Abstract 3866: The Inhibition of WWP-1 and Activation of AMPKa2 Are Important Mediators of Ischemic Stroke

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Yong-Joo Ahn ◽  
Jung Ok Lee ◽  
Seo-Kyoung Hwang ◽  
Hyeon Soo Kim ◽  
James K. Liao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Signaling Pathways ◽  
Focal Cerebral Ischemia ◽  
Mtor Signaling ◽  
Cerebral Infarct ◽  
Acute Administration ◽  
Therapeutic Benefits ◽  
Ischemic Core

Background: Tuberous sclerosis complex (TSC) and Mammalian target of rapamycin (mTOR) mediate various functions such as cell survival, obesity, and cellular responses in injury. However, the signaling mechanism linking focal cerebral ischemia is unknown. Because inhibition of the mTOR signaling pathway contributes to the pathogenesis of ischemic stroke, we hypothesize that inhibition of WW domain protein 1 (WWP-1) and activation of AMPKα2 mediate neuroprotection effect via WWP-1/AMPKα2/TSC/mTOR/S6 signaling pathways. Methods: To investigate whether the inhibition of WWP-1 and activation of AMPKα2 could exert neuroprotective effect via mTOR signaling pathways, we performed transient focal cerebral ischemia. Wild-type and TSC2 +− mice (20-22g) were administered either vehicle or rapamycin (5 mg/kg, i.p., 1d and 5d), before MCAO. After 2 hrs of MCAO followed by 22 hrs of reperfusion, Infarct size was determined with TTC staining and protein levels were assessed in ischemic core and contralateral (non-ischemic core) hemisphere region. Results: Compare to vehicle mice, mTOR/S6 level was decreased in ischemic brain region during ischemia (0.5, 1, 2h MCAO). After reperfusion (after 2h MCAO), phospho-S6 in mice brain was quickly over-expressed. Acute administration of rapamycin had no effect on cerebral infarct size in WT mice but chronic administration of rapamycin exhibited significantly increased infarct size and higher NDS following MCAO. Compare to vehicle mice, TSC2 +− mice showed increased mTOR/S6 level in brain and reduced cerebral infarct size (64.2 ± 5.96; n =7 vs 92.6 ± 6.08, n =7, p <0.01). Conclusions: These findings indicate that the inhibition of WWP-1 and activation of AMPKα2 reduced infarct size via TSC2/mTOR/S6 signal transduction in focal cerebral ischemia. These results suggest that inhibition of WWP-1 and activation of AMPKα2 may have therapeutic benefits in ischemic stroke.

scholarly journals Neuroprotective Effects of Danshen Chuanxiongqin Injection Against Ischemic Stroke: Metabolomic Insights by UHPLC-Q-Orbitrap HRMS Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Peipei Zhou ◽  
Lin Zhou ◽  
Yingying Shi ◽  
Zhuolun Li ◽  
Liwei Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Brain Tissue ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Cerebral Infarct ◽  
Sphingolipid Metabolism ◽  
Neuroprotective Effects ◽  
Behavioral Abnormality

The incidence of cerebral ischemic stroke characterized by high mortality is increasing every year. Danshen Chuanxiongqin Injection (DSCXQ), a traditional Chinese medicine (TCM) preparation, is often applied to treat cerebral apoplexy and its related sequelae. However, there is a lack of systematic research on how DSCXQ mediates its protective effects against cerebral ischemia stroke. Metabolomic analysis based on UHPLC-Q-Orbitrap HRMS was employed to explore the potential mechanisms of DSCXQ on ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). Pattern analysis and metabolomic profiling, combined by multivariate analysis disclosed that 55 differential metabolites were identified between Sham group and Model group, involving sphingolipid metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, primary bile acid biosynthesis, pantothenate and CoA synthesis and valine, leucine and isoleucine biosynthesis pathways. DSCXQ could reverse brain metabolic deviations in stroke by significantly upregulating the levels of L-tryptophan, Lyso (18:0/0:0), LPC (18:2), Indole-3-methyl acetate, and downregulating the levels of sphinganine 1-phosphate, L-threonic acid, glutaconic acid and N6,N6,N6-Trimethyl-L-lysine. In our study, we focused on the neuroprotective effects of DSCXQ against neuroinflammatory responses and neuronal apoptosis on a stroke model based on sphingolipid metabolism. The expressions of Sphk1, S1PR1, CD62P, Bcl-2, Bax, and cleaved Caspase-3 in brain tissue were evaluated. The neurological deficit, cerebral infarct size and behavioral abnormality were estimated. Results showed that DSCXQ intervention significantly reduced cerebral infarct size, ameliorated behavioral abnormality, inhibited the expression of Sphk1, S1PR1, CD62P, Bax, Cleaved Caspase-3, while increased the level of Bcl-2, and prevented neuronal apoptosis. The limitations are that our study mainly focused on the verification of sphingolipid metabolism pathway in stroke, and while other metabolic pathways left unverified. Our study indicates that SphK1-SIP axis may potentiate neuroinflammatory responses and mediate brain damage through neuronal apoptosis, and DSCXQ could suppress the activity of SphK1-SIP axis to protect brain tissue in cerebral ischemia. In conclusion, this study facilitates our understanding of metabolic changes in ischemia stroke and the underlying mechanisms related to the clinical application of DSCXQ.

scholarly journals Angiogenesis in the ischemic core: A potential treatment target?

2019 ◽  
Vol 39 (5) ◽  
pp. 753-769 ◽  
Author(s):  
Masato Kanazawa ◽  
Tetsuya Takahashi ◽  
Masanori Ishikawa ◽  
Osamu Onodera ◽  
Takayoshi Shimohata ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Neurovascular Unit ◽  
Focal Ischemia ◽  
Model Systems ◽  
Surrounding Tissue ◽  
Model Studies ◽  
Ischemic Core

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

Treatment of experimental stroke with opiate antagonists

1986 ◽  
Vol 64 (1) ◽  
pp. 99-103 ◽  
Author(s):  
David S. Baskin ◽  
Yoshio Hosobuchi ◽  
Joachim C. Grevel
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Focal Cerebral Ischemia ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Acute Administration ◽  
Continuous Administration ◽  
Content Type ◽  
Opiate Antagonists ◽  
Feline Model

✓ The effects are reported of acute and long-term continuous administration of three opiate antagonists — naloxone, naltrexone, and diprenorphine — on neurological function, survival, and infarct size in a feline model of acute focal cerebral ischemia. All three drugs produced statistically significant improvement in motor function following acute administration without concomitant changes in level of consciousness; saline had no effect. Naloxone and naltrexone significantly prolonged survival (p < 0.01); diprenorphine did not. Infarct size was not altered by any treatment administered. These findings confirm previous work suggesting that, with the appropriate methodology, treatment with opiate antagonists partially reverses neurological deficits. They also show that opiate antagonists prolong survival in certain conditions of acute and subacute focal cerebral ischemia without altering the area of infarcted tissue.

Comparison of the Effects of Propofol and Pentobarbital on Neurologic Outcome and Cerebral Infarct Size after Temporary Focal Ischemia in the Rat 

1997 ◽  
Vol 87 (5) ◽  
pp. 1139-1144 ◽  
Author(s):  
Janet E. Pittman ◽  
Huaxin Sheng ◽  
Robert Pearlstein ◽  
Ann Brinkhouse ◽  
Franklin Dexter ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Wistar Rats ◽  
Focal Cerebral Ischemia ◽  
Focal Ischemia ◽  
Cerebral Infarct ◽  
Early Reperfusion ◽  
Recovery Interval ◽  
Neurologic Function ◽  
Cerebral Physiology

Background Although propofol is known to have effects on cerebral physiology similar to the barbiturates, a direct comparison of the relative effects of these drugs on outcome from cerebral ischemia has not been performed. The authors postulated that pentobarbital or propofol would yield similar effects on neurologic and histologic outcome from temporary focal ischemia in the rat. Methods Wistar rats were anesthetized with sufficient doses of pentobarbital (n = 20) or propofol (n = 20) to cause electroencephalographic burst suppression. The middle cerebral artery was then occluded for 75 min. Animals were awakened 4-6 h after onset of reperfusion and allowed to recover for 1 week. Neurologic function and infarct size were then assessed. Results Relevant physiologic values were similar between groups during ischemia and early reperfusion. No difference between groups was observed for severity of hemiparesis (P = 0.10). Total cerebral infarct volumes (median +/- quartile deviation) were similar for the two groups (pentobarbital = 190 +/- 36 mm3; propofol = 200 +/- 24 mm3, P = 0.35). Conclusion Neurologic and histologic outcome were similar in pentobarbital or propofol anesthetized rats undergoing temporary focal cerebral ischemia and a 1-week recovery interval.

L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR

1992 ◽  
Vol 263 (5) ◽  
pp. H1632-H1635 ◽  
Author(s):  
E. Morikawa ◽  
Z. Huang ◽  
M. A. Moskowitz
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Focal Cerebral Ischemia ◽  
Arterial Occlusion ◽  
Cerebral Blood Vessels ◽  
Hypertensive Rats ◽  
Vessel Occlusion ◽  
Spontaneously Hypertensive ◽  
Cerebral Arterial Occlusion ◽  
Carotid Arterial

L-Arginine, but not D-arginine, serves as a precursor for the synthesis of nitric oxide (NO), a potent dilator of cerebral blood vessels. We examined the effects of administering L-arginine (300 mg/kg ip) on the volume of infarction in two models of focal cerebral ischemia in spontaneously hypertensive rats (SHR). L-Arginine was administered before (16 and 3 h) and after (5 min and 2 h) vessel occlusion, and animals were killed 24 h later. L-Arginine treatment decreased infarct size in rats subjected to distal middle cerebral arterial (MCA) plus ipsilateral common carotid arterial (CCA) occlusion by 31% [147 +/- 12 (saline) vs. 101 +/- 9 mm3 (L-arginine), P < 0.05]. D-Arginine, administered according to the same dosage and protocol, was without effect. In the group subjected to proximal MCA occlusion, L-arginine decreased infarction size in the striatum by 28% [47 +/- 5 (saline) vs. 34 +/- 3 mm3 (L-arginine), P < 0.05] and neocortex by 11% [193 +/- 7 (saline) vs. 171 +/- 8 mm3 (L-arginine), P < 0.05]. Changes in blood pressure or other measured physiological parameters did not account for the observed differences. The possible use of L-arginine for the treatment of focal cerebral ischemia merits further investigation.

scholarly journals KADAR FIBRIN MONOMER DAN UKURAN INFARK DI STROK ISKEMIK AKUT

2016 ◽  
Vol 20 (3) ◽  
pp. 171
Author(s):  
Ani Kartini ◽  
Mansyur Arif ◽  
Hardjoeno Hardjoeno
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Acute Ischemic Stroke ◽  
Thrombus Formation ◽  
Infarct Volume ◽  
Cross Sectional Study ◽  
Cerebral Infarct ◽  
Cross Sectional ◽  
Fibrin Monomer ◽  
Significant Difference

Coagulation activation and thrombosis frequently exist in ischemic stroke, thrombus formation can be detected early by the presence of fibrin monomer. The purpose of this study was to know the correlation of fibrin monomer level with cerebral infarct size in acute ischemic stroke patients. This was a cross sectional study with a total of 39 samples. The fibrin monomer level was determined by immunoturbidimetry method using STA-Compact and the measurement of the infarct size was done by CT scan of the head using Broderick formula. The results of this study showed that the median level of fibrin monomer in acute ischemic stroke with nonlacunar infarct type and lacunar infarct type were 14.46 μg/mL and 4.29 μg/mL, respectively. Mann-Whitney test showed there was a significant difference of fibrin monomer levels between nonlacunar infarct type and the lacunar type, p=0.000. The cut-off point analysis result of the fibrin monomer level was 5.96 μg/mL with a sensitivity of 88.9% and specificity of 76.4%, respectively. Spearman correlation test showed that fibrin monomer level was positively correlated with cerebral infarct volume in acute ischemic stroke (r=0.56, p=0.000). Based on this study, it can be concluded that fibrin monomer level can be used as a marker to predict the type of cerebral infarct and volume of acute ischemic stroke as well.

scholarly journals Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 460
Author(s):  
Orsolya M. Tóth ◽  
Ákos Menyhárt ◽  
Rita Frank ◽  
Dóra Hantosi ◽  
Eszter Farkas ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Targeted Delivery ◽  
Focal Cerebral Ischemia ◽  
Ischemic Penumbra ◽  
Risk Of Injury ◽  
Ischemic Tissue ◽  
Tissue Acidosis ◽  
Injury Progression

Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

Pretreatment with intraventricular basic fibroblast growth factor decreases infarct size following focal cerebral ischemia in rats

1994 ◽  
Vol 35 (4) ◽  
pp. 451-457 ◽  
Author(s):  
Naoki Koketsu ◽  
David J. Berlove ◽  
Michael A. Moskowitz ◽  
Neil W. Kowall ◽  
Cornelio G. Caday ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Growth Factor ◽  
Infarct Size ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Focal Cerebral Ischemia ◽  
Fibroblast Growth

scholarly journals Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Juhyun Song ◽  
Joohyun Park ◽  
Yumi Oh ◽  
Jong Eun Lee
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Infarction ◽  
Infarct Size ◽  
Cell Survival ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Cerebral Infarct ◽  
Ros Scavenging ◽  
The Brain

Ischemic stroke interrupts the flow of blood to the brain and subsequently results in cerebral infarction and neuronal cell death, leading to severe pathophysiology. Glutathione (GSH) is an antioxidant with cellular protective functions, including reactive oxygen species (ROS) scavenging in the brain. In addition, GSH is involved in various cellular survival pathways in response to oxidative stress. In the present study, we examined whether GSH reduces cerebral infarct size after middle cerebral artery occlusionin vivoand the signaling mechanisms involved in the promotion of cell survival after GSH treatment under ischemia/reperfusion conditionsin vitro. To determine whether GSH reduces the extent of cerebral infarction, cell death after ischemia, and reperfusion injury, we measured infarct size in ischemic brain tissue and the expression of claudin-5 associated with brain infarct formation. We also examined activation of the PI3K/Akt pathway, inactivation of FOXO3, and expression of Bcl2 to assess the role of GSH in promoting cell survival in response to ischemic injury. Based on our results, we suggest that GSH might improve the pathogenesis of ischemic stroke by attenuating cerebral infarction and cell death.

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