scholarly journals Transcriptomic characterization of microglia activation in a rat model of ischemic stroke

2020 ◽  
Vol 40 (1_suppl) ◽  
pp. S34-S48
Author(s):  
Wenjun Deng ◽  
Emiri Mandeville ◽  
Yasukazu Terasaki ◽  
Wenlu Li ◽  
Julie Holder ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Phenotypic Diversity ◽  
Focal Cerebral Ischemia ◽  
Wide Spectrum ◽  
Spontaneously Hypertensive ◽  
Transient Focal Cerebral Ischemia ◽  
Microglial Response ◽  
Whole Transcriptome

Microglia are key regulators of inflammatory response after stroke and brain injury. To better understand activation of microglia as well as their phenotypic diversity after ischemic stroke, we profiled the transcriptome of microglia after 75 min transient focal cerebral ischemia in 3-month- and 12-month-old male spontaneously hypertensive rats. Microglia were isolated from the brains by FACS sorting on days 3 and 14 after cerebral ischemia. GeneChip Rat 1.0ST microarray was used to profile the whole transcriptome of sorted microglia. We identified an evolving and complex pattern of activation from 3 to 14 days after stroke onset. M2-like patterns were extensively and persistently upregulated over time. M1-like patterns were only mildly upregulated, mostly at day 14. Younger 3-month-old brains showed a larger microglial response in both pro- and anti-inflammatory pathways, compared to older 12-month-old brains. Importantly, our data revealed that after stroke, most microglia are activated towards a wide spectrum of novel polarization states beyond the standard M1/M2 dichotomy, especially in pathways related to TLR2 and dietary fatty acid signaling. Finally, classes of transcription factors that might potentially regulate microglial activation were identified. These findings should provide a comprehensive database for dissecting microglial mechanisms and pursuing neuroinflammation targets for acute ischemic stroke.

scholarly journals Lack of Neuroprotection of Inhibitory Peptides Targeting Jun/JNK after Transient Focal Cerebral Ischemia in Spontaneously Hypertensive Rats

2011 ◽  
Vol 31 (12) ◽  
pp. e1-e8 ◽  
Author(s):  
William R Gow ◽  
Kym Campbell ◽  
Amanda J Meade ◽  
Paul M Watt ◽  
Nadia Milech ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Receptor Activation ◽  
Glutamate Excitotoxicity ◽  
Functional Score ◽  
Adhesive Tape ◽  
Tat Peptide ◽  
Spontaneously Hypertensive ◽  
Transient Focal Cerebral Ischemia

In this study, we have assessed the ability of two TAT-fused peptides PYC36d-TAT and JNKI-1d-TAT (JNKI-1 or XG-102), which respectively inhibit jun proto-oncogene (c-Jun) and c-Jun N-terminal kinase (JNK) activation, to reduce infarct volume and improve functional outcome (adhesive tape removal) after transient focal cerebral ischemia in Spontaneously Hypertensive (SH) rats. PYC36d-TAT and JNKI-1d-TAT peptide batches used for experiments were tested in vitro and protected cortical neurons against glutamate excitotoxicity. Rats were treated intravenously with three different doses of PYC36d-TAT (7.7, 76, or 255 nmol/kg), JNKI-1d-TAT (255 nmol/kg), d-TAT peptide (255 nmol/kg), or saline (vehicle control), 10 minutes after reperfusion after 90 minutes of middle cerebral artery occlusion (MCAO). Contrary to other stroke models, no treatment significantly reduced infarct volume or improved functional score measurements compared with vehicle-treated animals when assessed 48 hours after MCAO. Additionally, assessment of the JNKI-1d-TAT peptide, when administered 1 or 2 hours after reperfusion after 90 minutes of MCAO, also did not improve histological or functional outcomes at 48 hours after occlusion. This study is the first to evaluate the efficacy of PYC36d-TAT and JNKI-1d-TAT using the SH rat, which has recently been shown to be more sensitive to AMPA receptor activation rather than to NMDA receptor activation after cerebral ischemia, and which may have contributed to the negative findings.

Role of Arginine Vasopressin V1 and V2 Receptors for Brain Damage After Transient Focal Cerebral Ischemia

2005 ◽  
Vol 25 (8) ◽  
pp. 1012-1019 ◽  
Author(s):  
Abedin Vakili ◽  
Hiroharu Kataoka ◽  
Nikolaus Plesnila
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Brain Edema ◽  
Brain Damage ◽  
Arginine Vasopressin ◽  
Focal Cerebral Ischemia ◽  
Edema Formation ◽  
Transient Focal Cerebral Ischemia ◽  
Brain Edema Formation

Brain edema formation is one of the most important mechanisms responsible for brain damage after ischemic stroke. Despite considerable efforts, no specific therapy is available yet. Arginine vasopressin (AVP) regulates cerebral water homeostasis and has been involved in brain edema formation. In the current study, we investigated the role of AVP V1 and V2 receptors on brain damage, brain edema formation, and functional outcome after transient focal cerebral ischemia, a condition comparable with that of stroke patients undergoing thrombolysis. C57/BL6 mice were subjected to 60-min middle cerebral artery occlusion (MCAO) followed by 23 h of reperfusion. Five minutes after MCAO, 100 or 500 ng of [deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-vasopressin (AVP V1 receptor antagonist) or [adamantaneacetyl(1), O-Et-d-Tyr(2), Val(4), Abu(6), Arg(8,9)]-vasopressin (AVP V2 receptor antagonist) were injected into the left ventricle. Inhibition of AVP V1 receptors reduced infarct volume in a dose-dependent manner by 54% and 70% (to 29±13 and 19±10 mm3 versus 63±17 mm3 in controls; P<0.001), brain edema formation by 67% (to 80.4%±1.0% versus 82.7%±1.2% in controls; P<0.001), blood-brain barrier disruption by 75% ( P<0.001), and functional deficits 24 h after ischemia, while V2 receptor inhibition had no effect. The current findings indicate that AVP V1 but not V2 receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. Although further studies are needed to clarify the mechanisms of neuroprotection, AVP V1 receptors seem to be promising targets for the treatment of ischemic stroke.

scholarly journals Endonuclease G does not play an obligatory role in poly(ADP-ribose) polymerase-dependent cell death after transient focal cerebral ischemia

2010 ◽  
Vol 299 (1) ◽  
pp. R215-R221 ◽  
Author(s):  
Zhenfeng Xu ◽  
Jian Zhang ◽  
Karen K. David ◽  
Zeng-Jin Yang ◽  
Xiaoling Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Wild Type ◽  
Endonuclease G ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Inducing Factor

Activation of poly(ADP-ribose) polymerase (PARP) and subsequent translocation of apoptosis-inducing factor contribute to caspase-independent neuronal injury from N-methyl-d-aspartate, oxygen-glucose deprivation, and ischemic stroke. Some studies have implicated endonuclease G in the DNA fragmentation associated with caspase-independent cell death. Here, we compared wild-type and endonuclease G null mice to investigate whether endonuclease G plays a role in the PARP-dependent injury that results from transient focal cerebral ischemia. Latex casts did not reveal differences in the cerebral arterial distribution territory or posterior communicating arterial diameter, and the decrease in laser-Doppler flux during middle cerebral artery occlusion was similar in wild-type and endonuclease G null mice. After 90 min of occlusion and 1 day of reperfusion, similar degrees of nuclear translocation of apoptosis-inducing factor and DNA degradation were evident in male wild-type and null mice. At 3 days of reperfusion, infarct volume and neurological deficit scores were not different between male wild-type and endonuclease G null mice or between female wild-type and endonuclease G null mice. These data demonstrate that endonuclease G is not required for the pathogenesis of transient focal ischemia in either male or female mice. Treatment with a PARP inhibitor decreased infarct volume and deficit scores equivalently in male wild-type and endonuclease G null mice, indicating that the injury in endonuclease G null mice remains dependent on PARP. Thus endonuclease G is not obligatory for executing PARP-dependent injury during ischemic stroke.

scholarly journals Ornithine Decarboxylase Knockdown Exacerbates Transient Focal Cerebral Ischemia-Induced Neuronal Damage in Rat Brain

2001 ◽  
Vol 21 (8) ◽  
pp. 945-954 ◽  
Author(s):  
Raghavendra Vemuganti L. Rao ◽  
Aclan Dogan ◽  
Kellie K. Bowen ◽  
Robert J. Dempsey
Keyword(s):  
Cerebral Ischemia ◽  
Ornithine Decarboxylase ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Motor Deficits ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Transient Focal Cerebral Ischemia

Transient cerebral ischemia leads to increased expression of ornithine decarboxylase (ODC). Contradicting studies attributed neuroprotective and neurotoxic roles to ODC after ischemia. Using antisense oligonucleotides (ODNs), the current study evaluated the functional role of ODC in the process of neuronal damage after transient focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats. Transient MCAO significantly increased the ODC immunoreactive protein levels and catalytic activity in the ipsilateral cortex, which were completely prevented by the infusion of antisense ODN specific for ODC. Transient MCAO in rats infused with ODC antisense ODN increased the infarct volume, motor deficits, and mortality compared with the sense or random ODN-infused controls. Results of the current study support a neuroprotective or recovery role, or both, for ODC after transient focal ischemia.

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