Melatonin and calpeptin synergistically protect against post-reperfusion injury in a rat middle cerebral artery occlusion stroke model

2021 ◽  
Vol 4 (4) ◽  
pp. 592-612
Author(s):  
Ye Feng ◽  
Qian Xu ◽  
Raymond Tak Fai Cheung
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Reperfusion Injury ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neurological Deficit ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Stroke Model ◽  
Cerebral Artery Occlusion

Cerebral ischemia induces oxidative injury and increases the intracellular calcium ion concentration to activate several calcium-dependent proteases such as calpains. Calpain activation leads to various necrotic and apoptotic processes. Calpeptin is a potent, cell-permeable calpain inhibitor. As a strong antioxidant and free radical scavenger, melatonin shows beneficial effect in rodent models of focal cerebral ischemia when given prior to ischemia or reperfusion. This study was focused on the neuroprotective effects of melatonin and/or calpeptin given after onset of reperfusion. For this purpose, right-sided middle cerebral artery occlusion (MCAO) for 90 minutes followed by 24 or 72 hours of reperfusion was performed in male Sprague Dawley rats, then, melatonin 50 or 150 µg/kg, calpeptin 10, 15 or 50 µg/kg or a combination of melatonin 50 µg/kg plus calpeptin 15 or 50 µg/kg were injected via an intracerebroventricular route at 15 minutes after onset of reperfusion. Melatonin or calpeptin tended to reduce the relative infarct volume and significantly decreased the neurological deficit at 24 hours. The combination achieved a greater protection than each of them alone. Melatonin, calpeptin or the combination all decreased Fluoro-Jade B (FJB)+ degenerative neurons and cleaved/total caspase-3 ratio at 24 hours. These treatments did not significantly impact the density of surviving neurons and ED-1+ macrophage/activated microglia. At the 72-hour-reperfusion, melatonin or the combination decreased the relative infarct volume and neurological deficit. Nevertheless, only the combination reduced FJB+ degenerating neurons at 72 hours. In conclusion, a combination of melatonin and calpeptin exerted synergistic protection against post-reperfusion injury in a rat MCAO stroke model.

scholarly journals Inhibition of MicroRNA-383 Ameliorates Injury After Focal Cerebral Ischemia via Targeting PPARγ

2016 ◽  
Vol 39 (4) ◽  
pp. 1339-1346 ◽  
Author(s):  
Lichun Pei ◽  
Songyan Meng ◽  
Weigang Yu ◽  
Qiujun Wang ◽  
Fangfang Song ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Protein Level ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Luciferase Assay ◽  
Cerebral Artery Occlusion

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a critical role in protecting against distinct brain damages, including ischemia. Our previous data have shown that the protein level of PPARγ is increased in the cortex after middle cerebral artery occlusion (MCAO); PPARγ up-regulation contributes to PPARγ activation and is effective in reducing ischemic damage to brain. However, the regulatory mechanism of PPARγ after focal cerebral ischemia in rats is still unclear. In this study, we evaluated the effect of microRNA on PPARγ in rats subjected to MCAO. Methods: Focal cerebral ischemia was established by surgical middle cerebral artery occlusion; the protein level of PPARγ was detected by Western blotting; the level of microRNA-383 (miR-383) was quantified by real-time PCR; the neurological outcomes were defined by infarct volume and neurological deficits. Luciferase assay was used to identify the luciferase activities of PPARγ and miR-383. Results: We showed here that miR-383 level was down-regulated in the ischemic hemisphere of rats 24h after MCAO. Overexpression of miR-383 by miR-383 agomir increased infarct volume and aggravated neurological damage. Administration of miR-383 antagomir had the opposite effects. Furthermore, we found that PPARγ protein was down-regulated by miR-383 overexpression, and up-regulated by miR-383 inhibition both in rat model of MCAO and in primary culture cells. Finally, we found that miR-383 suppressed the luciferase activity of the vector carrying the 3'UTR of PPARγ, whereas mutation of the binding sites relived the repressive effect of miR-383. Conclusion: Our study demonstrated that miR-383 may play a key role in focal cerebral ischemia by regulating PPARγ expression at the post-transcriptional level, and miR-383 may be a potential therapeutic target for stroke.

scholarly journals A Promising Approach to Integrally Evaluate the Disease Outcome of Cerebral Ischemic Rats Based on Multiple-Biomarker Crosstalk

2017 ◽  
Vol 2017 ◽  
pp. 1-10
Author(s):  
Guimei Ran ◽  
Yixuan Wang ◽  
Haochen Liu ◽  
Chunxiang Wei ◽  
Tao Zhu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neurological Deficit ◽  
Mathematic Model ◽  
Artery Occlusion ◽  
Disease Outcome ◽  
Multiple Biomarkers ◽  
Cerebral Artery Occlusion

Purpose. The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia.Methods. Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100β, HIF-1α, IL-1β, PGI2, TXA2, and GSH-Px. The levels or activities of these biomarkers in plasma were detected before and after ischemia. Concurrently, neurological deficit scores and cerebral infarct volumes were assessed. Based on a mathematic model, network balance maps and three integral disruption parameters (k,φ, andu) of the simplified crosstalk network were achieved.Results. The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameteruvalues correlated significantly with neurological deficit scores and infarct volumes.Conclusion. Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia.

scholarly journals Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4124
Author(s):  
Maozhu Liu ◽  
Mengyuan Chen ◽  
Ying Luo ◽  
Hong Wang ◽  
Haifeng Huang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sphingolipid Metabolism ◽  
Tunel Staining ◽  
Cerebral Artery Occlusion

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.

High-soy diet decreases infarct size after permanent middle cerebral artery occlusion in female rats

2005 ◽  
Vol 289 (1) ◽  
pp. R103-R108 ◽  
Author(s):  
Derek A. Schreihofer ◽  
Khoi D. Do ◽  
Ann M. Schreihofer
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neurological Deficit ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Estrogen Treatment ◽  
Cerebral Artery Occlusion

Estrogen is a powerful neuroprotective agent in rodent models of ischemic stroke. However, in humans, estrogen treatment can increase risk of stroke. Health risks associated with hormone replacement have led many women to consider alternative therapies including high-soy diets or supplements containing soy isoflavones, which act as estrogen receptor ligands to selectively mimic some of estrogen's actions. We hypothesized that a high-soy diet would share the neuroprotective actions of estrogen in focal cerebral ischemia. Female Sprague-Dawley rats were ovariectomized and divided into three groups: isoflavone-free diet + placebo (IF-P), isoflavone-free diet + estradiol (IF-E), or high-soy diet + placebo (S-P). Two weeks after being placed on diets, rats underwent left permanent middle cerebral artery occlusion (MCAO). Reductions in ipsilateral cerebral blood flow were equivalent across groups (∼50%). Twenty-four hours later neurological deficit was determined, and brains were collected for assay of cerebral infarct by TTC staining. In the IF-P rats MCAO produced a 50 ± 4% cerebral infarct. Estrogen and high-soy diet both significantly reduced the size of the infarcts to 26 ± 5% in IF-E rats and to 37 ± 5% in S-P rats. Analysis at five rostro-caudal levels revealed that estrogen treatment was slightly more effective at reducing infarct size than high soy diet. Overall neurological deficit scores at 24 h correlated with infarct size; however, there were no statistically significant differences among the treatment groups. These data show that 2 wk of a high-soy diet is an effective prophylactic strategy for reducing stroke size in a rat model of focal cerebral ischemia.

MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

2002 ◽  
Vol 283 (3) ◽  
pp. H1005-H1011 ◽  
Author(s):  
Katsuyoshi Shimizu ◽  
Zsombor Lacza ◽  
Nishadi Rajapakse ◽  
Takashi Horiguchi ◽  
James Snipes ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion Injury ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sham Treatment ◽  
Cerebral Artery Occlusion

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% ( n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% ( n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels ( n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

Abstract 11511: Genetic Variation in Retinal Vascular Patterning Predicts Variation in Pial Collateral Extent and Infarct Volume After Middle Cerebral Artery Occlusion

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Pranay Prabhakar ◽  
Hua Zhang ◽  
De Chen ◽  
Stephen Lockett ◽  
James E Faber
Keyword(s):  
Genetic Variation ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Genetic Background ◽  
Infarct Volume ◽  
Indirect Evidence ◽  
Artery Occlusion ◽  
Stroke Severity ◽  
Cerebral Artery Occlusion

Introduction: The presence of a native (pre-existing) collateral circulation in tissues lessens injury in stroke and other occlusive diseases. However, differences in genetic background are accompanied by wide variation in the number and diameter (extent) of native collaterals in mice, resulting in large variation in protection. Indirect evidence suggests a similar wide variation also exists in humans. However, methods of measurement in humans are indirect, invasive and not widely available. Hypothesis: We sought to determine if differences in genetic background in mice result in variation in branch-patterning of the retinal circulation, and if these differences predict differences in collateral extent and, in turn, differences in severity of ischemic stroke. Methods: Patterning metrics were obtained for the retinal arterial trees of 10 mouse strains (n=8 per strain) that differ widely in collateral extent in brain and other tissues. We also obtained pial collateral number and diameter, and infarct volume 24h after permanent middle cerebral artery occlusion. Forward- and reverse-stepwise multivariate regression analysis was conducted and model performance assessed using K-fold cross-validation. Results: Twenty-one metrics varied significantly with genetic strain (p<0.01). Ten metrics (eg, vessel caliber, bifurcation angle, lacunarity, optimality, branch length) strongly predicted collateral number and diameter across 7 regression models. The best models closely predicted (p<0.0001) collateral number (K-fold R 2 =0.83-0.98), diameter (0.73-0.88) and infarct volume (0.85-0.87). Conclusions: Differences in retinal tree patterning are specified by genetic background and closely predict genetic variation in pial collateral extent and, in turn, stroke severity. If these findings can be confirmed in humans, and given that genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar “retinal predictor index” could be developed as a biomarker for collateral extent in brain and other tissues. This could aid prediction of the risk-severity of tissue injury in occlusive disease as well as stratification of patients for treatment options and enrollment in clinical studies.

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