Active Compounds of Rhubarb Root and Rhizome in Animal Model Experiments of Focal Cerebral Ischemia

Rhubarb root and rhizome (RRR) has been clinically used for stroke at least 2000 years and is still used in modern times in both China and elsewhere worldwide. The objective of present study was to evaluate the efficacy of active compounds of RRR (ACRRR) for experimental ischemic stroke. Studies of ACRRR in animal models of ischemic stroke were identified from 5 databases until April 2014. Study quality for each included article was evaluated according to the CAMARADES 10-item checklist. Outcome measures were neurological deficit score and infarct size. All the data were analyzed using RevMan 5.1 software. As a result, 20 studies were identified describing procedures involving 577 animals. The quality score of studies ranges from 2 to 6, and the median was 3.4. Six studies showed significant effects of ACRRR for improving infarct size compared with model group (P<0.01). Six studies indicated significant effects of ACRRR for improving the neurological deficit scores according to Zea longa criterion or eight-point criterion (P<0.01). In conclusion, these findings demonstrated a possible efficacy of ACRRR that have potential neuroprotective effect for experimental ischemic stroke. However, these apparently positive findings should be interpreted with caution because of the methodological flaws.

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Neuroexcitatory Amino Acids and Their Relation to Infarct Size and Neurological Deficit in Ischemic Stroke

Stroke ◽

10.1161/01.str.27.6.1060 ◽

1996 ◽

Vol 27 (6) ◽

pp. 1060-1065 ◽

Cited By ~ 159

Author(s):

José Castillo ◽

Antoni Dávalos ◽

Javier Naveiro ◽

Manuel Noya

Keyword(s):

Amino Acids ◽

Ischemic Stroke ◽

Infarct Size ◽

Neurological Deficit

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High Prestroke Physical Activity Is Associated with Reduced Infarct Growth in Acute Ischemic Stroke Patients Treated with Intravenous tPA and Randomized to Remote Ischemic Perconditioning

Cerebrovascular Diseases ◽

10.1159/000477359 ◽

2017 ◽

Vol 44 (1-2) ◽

pp. 88-95 ◽

Cited By ~ 8

Author(s):

Rolf A. Blauenfeldt ◽

Kristina D. Hougaard ◽

Kim Mouridsen ◽

Grethe Andersen

Keyword(s):

Physical Activity ◽

Ischemic Stroke ◽

Infarct Size ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Intravenous Thrombolysis ◽

Stroke Patients ◽

Remote Ischemic Perconditioning ◽

Final Infarct Size

Background: A high prestroke physical activity (PA) level is associated with reduced stroke rate, stroke mortality, better functional outcome, and possible neuroprotective abilities. The aim of the present study was to examine the possible neuroprotective effect of prestroke PA on 24-h cerebral infarct growth in a cohort of acute ischemic stroke patients treated with intravenous tPA and randomized to remote ischemic perconditioning. Methods: In this predefined subanalysis, data from a randomized clinical trial investigating the effect of remote ischemic perconditioning (RIPerC) on AIS was used. Prestroke (7 days before admission) PA was quantified using the PA Scale for the Elderly (PASE) questionnaire at baseline. Infarct growth was evaluated using MRI (acute, 24-h, and 1-month). Results: PASE scores were obtained from 102 of 153 (67%) patients with a median (interquartile range) age of 66 (58-73) years. A high prestroke PA level correlated significantly with reduced acute infarct growth (24 h) in the linear regression model (4th quartile prestroke PA level compared with the 1st quartile), β4th quartile = -0.82 (95% CI -1.54 to -0.10). However, the effect of prestroke PA was present mainly in patients randomized to RIPerC, β4th quartile = -1.14 (95% CI -2.04 to -0.25). In patients randomized to RIPerC, prestroke PA was a predictor of final infarct size (1-month infarct volume), β4th quartile = -1.78 (95% CI -3.15 to -0.41). Conclusion: In AIS patients treated with RIPerC, as add-on to intravenous thrombolysis, the level of PA the week before the stroke was associated with decreased 24-h infarct growth and final infarct size. These results are highly encouraging and stress the need for further exploration of the potentially protective effects of both PA and remote ischemic conditioning.

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

Stroke ◽

10.1161/str.43.suppl_1.a3866 ◽

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.

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Abstract P781: Ischemic Postconditioning Protects Against Hemorrhagic Transformation Induced by Hyperglycemia in Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.p781 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Hansen Chen ◽

Michelle Y Cheng ◽

Tonya Bliss ◽

Heng Zhao ◽

Gary Steinberg

Keyword(s):

Ischemic Stroke ◽

Mortality Rate ◽

Infarct Size ◽

Brain Edema ◽

Neurological Deficit ◽

Hemorrhagic Transformation ◽

Artery Occlusion ◽

Ischemic Postconditioning ◽

Brain Infarct ◽

Acute Hyperglycemia

Background: Hyperglycemia occurs in over 40% of ischemic stroke patients, which induces hemorrhagic transformation (HT) and worsens stroke outcomes. The management of hyperglycemia with insulin did not show favorable outcomes. Thus, strategies for managing hyperglycemia-exacerbated stroke injury are urgently needed. We previously demonstrated that ischemic postconditioning (IPostC) (repeated transient interruption of cerebral blood flow during reperfusion) can reduce brain infarct size and improve neurological outcomes. In this study, we hypothesized that IPostC can reduce HT in ischemic stroke with acute hyperglycemia. Method: Male mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hour, followed by reperfusion to mimic ischemic stroke. Glucose was injected before MCAO to induce hyperglycemia. IPostC was initiated upon reperfusion with 3 cycles of 30-second reperfusion followed by 10 seconds of MCA occlusion. Brain infarct was visualized by TTC staining and quantitated using Image J. Hemorrhagic transformation was evaluated by hemorrhagic scores. Result: Acute hyperglycemia significantly increased the brain infarct size (by 25%, p<0.01), brain edema (p<0.001) and hemorrhagic transformation (HT) (average HT scores: 0.75 in MCAO group vs 15.6 in MCAO plus hyperglycemia group, p<0.001), Mice with hyperglycemia also exhibited more severe neurological deficit and higher mortality rate at 24 hours after MCAO. 2) IPostC treatment significantly reduced brain infarct size (p<0.01), brain edema (p<0.05) and attenuated HT (p<0.001). Neurological deficit and mortality rate was reduced with IPostC treatment. Conclusion: Our findings suggest that IPostC can counteract the effects of acute hyperglycemia and reduce brain injury, edema and HT after stroke. Grant/Other Support: NIH Grant R01NS064136C

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Abstract T P200: CD13 is an Immune Regulator in the CNS Following Ischemic Stroke

Stroke ◽

10.1161/str.45.suppl_1.tp200 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Sami Tarabishy ◽

Anthony Patrizz ◽

Nikolas S Mancini ◽

Linda Shapiro ◽

Louise D McCullough

Keyword(s):

Immune Response ◽

Ischemic Stroke ◽

Open Field ◽

Neurological Deficit ◽

Focal Cerebral Ischemia ◽

Brain Slices ◽

Motor Dysfunction ◽

Field Analysis ◽

Cresyl Violet ◽

Post Stroke

Background: Focal cerebral ischemia results in marked inflammatory response initiated by microglia and astrocyte activation, upregulation of pro-inflammatory cytokines, and disruption of the blood brain barrier leading to invasion of peripheral immune cells. CD13 (Aminopeptidase N), a 150 kD type II transmembrane metalloprotease highly expressed on myeloid cells, has recently been shown to possess several non-enzymatic functions involving the regulation of processes related to inflammation including antigen presentation and cell trafficking into sites of inflammation. We hypothesized that deletion of CD13 would alter the innate immune response after stroke leading to smaller infarcts and neuroprotection. Methods: C57BL/6 WT and CD13 KO male mice were subjected to transient focal ischemia by middle cerebral artery occlusion for 90 minutes. Motor and sensory deficits were assessed using the Benderson neurological deficit score and open field analysis. Mice were sacrificed at 48hrs and brain slices stained with Cresyl Violet for infarct analysis. Immunohistochemistry was performed on fresh frozen slices to visualize microglial activation. Results: There was significant reduction in total hemispheric and cortical infarct in KO compared to WT at 48 hours post stroke (Hemispheric 50.8 ± 2.0 WT vs. 40.7 ± 3.8 KO p=.04, Cortical 56.5 ± 4.0 WT vs. 40.1 ± 5.8 KO p=.04, n=6-10). Behaviorally, CD13 KO mice performed better in the open field test than WT, displaying less motor dysfunction (p=.047). 48hrs post stroke. CD13 KO mice had lower neurological deficit scores (3 WT vs. 2 KO, IQR=0, U=0, n=6-10). CD13 mice had less mortality at all time-points. IHC revealed increased microglia activation in the infarct hemisphere of KO mice when compared to WT. Conclusions: CD13 KO mice had smaller infarct sizes and better acute behavioral outcomes than WT mice. Furthermore, initial IHC results displayed a phenotypically different immune response in KO animals. Flow cytometry is characterizing the differences in the immune response between the groups and microglial phenotypes. Further identifying and targeting of the non-enzymatic functions of CD13 in the CNS may lead to novel therapeutic clinical treatments to reduce morbidity and mortality from ischemic stroke.

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Phytosome Loading the Combined Extract of Mulberry Fruit and Ginger Protects against Cerebral Ischemia in Metabolic Syndrome Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5305437 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Nut Palachai ◽

Jintanaporn Wattanathorn ◽

Supaporn Muchimapura ◽

Wipawee Thukham-mee

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Ischemic Stroke ◽

Cerebral Ischemia ◽

Brain Damage ◽

Neurological Deficit ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Neurological Deficit Score ◽

Mulberry Fruit

The prevalence of ischemic stroke in metabolic syndrome (MetS) is continually increasing and produces a great impact on both qualities of life and annual healthcare budget. Due to the efficiency limitation of the current therapeutic strategy, the poor availability of polyphenol substances induced by the first pass effect and the beneficial effects of mulberry fruit and ginger on brain and MetS-related diseases together with the synergistic concept, the neuroprotective effect against ischemic stroke in MetS condition of phytosome containing the combined extract of mulberry fruit and ginger (PMG) has been considered. To explore the neuroprotective effect and possible underlying mechanism of PMG on brain damage in cerebral ischemic rat with MetS, male Wistar rats were induced MetS by high-carbohydrate high-fat diet (HCHF) for 16 weeks and subjected to the cerebral ischemia/reperfusion injury (CIRI) at the right middle cerebral artery (Rt. MCAO). PMG at doses of 50, 100, and 200 mg/kg were orally fed with for 21 days, and they were assessed brain damage, neurological deficit score, and the changes of oxidative stress markers, inflammatory markers, PPARγ expression, and epigenetic modification via DNMT-1 were performed. All doses of PMG significantly improved brain infarction, brain edema, and neurological deficit score. In addition, the reduction in DNMT-1, MDA level, NF-κB, TNFα, and C-reactive protein together with the increase in SOD, CAT, and GPH-Px activities, and PPARγ expression in the lesion brain were also observed. The current data clearly revealed the neuroprotective effect against cerebral ischemia with MetS condition. The possible underlying mechanism might occur partly via the suppression of DNMT-1 giving rise to the improvement of signal transduction via PPARγ resulting in the decreasing of inflammation and oxidative stress. In conclusion, PMG is the potential neuroprotectant candidate against ischemic stroke in the MetS condition. However, the clinical trial is still essential.

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Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

Cells ◽

10.3390/cells9081860 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1860 ◽

Cited By ~ 1

Author(s):

Mark B. Plotnikov ◽

Galina A. Chernysheva ◽

Vera I. Smolyakova ◽

Oleg I. Aliev ◽

Eugene S. Trofimova ◽

...

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Rat Model ◽

Focal Cerebral Ischemia ◽

Neuroprotective Effect ◽

Specific Inhibitor ◽

Fold Increase ◽

Neuroprotective Activity ◽

Prophylactic Regimen ◽

Neuroprotective Effects

A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00642.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. R103-R108 ◽

Cited By ~ 36

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.

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Neuroprotective Effect of Low-dose Lidocaine in a Rat Model of Transient Focal Cerebral Ischemia

Anesthesiology ◽

10.1097/00000542-200108000-00029 ◽

2001 ◽

Vol 95 (2) ◽

pp. 445-451 ◽

Cited By ~ 63

Author(s):

Baiping Lei ◽

James E. Cottrell ◽

Ira S. Kass

Keyword(s):

Weight Loss ◽

Infarct Size ◽

Low Dose ◽

Focal Cerebral Ischemia ◽

Neuroprotective Effect ◽

Body Weight Loss ◽

Neurologic Outcome ◽

Triphenyltetrazolium Chloride ◽

Lidocaine Group

Background A low concentration of lidocaine (10 microM) has been shown to reduce anoxic damage in vitro. The current study examined the effect of low-dose lidocaine on infarct size in rats when administered before transient focal cerebral isehemia. Methods Male Wistar rats (weight, 280-340 g) were anesthetized with isoflurane, intubated, and mechanically ventilated. After surgical preparation, animals were assigned to lidocaine 2-day (n = 10), vehicle 2-day (n 12), lidocaine 7-day (n = 13), and vehicle 7-day (n = 14) groups. A 1.5-mg/kg bolus dose of ildocaine was injected intravenously 30 mm before isehemia in the lidocaine 2-day and 7-day groups. Thereafter, an infusion was initiated at a rate of 2 mg x kg(-1) x h(-1) until 60 min of reperfusion after isehemia. Rats were subjected to 90 min of focal cerebral isehemia using the intraluminal suture method. Infarct size was determined by image analysis of 2,3,5-triphenyltetrazolium chloride-stained sections at 48 h or hematoxylin and eosin-stained sections 7 days after reperfusion. Neurologic outcome and body weight loss were also evaluated. Results The infarct size was significantly smaller in the lidocaine 2-day group (185.0+/-43.7 mm3) than in the vehicle 2-day group (261.3+/-45.8 mm3, P < 0.01). The reduction in the size of the infarct in the lidocaine 7-day group (130.4+/-62.9 mm3) was also significant compared with the vehicle 7-day group (216.6+/-73.6 mm3, P < 0.01). After 7 days of reperfusion, the rats in the lidocaine group demonstrated better neurologic outcomes and less weight loss. Conclusions The current study demonstrated that a clinical anriarrhythmic dose of lidocaine, when given before and during transient focal cerebral isehemia, significantly reduced infaret size, improved neurologic outcome, and inhibited postisehemic weight loss.

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Enantiomers of 3-pentylbenzo[c]thiophen-1(3H)-one: preparation and evaluation of anti-ischemic stroke activities

RSC Advances ◽

10.1039/c6ra04251a ◽

2016 ◽

Vol 6 (43) ◽

pp. 36888-36897 ◽

Cited By ~ 4

Author(s):

Yanlin Jian ◽

Jing Ji ◽

Zhangjian Huang ◽

Yang Gao ◽

Xiao Sheng ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Water Content ◽

Neurological Deficit ◽

Brain Water Content ◽

Antiplatelet Aggregation ◽

Preparation And Evaluation ◽

Brain Water

(R)- and (S)-1 were as potent as racemate 1 in antiplatelet aggregation, antioxidation, reduction of infarct size and brain-water content, as well as neurological deficit.

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