N-Myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury

2021 ◽  
Author(s):  
Lixia Zhang ◽  
Yulong Ma ◽  
Min Liu ◽  
Miao Sun ◽  
Jin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Female Mice ◽  
Ndrg2 Expression ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Abstract Growing evidence indicates that estrogen plays a pivotal role in neuroprotection against cerebral ischemia, but the molecular mechanism of this protection is still elusive. N-myc downstream‐regulated gene 2 (Ndrg2), an estrogen-targeted gene, has been shown to exert neuroprotective effects against cerebral ischemia in male mice. However, the role of Ndrg2 in the neuroprotective effect of estrogen remains unknown. In this study, we first detected NDRG2 expression levels in the cortex and striatum in both female and male mice with western blot analyses. We then detected cerebral ischemic injury by constructing middle cerebral artery occlusion and reperfusion (MCAO-R) models in Ndrg2 knockout or conditional knockdown female mice. We further implemented estrogen, ERα or ERβ agonist replacement in the ovariectomized (OVX) Ndrg2 knockouts or conditional knockdowns female mice, then tested for NDRG2 expression, glial fibrillary acidic protein (GFAP) expression, and extent of cerebral ischemic injury. We found that NDRG2 expression was significantly higher in female than in male mice in both the cortex and striatum. Ndrg2 knockouts and conditional knockdowns showed significantly aggravated cerebral ischemic injury in female mice. Estrogen and ERβ replacement treatment (DPN) led to NDRG2 upregulation in both the cortex and striatum of OVX mice. Estrogen and DPN also led to GFAP upregulation in OVX mice. However, the effect of estrogen and DPN in activating astrocytes was lost in Ndrg2 knockouts OVX mice and primary cultured astrocytes, but partially retained in conditional knockdowns OVX mice. Most importantly, we found that the neuroprotective effects of E2 and DPN against cerebral ischemic injury were lost in Ndrg2 knockouts OVX mice but partially retained in conditional knockdowns OVX mice. These findings demonstrate that estrogen alleviated cerebral ischemic injury via ERβ upregulation of Ndrg2, which could activate astrocytes, indicating that Ndrg2 is a critical mediator of E2-induced neuroprotection against cerebral ischemic injury.

scholarly journals Neuroprotective Effect of Quercetin during Cerebral Ischemic Injury Involves Regulation of Essential Elements, Transition Metals, Cu/Zn Ratio, and Antioxidant Activity

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6128
Author(s):  
Ming-Cheng Lin ◽  
Chien-Chi Liu ◽  
Chin-Sheng Liao ◽  
Ju-Hai Ro
Keyword(s):  
Antioxidant Activity ◽  
Cerebral Ischemia ◽  
Transition Metals ◽  
Brain Cortex ◽  
Ischemic Injury ◽  
Essential Elements ◽  
Neuroprotective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
The Right

Cerebral ischemia results in increased oxidative stress in the affected brain. Accumulating evidence suggests that quercetin possesses anti-oxidant and anti-inflammatory properties. The essential elements magnesium (Mg), zinc (Zn), selenium (Se), and transition metal iron (Fe), copper (Cu), and antioxidants superoxide dismutase (SOD) and catalase (CAT) are required for brain functions. This study investigates whether the neuroprotective effects of quercetin on the ipsilateral brain cortex involve altered levels of essential trace metals, the Cu/Zn ratio, and antioxidant activity. Rats were intraperitoneally administered quercetin (20 mg/kg) once daily for 10 days before ischemic surgery. Cerebral ischemia was induced by ligation of the right middle cerebral artery and the right common carotid artery for 1 h. The ipsilateral brain cortex was homogenized and the supernatant was collected for biochemical analysis. Results show that rats pretreated with quercetin before ischemia significantly increased Mg, Zn, Se, SOD, and CAT levels, while the malondialdehyde, Fe, Cu, and the Cu/Zn ratio clearly decreased as compared to the untreated ligation subject. Taken together, our findings suggest that the mechanisms underlying the neuroprotective effects of quercetin during cerebral ischemic injury involve the modulation of essential elements, transition metals, Cu/Zn ratio, and antioxidant activity.

scholarly journals CELSR1 Promotes Neuroprotection in Cerebral Ischemic Injury Mainly through the Wnt/PKC Signaling Pathway

2020 ◽  
Vol 21 (4) ◽  
pp. 1267 ◽  
Author(s):  
Li-Hong Wang ◽  
Geng-Lin Zhang ◽  
Xing-Yu Liu ◽  
Ai Peng ◽  
Hai-Yuan Ren ◽  
...  
Keyword(s):  
Motor Function ◽  
Cell Apoptosis ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion

Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.

scholarly journals Protective Effect of Delayed Remote Limb Ischemic Postconditioning: Role of Mitochondrial KATP Channels in a Rat Model of Focal Cerebral Ischemic Reperfusion Injury

2012 ◽  
Vol 32 (5) ◽  
pp. 851-859 ◽  
Author(s):  
Jing Sun ◽  
Tong Li ◽  
Qi Luan ◽  
Jiao Deng ◽  
Yan Li ◽  
...  
Keyword(s):  
Neuroprotective Effect ◽  
Time Windows ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Ischemic Postconditioning ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Sprague Dawley ◽  
Neuroprotective Effects ◽  
Remote Ischemic Postconditioning ◽  
Cerebral Ischemic

Delayed remote ischemic postconditioning (DRIPost) has been shown to protect the rat brain from ischemic injury. However, extremely short therapeutic time windows hinder its translational use and the mechanism of action remains elusive. Because opening of the mitochondria KATP channel is crucial for cell apoptosis, we hypothesized that the neuroprotective effect of DRIPost may be associated with KATP channels. In the present study, the neuroprotective effects of DRIPost were investigated using adult male Sprague-Dawley rats. Rats were exposed to 90 minutes of middle cerebral artery occlusion followed by 72 hours of reperfusion. Delayed remote ischemic postconditioning was performed with three cycles of bilateral femoral artery occlusion/reperfusion for 5 minutes at 3 or 6 hours after reperfusion. Neurologic deficit scores and infarct volumes were assessed, and cellular apoptosis was monitored by terminal deoxynucleotidyl transferase nick-end labeling. Our results showed that DRIPost applied at 6 hours after reperfusion exerted neuroprotective effects. The KATP opener, diazoxide, protected rat brains from ischemic injury, while the KATP blocker, 5-hydroxydecanote, reversed the neuroprotective effects of DRIPost. These findings indicate that DRIPost reduces focal cerebral ischemic injury and that the neuroprotective effects of DRIPost may be achieved through opening of KATP channels.

scholarly journals Prdx6 Upregulation by Curcumin Attenuates Ischemic Oxidative Damage via SP1 in Rats after Stroke

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Gongwei Jia ◽  
Botao Tan ◽  
Jingxi Ma ◽  
Lina Zhang ◽  
Xinhao Jin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Specific Protein ◽  
Artery Occlusion ◽  
Sprague Dawley ◽  
Neuroprotective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Background. The role of Peroxiredoxin 6 (Prdx6) in brain ischemia remains unclear. Curcumin (Cur) treatment elicits neuroprotective effects against cerebral ischemic injury, and the associated mechanisms may involve Prdx6. In this study, we investigated whether Prdx6 and the transcription factor specific protein 1 (SP1) were involved in the antioxidant effect of Cur after stoke. Methods. Focal cerebral ischemic injury was induced by transient middle cerebral artery occlusion for 2 hours in male Sprague-Dawley rats treated with or without Prdx6 siRNA. Expression of Prdx6 in the penumbra was assessed by Real-Time PCR (RT-PCR), Western blot analysis, and immunoflourescent staining. In addition, infarct volume, neurological deficit score, and oxidative stress were evaluated. Prdx6 levels were also determined in the presence and absence of SP1 antagonist mithramycin A (MTM-A). Results. Cur treatment upregulated Prdx6 protein expression and the number of Prdx6-positive neuronal cells 24 hours after reperfusion. Cur treatment also attenuated oxidative stress and induced neuroprotective effects against ischemic damage, whereas the beneficial effects of Cur treatment were lost in animals treated with Prdx6-siRNA. Prdx6 upregulation by Cur treatment was abolished by SP1 antagonists MTM. Conclusions. Prdx6 upregulation by Cur treatment attenuates ischemic oxidative damage through SP1 induction in rats after stroke. This represents a novel mechanism of Cur-induced neuroprotection against cerebral ischemia.

scholarly journals Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Zun-Jing Liu ◽  
Wei Liu ◽  
Lei Liu ◽  
Cheng Xiao ◽  
Yu Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Ischemic Injury ◽  
Ppar Gamma ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPARγagonist in that it upregulated PPARγexpression and PPARγ-PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1β, TNF-α, PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed IκB degradation that was caused by cerebral ischemia. The present data also showed that PPARγinteracted with NF-κB-p65 and thus inhibited NF-κB activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPARγ. Our results as described above suggested that PPARγinduced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

Gingko biloba Extract (EGb 761) Attenuates the Focal Cerebral Ischemic Injury-Induced Decrease in Astrocytic Phosphoprotein PEA-15 Levels

2011 ◽  
Vol 39 (05) ◽  
pp. 971-979 ◽  
Author(s):  
Phil-Ok Koh
Keyword(s):  
Apoptotic Cell ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Male Rats ◽  
Egb 761 ◽  
Gingko Biloba ◽  
Proteomic Approach ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion

EGb 761 is an extract of Gingko biloba that is neuroprotective against focal cerebral ischemic injury. PEA-15 (phosphoprotein enriched in astrocytes 15) modulates cell proliferation and apoptosis. In this study, we investigated whether EGb 761 regulates the expression of PEA-15 and two phosphorylated forms of PEA-15 (Ser 104 and Ser 116) in middle cerebral artery occlusion (MCAO)-induced injury. Adult male rats were treated with vehicle or EGb 761 (100 mg/kg) prior to MCAO and cerebral cortices were collected 24 h after MCAO. A reduction in expression of PEA-15 and its phosphorylated forms induced by MCAO injury was detected using a proteomic approach. EGb 761 pretreatment prevented the ischemic injury-induced decrease in PEA-15 expression. Western blot analysis demonstrated that EGb 761 attenuates the injury-induced reduction in PEA-15, phospho-PEA-15 (Ser 104), phospho-PEA-15 (Ser 116). Phosphorylation of PEA-15 influences its anti-apoptotic function; a decrease in PEA-15 phosphorylation induces apoptotic cell death. The maintenance of PEA-15 phosphorylation by EGb 761 pretreatment during cerebral ischemic injury indicates that EGb 761 is a neuroprotective against cerebral ischemic injury.

scholarly journals Prolonged Fasting Improves Endothelial Progenitor Cell-Mediated Ischemic Angiogenesis in Mice

2016 ◽  
Vol 40 (3-4) ◽  
pp. 693-706 ◽  
Author(s):  
Bao Xin ◽  
Chun-Long Liu ◽  
Hong Yang ◽  
Cheng Peng ◽  
Xiao-Hui Dong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Endothelial Progenitor Cell ◽  
Progenitor Cell ◽  
Ischemic Injury ◽  
Prolonged Fasting ◽  
Endothelial Progenitor ◽  
Ischemic Brain ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Background/Aims: Prolonged fasting (PF) was shown to be of great potency to promote optimal health and reduce the risk of many chronic diseases. This study sought to determine the effect of PF on the endothelial progenitor cell (EPC)-mediated angiogenesis in the ischemic brain and cerebral ischemic injury in mice. Methods: Mice were subjected to PF or periodic PF after cerebral ischemia, and histological analysis and behavioral tests were performed. Mouse EPCs were isolated and examined, and the effects of EPC transplantation on cerebral ischemic injury were investigated in mice. Results: It was found that PF significantly increased the EPC functions and angiogenesis in the ischemic brain, and attenuated the cerebral ischemic injury in mice that was previously subjected to cerebral ischemia. Periodic PF might reduce cortical atrophy and improve long-term neurobehavioral outcomes after cerebral ischemia in mice. The eNOS and MnSOD expression and intracellular NO level were increased, and TSP-2 expression and intracellular O2- level were reduced in EPCs from PF-treated mice compared to control. In addition, transplanted EPCs might home into ischemic brain, and the EPCs from PF-treated mice had a stronger ability to promote angiogenesis in ischemic brain and reduce cerebral ischemic injury compared to the EPCs from control mice. The EPC-conditioned media from PF-treated mice exerted a stronger effect on cerebral ischemic injury reduction compared to that from control mice. Conclusion: Prolonged fasting promoted EPC-mediated ischemic angiogenesis and improved long-term stroke outcomes in mice. It is implied that prolonged fasting might potentially be an option to treat ischemic vascular diseases.

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