Radix Scrophulariae Aqueous Extract Seems to Exert Neuroprotective Effects on Cerebral Ischemia and Reperfusion Injury with Inhibiting Apoptosis via ERK1/2 and p-38 MAPK Pathway

Ischemia stroke is one of a clinically common cerebrovascular disease. And Inhibition of brain tissue ischemia and reperfusion-induced damage, especially apoptosis, has an irreplaceable protective effect on ischemic nerves, and has special significance for the treatment of patients after treatment. However, the development of neuroprotective drugs still has certain challenges. Radix scrophulariae as a valuable medicine, has been discovered to has neuroprotective effects. Our researches initially proved that Radix scrophulariae aqueous extract (RSAE) exerting a neuroprotective effects on cerebral ischemia and reperfusion (I/R) injury in oxygen glucose deprivation and reperfusion (OGD/R)-induced PC12 cells and middle cerebral artery occlusion/reperfusion (MCAO/R) model mice, were associated with attenuation of infarct volume, brain water content, nitric oxide (NO) and malondialdehyde (MDA), inhibiting I/R-induced damage by reducing the levels of LDH release, improving anti-oxidant capacity by upregulating the SOD, GSH-Px and CAT activity, stabilizing mitochondrial membrane potential, reducing neuronal apoptosis, necrosis and neuronal loss by regulating the expression of anti-apoptotic BCL-2and pro-apoptotic protein Bax, and elucidating downregulate the phosphorylation levels of MAPK pathways. Our findings may elaborate the neuroprotective effects and potential mechanisms of RSAE on focal cerebral I/R injury in mice. Since, Radix scrophulariae, as a potential neuroprotective natural plant, has originally been identified to, our results may offer directions and clues for discovering new active compounds or drugs for treatment of ischemic stroke, which allows us to discover many new natural active chemicals by chemical separation and identification, and provide new insights into therapeutic targets in stroke patients.

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HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways

Biomolecules ◽

10.3390/biom9100512 ◽

2019 ◽

Vol 9 (10) ◽

pp. 512 ◽

Cited By ~ 14

Author(s):

Xie ◽

Zhu ◽

Dong ◽

Nan ◽

Meng ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Infarct Volume ◽

Neuronal Loss ◽

Ischemia And Reperfusion ◽

Protective Effects ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Cerebral Ischemia And Reperfusion

Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R) injury. This process has particular significance for the treatment of stroke patients. Notoginseng leaf triterpenes (PNGL), as a valuable medicine, have been discovered to have neuroprotective effects. However, it was not confirmed that whether PNGL may possess neuroprotective effects against cerebral I/R injury. To explore the neuroprotective effects of PNGL and their underlying mechanisms, a middle cerebral artery occlusion/reperfusion (MCAO/R) model was established. In vivo results suggested that in MCAO/R model rats, PNGL pretreatment (73.0, 146, 292 mg/kg) remarkably decreased infarct volume, reduced brain water content, and improved neurological functions; moreover, PNGL (73.0, 146, 292 mg/kg) significantly alleviated blood-brain barrier (BBB) disruption and inhibited neuronal apoptosis and neuronal loss caused by cerebral I/R injury, while PNGL with a different concertation (146, 292 mg/kg) significantly reduced the concentrations of IL-6, TNF-α, IL-1 β, and HMGB1 in serums in a dose-dependent way, which indicated that inflammation inhibition could be involved in the neuroprotective effects of PNGL. The immunofluorescence and western blot analysis showed PNGL decreased HMGB1 expression, suppressed the HMGB1-triggered inflammation, and inhibited microglia activation (IBA1) in hippocampus and cortex, thus dose-dependently downregulating inflammatory cytokines including VCAM-1, MMP-9, MMP-2, and ICAM-1 concentrations in ischemic brains. Interestingly, PNGL administration (146 mg/kg) significantly downregulated the levels of p-P44/42, p-JNK1/2 and p-P38 MAPK, and also inhibited expressions of the total NF-κB and phosphorylated NF-κB in ischemic brains, which was the downstream pathway triggered by HMGB1. All of these results indicated that the protective effects of PNGL against cerebral I/R injury could be associated with inhibiting HMGB1-triggered inflammation, suppressing the activation of MAPKs and NF-κB, and thus improved cerebral I/R-induced neuropathological changes. This study may offer insight into discovering new active compounds for the treatment of ischemic stroke.

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Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats

Cellular Physiology and Biochemistry ◽

10.1159/000487031 ◽

2018 ◽

Vol 45 (2) ◽

pp. 537-546 ◽

Cited By ~ 23

Author(s):

Yong Wang ◽

Qianyao Ren ◽

Xing Zhang ◽

Huiling Lu ◽

Jian Chen

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Brca1 Gene ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Cerebral Ischemia And Reperfusion ◽

Tnf Α

Background/Aims: Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. Methods: A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-α in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. Results: The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-α significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-α. Conclusions: All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti-apoptotic and anti-inflammatory action.

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Barbaloin Alleviates Cerebral Ischemia and Reperfusion Injury in Rats and Inhibits Lipopolysaccharide-stimulated Inflammatory Responses in BV2 Microglial Cells

10.21203/rs.3.rs-118330/v1 ◽

2020 ◽

Author(s):

Lin Wang ◽

Lijuan Zhang

Keyword(s):

Cerebral Ischemia ◽

Inflammatory Responses ◽

Infarct Volume ◽

Microglial Cells ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Protein Levels ◽

Cerebral Ischemia And Reperfusion

Abstract Background: Barbaloin (BAR) is a bioactive anthracycline derived from the leaf exudates of aloe plants with a variety of biological and pharmacological properties. The present study was performed to investigate the neuroprotective effects of BAR against cerebral ischemia and reperfusion (I/R) injury in rats as well as the possible underlying mechanisms. Middle cerebral artery occlusion followed by reperfusion was used to induce cerebral I/R injury in rats, and BAR was administered intraperitoneally after the onset of ischemia. Results: We found that BAR remarkably improved neurological scores, reduced brain infarct volume, and inhibited neuronal apoptosis in cerebral I/R rats. Furthermore, BAR up-regulated Bcl-2 protein levels and down-regulated Bax, active caspase-3, and inducible nitric oxide synthase (iNOS) in ischemic cortex. I/R injury-induced increases in malondialdehyde content and decreases in glutathione peroxidase, glutathione, and superoxide dismutase activities were significantly attenuated by BAR administration. In vitro, BAR pretreatment inhibited the contents of proinflammatory cytokines (tumor necrosis factor-α, iNOS, and interleukin-6) and reduced protein levels of iNOS and nuclear expression of nuclear factor-κB p65 in lipopolysaccharide-stimulated BV-2 microglial cells. Conclusion: Taken together, our data suggest that BAR possesses neuroprotective effects against cerebral I/R injury through anti-oxidative, anti-apoptotic, and anti-inflammatory activities.

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Neuroprotective effects of Tongxinluo on focal cerebral ischemia and reperfusion injury in rats associated with the activation of the MEK1/2/ERK1/2/p90RSK signaling pathway

Brain Research ◽

10.1016/j.brainres.2018.01.036 ◽

2018 ◽

Vol 1685 ◽

pp. 9-18 ◽

Cited By ~ 11

Author(s):

Zhonghai Yu ◽

Min Cai ◽

Xianting Li ◽

Jingsi Zhang ◽

Ting Wu ◽

...

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Signaling Pathway ◽

Focal Cerebral Ischemia ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Cerebral Ischemia And Reperfusion

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Abstract WMP37: MicroRNA-29a Protects Against Cerebral Ischemia and Reperfusion Injury by Targeting NADPH Oxidase 4

Stroke ◽

10.1161/str.48.suppl_1.wmp37 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yong-Hua Tuo ◽

Zhong Liu ◽

Lei Feng ◽

Zhong-Song Shi

Keyword(s):

Cerebral Ischemia ◽

Nadph Oxidase ◽

Reperfusion Injury ◽

Blood Brain Barrier ◽

Neurological Outcome ◽

Infarct Volume ◽

Brain Barrier ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Cerebral Ischemia And Reperfusion

Background: MicroRNA-29a (miR-29a) is involved in regulating cerebral ischemia process, but its underlying mechanism is unclear. We previously showed that inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) pathway improves the neurological outcome and increases the expression of miR-29a in transient middle cerebral artery occlusion (tMCAO) animal model. This study investigated the role of miR-29a in cerebral ischemia and reperfusion injury after mechanical reperfusion. Methods: The intraluminal filament tMCAO model was established in male rats with 2 hour ischemia followed by reperfusion. The expression of miR-29a and NOX4 in the infarction core and peri-infarct cortex were quantified at 0, 3, 12, and 24 hour after reperfusion. Permanent MCAO model was also evaluated after 2 hour and 24 hour ischemia. Intravenous miR-29a agomir was delivered immediately after reperfusion. Infarct volume, brain water content, neurological score, blood-brain barrier damage, and levels of miR-29a and NOX4 were determined at 24-hour after cerebral ischemia. Results: MiR-29a levels in the infarction core and peri-infarct cortex were significantly decreased at 3 hours after reperfusion in tMCAO group compared with the sham-operated group. The decreased levels of miR-29a lasted for 24 hours after cerebral ischemia. Dual-luciferase reporter system showed that NOX4 was the direct target gene of miR-29a. Intravenous miR-29a agomir increased the expression of miR-29a and suppressed NOX4 up-regulation in both the infarction core and peri-infarct cortex at 24-hour after ischemia compared with the tMCAO group (all p<0.05). Intravenous miR-29a agomir reduced infarct volume (24.7% ± 4.0% versus 37.8% ± 7.5%, p<0.01) at 24-hour after ischemia compared to the tMCAO group. MiR-29a agomir attenuated brain edema and reduced reperfusion-induced blood-brain barrier breakdown, resulting in improved neurological outcome (all p<0.05). Conclusions: MiR-29a overexpression protects against cerebral ischemia and reperfusion injury via downregulating NOX4. Infusion of miR-29a agomir immediately after reperfusion represents a novel adjunctive therapeutic strategy to improve outcome after mechanical reperfusion for acute ischemic stroke.

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Protective Effects and Target Network Analysis of Ginsenoside Rg1 in Cerebral Ischemia and Reperfusion Injury: A Comprehensive Overview of Experimental Studies

Cells ◽

10.3390/cells7120270 ◽

2018 ◽

Vol 7 (12) ◽

pp. 270 ◽

Cited By ~ 27

Author(s):

Weijie Xie ◽

Ping Zhou ◽

Yifan Sun ◽

Xiangbao Meng ◽

Ziru Dai ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia And Reperfusion ◽

Protective Effects ◽

Pharmacological Effects ◽

Ginsenoside Rg1 ◽

Ischemia And Reperfusion Injury ◽

Neuroprotective Effects ◽

Cerebral Ischemia And Reperfusion

Cerebral ischemia-reperfusion is a complicated pathological process. The injury and cascade reactions caused by cerebral ischemia and reperfusion are characterized by high mortality, high recurrence, and high disability. However, only a limited number of antithrombotic drugs, such as recombinant tissue plasminogen activator (r-TPA), aspirin, and heparin, are currently available for ischemic stroke, and its safety concerns is inevitable which associated with reperfusion injury and hemorrhage. Therefore, it is necessary to further explore and examine some potential neuroprotective agents with treatment for cerebral ischemia and reperfusion injury to reduce safety concerns caused by antithrombotic drugs in ischemic stroke. Ginseng Rg1 (G-Rg1) is a saponin composed of natural active ingredients and derived from the roots or stems of Panax notoginseng and ginseng in traditional Chinese medicine. Its pharmacological effects exert remarkable neurotrophic and neuroprotective effects in the central nervous system. To explore and summarize the protective effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury, we conducted this review, in which we searched the PubMed database to obtain and organize studies concerning the pharmacological effects and mechanisms of ginsenoside Rg1 against cerebral ischemia and reperfusion injury. This study provides a valuable reference and clues for the development of new agents to combat ischemic stroke. Our summarized review and analysis show that the pharmacological effects of and mechanisms underlying ginsenoside Rg1 activity against cerebral ischemia and reperfusion injury mainly involve 4 sets of mechanisms: anti-oxidant activity and associated apoptosis via the Akt, Nrf2/HO-1, PPARγ/HO-1, extracellular regulated protein kinases (ERK), p38, and c-Jun N-terminal kinase (JNK) pathways (or mitochondrial apoptosis pathway) and the caspase-3/ROCK1/MLC pathway; anti-inflammatory and immune stimulatory-related activities that involve apoptosis or necrosis via MAPK pathways (the JNK1/2 + ERK1/2 and PPARγ/HO-1 pathways), endoplasmic reticulum stress (ERS), high mobility group protein1 (HMGB1)-induced TLR2/4/9 and receptor for advanced glycation end products (RAGE) pathways, and the activation of NF-κB; neurological cell cycle, proliferation, differentiation, and regeneration via the MAPK pathways (JNK1/2 + ERK1/2, PI3K-Akt/mTOR, PKB/Akt and HIF-1α/VEGF pathways); and energy metabolism and the regulation of cellular ATP levels, the blood-brain barrier and other effects via N-methyl-D-aspartic acid (NMDA) receptors, ERS, and AMP/AMPK-GLUT pathways. Collectively, these mechanisms result in significant neuroprotective effects against cerebral ischemic injury. These findings will be valuable in that they should further promote the development of candidate drugs and provide more information to support the application of previous findings in stroke clinical trials.

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Nanoparticles for Targeted Delivery of Antioxidant Enzymes to the Brain after Cerebral Ischemia and Reperfusion Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.209 ◽

2013 ◽

Vol 33 (4) ◽

pp. 583-592 ◽

Cited By ~ 74

Author(s):

Xiang Yun ◽

Victor D Maximov ◽

Jin Yu ◽

g Zhu ◽

Alexey A Vertegel ◽

...

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Targeted Delivery ◽

Infarct Volume ◽

The United States ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Targeted Nanoparticles ◽

Cerebral Ischemia And Reperfusion ◽

The Impact

Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-D-aspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke.

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E-Selectin in Focal Cerebral Ischemia and Reperfusion in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199611000-00006 ◽

1996 ◽

Vol 16 (6) ◽

pp. 1126-1136 ◽

Cited By ~ 75

Author(s):

Rui Lan Zhang ◽

Michael Chopp ◽

Zheng G. Zhang ◽

M. Laurie Phillips ◽

Craig L. Rosenbloom ◽

...

Keyword(s):

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Cell Damage ◽

Leukocyte Adhesion ◽

Infarct Volume ◽

Ischemia And Reperfusion ◽

Ischemia And Reperfusion Injury ◽

Ischemic Lesion ◽

Mca Occlusion ◽

Cerebral Ischemia And Reperfusion

The selectin family of glycoproteins facilitates the early phase of polymorphonuclear leukocyte adhesion to the endothelial cell and, thus, may promote ischemic cell damage. To evaluate E-selectin in the pathogenesis of focal cerebral ischemia and reperfusion injury, we cloned rat E-selectin cDNA and measured the temporal profiles E-selectin mRNA (Northern blot) and protein (immunohistochemistry) during (1 h of ischemia) and after (up to 1 week) transient (2 h) middle cerebral artery (MCA) occlusion in the male Wistar rat. We also tested the effect on these rats of administration of CY-1503, an analog of sialyl Lewisx (SLex), on ischemia cell damage. mRNA for E-selectin was first detected in the ischemic hemisphere at 2 h of reperfusion and persisted to 46 h of reperfusion. E-selectin (protein) was localized to microvessels within the ischemic lesion at 0 h of reperfusion and persisted to 70 h of reperfusion. Treatment of the ischemic animals with CY-1503 (50 mg/kg) (n = 8) significantly reduced infarct volume by 42% ( p < 0.05) and significantly reduced myeloperoxidase immunoreactive cells in the ischemic lesion by 60% ( p < 0.05). These findings provide the first direct evidence for the involvement of E-selectin in transient MCA occlusion in rats and suggest that the E-selectin may facilitate neutrophil adhesion and subsequent cerebral ischemic cell damage.

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