+ astrocytes and pSTAT3+ microglia/macrophages was seen by confocal micrographs. In conclusion, our study highlights a synchronized expression of some pro- and anti-inflammatory cytokines, especially in the long term not previously defined. It also points towards a significant role of STAT3 signaling following micro- and astrogliosis in the pathophysiology of neonatal HI-related brain injury. In the study, a shift from pro-inflammatory to anti-inflammatory cytokine profile was also noted as the injury progressed. We suggest that while designing efficient neuroprotective therapies using inflammatory molecules, the time of intervention and balance between the pro- and anti-inflammatory cytokines must be considered.

show abstract

“…22 Sildenafil (1 μmol/L) treatment has been shown to decrease TUNEL-positive cells in isolated adult 23 and neonatal 24 cardiomyocytes in culture by increasing protein kinase G activity, as well as in ischemic cardiomyopathy in mice. 11 Our data are also consistent with a recent work demonstrating that sildenafil leads to a decrease in GFAP expression and astrocyte activation as well as microglial/macrophage activation and recruitment, in association with the downregulation of cytokine production in a mouse model of cuprizone-induced multiple sclerosis.…”

Section: March 2014mentioning

confidence: 99%

Sildenafil Mediates Blood-Flow Redistribution and Neuroprotection After Neonatal Hypoxia-Ischemia

Charriaut‐Marlangue

Nguyen

Bonnin

et al. 2014

Stroke

View full text Add to dashboard Cite

The goal of this study was to test the hypothesis that boosting NO-cGMP signaling through PDE-5 inhibition with sildenafil would enhance microcirculatory CBF, reduce ipsilateral Background and Purpose-The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. Methods-HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. Results-Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. Conclusions-Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

show abstract

Short and Long-Term Analysis and Comparison of Neurodegeneration and Inflammatory Cell Response in the Ipsilateral and Contralateral Hemisphere of the Neonatal Mouse Brain after Hypoxia/Ischemia

Cited by 28 publications

References 117 publications

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Sildenafil Mediates Blood-Flow Redistribution and Neuroprotection After Neonatal Hypoxia-Ischemia

Contact Info

Product

Resources

About