A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction.

Chen, S. T.; Hsu, Chung Y.; Hogan, Edward L.; Maricq, Hildegard R.; Balentine, J. Douglas

doi:10.1161/01.str.17.4.738

Cited by 546 publications

(362 citation statements)

References 40 publications

Supporting

Mentioning

347

Contrasting

Unclassified

Order By: Relevance

“…ANIMAL STROKE MODEL-Surgery to produce focal cerebral ischemia was conducted under Nembutal anesthesia (50 mg/kg) and has been detailed in previous publications [45][46][47][48]. This model is characterized by a severe ischemia (blood flow reduction by 88-92%) confined to the cortex of the right middle cerebral artery (MCA) territory.…”

Section: Methodsmentioning

confidence: 99%

“…The peptide was denatured in 30 μl of 1X sodium dodecyl sulfate (SDS) gel loading buffer (50 mM Tris-HCl [pH 6.8], 100 mM dithiothreitol [DTT], 2% SDS, 0.1% bromophenol blue, 10% glycerol) at 95°C for 3 minutes, followed by brief centrifugation; 15 μl of the immunol-purified peptide in the supernatant was resolved in 7.5% stacking SDS-polyacrylamide gel electrophoresis (SDS-PAGE) using Tris-glycine electrophoresis buffer (25 mM Tris, 250 mM glycine, pH 8.3, 0.1% SDS), followed by autoradiography [44]. The autoradiograms were quantitated by using a densitometer (E-C Apparatus Corp, St Petersburg, FL).ANIMAL STROKE MODEL-Surgery to produce focal cerebral ischemia was conducted under Nembutal anesthesia (50 mg/kg) and has been detailed in previous publications [45][46][47][48]. This model is characterized by a severe ischemia (blood flow reduction by 88-92%) confined to the cortex of the right middle cerebral artery (MCA) territory.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

View full text Add to dashboard Cite

Activation of c-fos, an immediate early gene, and the subsequent expression of the Fos protein have been noted following focal cerebral ischemia. Fos and Jun form a heterodimer as activator protein 1 (AP-1), which transregulates the expression of several genes. To study the postischemic events related to c-fos expression, we suppressed the expression of c-fos by intraventricular infusion of an antisense Oligodeoxynucleotide (anti-rncfosr 115 ) of c-fos mRNA. The effectiveness of antirncfosr 115 was confirmed first by its capability to block in vitro c-fos mRNA translation. In vivo, after intraventricular infusion of 32 P-labeled anti-rncfosr 115 , the oligodeoxynucleotide was internalized within 6 hours and detectable also in the nucleic acids fraction up to 41 hours. Treatment of the recovered nucleic acids with RNase H separated the labeled Oligodeoxynucleotide from the nucleic acid fraction, indicating an association of the antisense Oligodeoxynucleotide and cellular RNA after uptake. When focal cerebral ischemia was induced 16 hours after the infusion of antirncfosr 115 , the postischemic increase in Fos expression and AP-1 binding activity were suppressed. Specificity of the effect of anti-rncfosr 115 was suggested by its failure to suppress the DNA binding activity of nuclear cyclic AMP response elements. These results support the hypothesis that increased AP-1 binding activity following focal cerebral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c-fos oligodeoxynucleotides.The molecular events of brain adaptation to injury that may underlie functional recovery after stroke remain largely undefined. Recent observations of altered gene expression in ischemic brain using animal stroke models have opened new avenues for exploration of the biochemical cascades after stroke [1][2][3][4][5][6][7][8][9][10][11]. These postischemic events include an increase in extracellular excitatory amino acid neurotransmitters such as glutamate. Glutamate receptor-mediated activation of phospholipases and protein kinases results in the alteration of nuclear regulatory processes, including the expression of immediate early genes such as c-fos, junB, and c-jun [5,12]. The Fos, Jun, and JunB proteins have been shown to form activator protein 1 (AP-1) through a conserved dimerization domain, i.e., the leucine zipper [13]. Transcription regulator AP-1 protein binds a specific DNA motif and is believed to transactivate the expression of a number of late effector genes [14][15][16][17][18][19]. In the ischemic brain, we have previously demonstrated an increase in AP-1 binding activity [9]. A number of genes that bear neurotrophic properties may be regulated by transcription regulator AP-1. These genes, such as heat shock protein [1,4,[19][20][21][22], amyloid [23], neurotrophins [7], and protein tyrosine kinase receptor trkB [24], have been shown to be induced following cerebral ischemia. The causal relationship between the Fos/Jun-AP-1 cascade and the subsequent expression of the late e...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Liu

Salminen

et al. 1994

Annals of Neurology

View full text Add to dashboard Cite

show abstract

“…Focal cerebral ischemia was induced by 90 minutes transient occlusion of the middle cerebral artery (tMCAO) as described previously (Chen et al, 1986;Liu et al, 1989). Isofluorane (5% for induction and 1.5% during surgery) was used as anesthetic in a mixture of 70% N 2 O and 30% O 2 .…”

Section: Focal Cerebral Ischemiamentioning

confidence: 99%

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Pradillo

Greenhalgh

Boutin

et al. 2012

J Cereb Blood Flow Metab

123

108

View full text Add to dashboard Cite

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood-brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

show abstract

“…The physiological variables studied were not significantly different between groups of animals before, during or after middle cerebral artery occlusion (MCAO) (data not shown). The surgical procedure was a variant of that described by Chen et al 29 and Liu et al 30 A small craniectomy was made over the trunk of the MCA and above the rhinal fissure, and the artery was transitorily ligated with a 9-0 suture just before its bifurcation into the frontal and parietal branches. Complete interruption of the blood flow was confirmed under an operating microscope.…”

Section: Animal Model Of Cerebral Ischemiamentioning

confidence: 99%

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

et al. 2007

View full text Add to dashboard Cite

The N-methyl-D-aspartate receptor (NMDAR) is central to physiological and pathological functioning of neurons. Although promising results are beginning to be obtained in the treatment of dementias, clinical trials with NMDAR antagonists for stroke, trauma and neurodegenerative disorders, such as Hungtinton's disease, have failed before. In order to design effective therapies to prevent excitotoxic neuronal death, it is critical to characterize the consequences of excessive NMDAR activation on its expression and function. Previous data have reported partial downregulation of the NR1 and NR2B receptor subunits in response to excitotoxicity and cerebral ischemia. However, the effect of NMDAR overactivation on NR2A, a subunit fundamental to synaptic transmission and neuronal survival, is still elusive. In this study, we report the rapid and extensive proteolytic processing of NR2A, together with the scaffolding protein postsynaptic density-95 (PSD-95), induced by excitotoxic stimulation of cortical neurons in vitro and by transient focal cerebral ischemia. Processing of the C terminus of NR2A is irreversibly induced by brief agonist exposure of NR2B-containing receptors, and requires calcium influx and the activity of calpain, also responsible for PSD-95 cleavage. The outcome is a truncated NR2A subunit that is stable and capable to interact with NR1 at the surface of neurons, but lacking the structural domains required for association with scaffolding, downstream signaling and cytoskeletal proteins. Therefore, a rapid and significant uncoupling of synaptic NMDARs from downstream survival pathways is expected to occur during ischemia. This novel mechanism induced by excitotoxicity helps to explain the failure of most therapies based on NMDAR antagonists.

show abstract

A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction.

Cited by 546 publications

References 40 publications

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Suppression of ischemia‐induced fos expression and AP‐1 activity by an antisense oligodeoxynucleotide to c‐fos mRNA

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

Contact Info

Product

Resources

About