The AAA + ATPase Thorase is neuroprotective against ischemic injury

Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo. Thorase provides neuroprotection in an ATP-dependent manner against oxygen–glucose deprivation (OGD) neurotoxicity or glutamate N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in vitro. Knock-down of Thorase prevents the establishment of preconditioning induced neuroprotection against OGD or NMDA neurotoxicity. Transgenic overexpression of Thorase provides neuroprotection in vivo against middle cerebral artery occlusion (MCAO)-induced stroke in mice, while genetic deletion of Thorase results in increased injury in vivo following stroke. These results define Thorase as a neuroprotective protein and understanding Thorase signaling could offer a new therapeutic strategy for the treatment of neurologic disorders.

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Contraceptive drugs mitigate experimental stroke-induced brain injury

Cardiovascular Research ◽

10.1093/cvr/cvy248 ◽

2018 ◽

Vol 115 (3) ◽

pp. 637-646 ◽

Cited By ~ 5

Author(s):

Mohamad El Amki ◽

Nadine Binder ◽

Riccardo Steffen ◽

Hannah Schneider ◽

Andreas R Luft ◽

...

Keyword(s):

Brain Injury ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Experimental Models ◽

Experimental Stroke ◽

Protective Effects ◽

New Generation ◽

Cerebral Artery Occlusion

AbstractAimsEffective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells.Methods and resultsMCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro.ConclusionFor the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke.

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Restoration of Polyamine Metabolic Patterns inIn VivoandIn VitroModel of Ischemic Stroke following Human Mesenchymal Stem Cell Treatment

Stem Cells International ◽

10.1155/2016/4612531 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Tae Hwan Shin ◽

Geetika Phukan ◽

Jeom Soon Shim ◽

Duc-Toan Nguyen ◽

Yongman Kim ◽

...

Keyword(s):

Ischemic Stroke ◽

Cell Model ◽

Glucose Deprivation ◽

Human Mesenchymal Stem Cell ◽

Artery Occlusion ◽

Control Group ◽

Stem Cell Treatment ◽

Cerebral Artery Occlusion

We investigated changes in PA levels by the treatment of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) in ischemic stroke in rat brain model and in cultured neuronal SH-SY5Y cells exposed to oxygen-glucose deprivation (OGD). In ischemic rat model, transient middle cerebral artery occlusion (MCAo) was performed for 2 h, followed by intravenous transplantation of hBM-MSCs or phosphate-buffered saline (PBS) the day following MCAo. Metabolic profiling analysis of PAs was examined in brains from three groups: control rats, PBS-treated MCAo rats (MCAo), and hBM-MSCs-treated MCAo rats (MCAo + hBM-MSCs). In ischemic cell model, SH-SY5Y cells were exposed to OGD for 24 h, treated with hBM-MSCs (OGD + hBM-MSCs) prior to continued aerobic incubation, and then samples were collected after coculture for 72 h. In thein vivoMCAo ischemic model, levels of some PAs in brain samples of the MCAo and MCAo + hBM-MSCs groups were significantly different from those of the control group. In particular, putrescine, cadaverine, and spermidine in brain tissues of the MCAo + hBM-MSCs group were significantly reduced in comparison to those in the MCAo group. In thein vitroOGD system,N1-acetylspermidine, spermidine,N1-acetylspermine, and spermine in cells of the OGD + hBM-MSCs group were significantly reduced compared to those of OGD group.

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GATA3 (GATA-Binding Protein 3)/KMT2A (Lysine-Methyltransferase-2A) Complex by Increasing H3K4-3me (Trimethylated Lysine-4 of Histone-3) Upregulates NCX3 (Na + -Ca 2+ Exchanger 3) Transcription and Contributes to Ischemic Preconditioning Neuroprotection

Stroke ◽

10.1161/strokeaha.121.034637 ◽

2021 ◽

Vol 52 (11) ◽

pp. 3680-3691

Author(s):

Natascia Guida ◽

Luigi Mascolo ◽

Angelo Serani ◽

Ornella Cuomo ◽

Serenella Anzilotti ◽

...

Keyword(s):

Ischemic Preconditioning ◽

Cortical Neurons ◽

Promoter Region ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Histone 3 ◽

Lysine Methyltransferase ◽

Cerebral Artery Occlusion

Background and Purpose: NCX3 (Na + -Ca 2+ exchanger 3) plays a relevant role in stroke; indeed its pharmacological blockade or its genetic ablation exacerbates brain ischemic damage, whereas its upregulation takes part in the neuroprotection elicited by ischemic preconditioning. To identify an effective strategy to induce an overexpression of NCX3, we examined transcription factors and epigenetic mechanisms potentially involved in NCX3 gene regulation. Methods: Brain ischemia and ischemic preconditioning were induced in vitro by exposure of cortical neurons to oxygen and glucose deprivation plus reoxygenation (OGD/Reoxy) and in vivo by transient middle cerebral artery occlusion. Western blot and quantitative real-time polymerase chain reaction were used to evaluate transcripts and proteins of GATA3 (GATA-binding protein 3), KMT2A (lysine-methyltransferase-2A), and NCX3. GATA3 and KMT2A binding on NCX3 gene was evaluated by chromatin immunoprecipitation and Rechromatin immunoprecipitation experiments. Results: Among the putative transcription factors sharing a consensus sequence on the ncx3 brain promoter region, GATA3 was the only able to up-regulate ncx3. Interestingly, GATA3 physically interacted with KMT2A, and their overexpression or knocking-down increased or downregulated NCX3 mRNA and protein, respectively. Notably, site-direct mutagenesis of GATA site on ncx3 brain promoter region counteracted GATA3 and KMT2A binding on NCX3 gene. More importantly, we found that in the perischemic cortical regions of preconditioned rats GATA3 recruited KMT2A and the complex H3K4-3me (trimethylated lysine-4 of histone-3) on ncx3 brain promoter region, thus reducing transient middle cerebral artery occlusion–induced damage. Consistently, in vivo silencing of either GATA3 or KMT2A prevented NCX3 upregulation and consequently the neuroprotective effect of preconditioning stimulus. The involvement of GATA3/KMT2A complex in neuroprotection elicited by ischemic preconditioning was further confirmed by in vitro experiments in which the knocking-down of GATA3 and KMT2A reverted the neuroprotection induced by NCX3 overexpression in cortical neurons exposed to anoxic preconditioning followed by oxygen and glucose deprivation plus reoxygenation. Conclusions: Collectively, our results revealed that GATA3/KMT2A complex epigenetically activates NCX3 gene transcription during ischemic preconditioning.

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DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke

10.21203/rs.2.17665/v1 ◽

2019 ◽

Author(s):

Li Peng ◽

Yang Zhou ◽

Ning Jiang ◽

Tingting Wang ◽

Jin Zhu ◽

...

Keyword(s):

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Reactive Astrocytes ◽

Primary Astrocyte ◽

Tnf Α ◽

Anti Inflammatory ◽

Cerebral Artery Occlusion

Abstract Background: Acute inflammation developed by reactive astrocytes after cerebral ischemia/reperfusion (I/R) injury is important in protecting the resultant lesion. Our previous study demonstrated the abundant expression of DJ-1 in reactive astrocytes after cerebral I/R injury. Here, we show that DJ-1 negatively regulates the inflammatory response by facilitating the interaction between SHP-1 and TRAF6, thereby inducing NLRX1 dissociation from TRAF6. Methods: We used oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro in primary astrocyte cultures and transient middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo to mimic ischemic reperfusion insult. Results: The inhibition of DJ-1 expression increased the expression of the inflammatory cytokines TNF-α, IL-1β, and IL-6. DJ-1 knockdown facilitated the interaction of NLRX1 with TRAF6. However, the loss of DJ-1 attenuated the interaction of SHP-1 with TRAF6. In subsequent experiments, an SHP-1 inhibitor altered the interaction of SHP-1 with TRAF6 and facilitated the interaction of NLRX1 with TRAF6 in DJ-1-overexpressing astrocytes.. Conclusion: This finding suggests that DJ-1 exerts an SHP-1-dependent anti-inflammatory effect and induces the dissociation of NLRX1 and TRAF6 in cerebral I/R injury. Thus, DJ-1 may be an efficacious therapeutic target for the treatment of I/R injury.

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GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia

Stroke ◽

10.1161/strokeaha.120.031479 ◽

2020 ◽

Vol 51 (12) ◽

pp. 3690-3700

Author(s):

Tao Wang ◽

Guokun Zhou ◽

Mindi He ◽

Yuanyuan Xu ◽

W.G. Rusyniak ◽

...

Keyword(s):

Neurological Diseases ◽

Neuronal Injury ◽

Artery Occlusion ◽

Dependent Manner ◽

Protective Effects ◽

Pkc Protein Kinase C ◽

Neuroprotective Function ◽

Cerebral Artery Occlusion

Background and Purpose: Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.

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Neuroprotective Role of Lactate after Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.97 ◽

2009 ◽

Vol 29 (11) ◽

pp. 1780-1789 ◽

Cited By ~ 118

Author(s):

Carole Berthet ◽

Hongxia Lei ◽

Jonathan Thevenet ◽

Rolf Gruetter ◽

Pierre J Magistretti ◽

...

Keyword(s):

Hippocampal Slices ◽

Glucose Deprivation ◽

Lesion Size ◽

Artery Occlusion ◽

Neurologic Outcome ◽

Moderate Increase ◽

Cerebral Artery Occlusion

It is well established that lactate can be used as an energy substrate by the brain by conversion to pyruvate and a subsequent oxidation in the mitochondria. Knowing the need for readily metabolizable substrates directly after ischemia and the protective effect of lactate after excitotoxicity, the aim of this study was to investigate whether lactate administration directly after ischemia could be neuroprotective. In vitro, the addition of 4 mmol/L l-lactate to the medium of rat organotypic hippocampal slices, directly after oxygen and glucose deprivation (OGD), protected against neuronal death, whereas a higher dose of 20 mmol/L was toxic. In vivo, after middle cerebral artery occlusion in the mouse, an intracerebroventricular injection of 2 μL of 100 mmol/L l-lactate, immediately after reperfusion, led to a significant decrease in lesion size, which was more pronounced in the striatum, and an improvement in neurologic outcome. A later injection 1 h after reperfusion did not reduce lesion size, but significantly improved neurologic outcome, which is an important point in the context of a potential clinical application. Therefore, a moderate increase in lactate after ischemia may be a therapeutic tool.

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DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke

10.21203/rs.2.17665/v3 ◽

2020 ◽

Author(s):

Li Peng ◽

Yang Zhou ◽

Ning Jiang ◽

Tingting Wang ◽

Jin Zhu ◽

...

Keyword(s):

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Reactive Astrocytes ◽

Primary Astrocyte ◽

Tnf Α ◽

Anti Inflammatory ◽

Cerebral Artery Occlusion

Abstract Background: Acute inflammation induced by reactive astrocytes after cerebral ischemia/reperfusion (I/R) injury is important for protecting the resultant lesion. Our previous study demonstrated that DJ-1 is abundantly expressed in reactive astrocytes after cerebral I/R injury. Here, we show that DJ-1 negatively regulates the inflammatory response by facilitating the interaction between SHP-1 and TRAF6, thereby inducing the dissociation of NLRX1 from TRAF6. Methods: We used oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro in primary astrocyte cultures and transient middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo to mimic I/R insult. Results: The inhibition of DJ-1 expression increased the expression of the inflammatory cytokines TNF-α, IL-1β, and IL-6. DJ-1 knockdown facilitated the interaction between NLRX1 and TRAF6. However, the loss of DJ-1 attenuated the interaction between SHP-1 and TRAF6. In subsequent experiments, a SHP-1 inhibitor altered the interaction between SHP-1 and TRAF6 and facilitated the interaction between NLRX1 and TRAF6 in DJ-1-overexpressing astrocytes. Conclusion: These findings suggest that DJ-1 exerts an SHP-1-dependent anti-inflammatory effect and induces the dissociation of NLRX1 from TRAF6 during cerebral I/R injury. Thus, DJ-1 may be an efficacious therapeutic target for the treatment of I/R injury.

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DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke

10.21203/rs.2.17665/v2 ◽

2020 ◽

Author(s):

Li Peng ◽

Yang Zhou ◽

Ning Jiang ◽

Tingting Wang ◽

Jin Zhu ◽

...

Keyword(s):

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Reactive Astrocytes ◽

Primary Astrocyte ◽

Tnf Α ◽

Anti Inflammatory ◽

Cerebral Artery Occlusion

Abstract Background : Acute inflammation developed by reactive astrocytes after cerebral ischemia/reperfusion (I/R) injury is important in protecting the resultant lesion. Our previous study demonstrated the abundant expression of DJ-1 in reactive astrocytes after cerebral I/R injury. Here, we show that DJ-1 negatively regulates the inflammatory response by facilitating the interaction between SHP-1 and TRAF6, thereby inducing NLRX1 dissociation from TRAF6. Methods : We used oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro in primary astrocyte cultures and transient middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo to mimic ischemic reperfusion insult. Results: The inhibition of DJ-1 expression increased the expression of the inflammatory cytokines TNF-α, IL-1β, and IL-6. DJ-1 knockdown facilitated the interaction of NLRX1 with TRAF6. However, the loss of DJ-1 attenuated the interaction of SHP-1 with TRAF6. In subsequent experiments, a SHP-1 inhibitor altered the interaction of SHP-1 with TRAF6 and facilitated the interaction of NLRX1 with TRAF6 in DJ-1-overexpressing astrocytes. Conclusion: This finding suggests that DJ-1 exerts a SHP-1-dependent anti-inflammatory effect and induces the dissociation of NLRX1 and TRAF6 in cerebral I/R injury. Thus, DJ-1 may be an efficacious therapeutic target for the treatment of I/R injury.

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LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽

10.1007/s13577-021-00527-x ◽

2021 ◽

Author(s):

Jiaying Zhu ◽

Zhu Zhu ◽

Yipin Ren ◽

Yukang Dong ◽

Yaqi Li ◽

...

Keyword(s):

Cerebral Ischemia ◽

Nuclear Translocation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Mice Model ◽

Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

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Modulator of apoptosis-1 is a potential therapeutic target in acute ischemic injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18794839 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2406-2418 ◽

Cited By ~ 3

Author(s):

Su Jing Chan ◽

Hui Zhao ◽

Kazuhide Hayakawa ◽

Chou Chai ◽

Chong Teik Tan ◽

...

Keyword(s):

Cortical Neurons ◽

Infarct Volume ◽

Neuronal Loss ◽

Ischemic Injury ◽

Glucose Deprivation ◽

Artery Occlusion ◽

In Vivo Models ◽

The Brain

Modulator of apoptosis 1 (MOAP-1) is a Bax-associating protein highly enriched in the brain. In this study, we examined the role of MOAP-1 in promoting ischemic injuries following a stroke by investigating the consequences of MOAP-1 overexpression or deficiency in in vitro and in vivo models of ischemic stroke. MOAP-1 overexpressing SH-SY5Y cells showed significantly lower cell viability following oxygen and glucose deprivation (OGD) treatment when compared to control cells. Consistently, MOAP-1−/− primary cortical neurons were observed to be more resistant against OGD treatment than the MOAP-1+/+ primary neurons. In the mouse transient middle cerebral artery occlusion (tMCAO) model, ischemia triggered MOAP-1/Bax association, suggested activation of the MOAP-1-dependent apoptotic cascade. MOAP-1−/− mice were found to exhibit reduced neuronal loss and smaller infarct volume 24 h after tMCAO when compared to MOAP-1+/+ mice. Correspondingly, MOAP-1−/− mice also showed better integrity of neurological functions as demonstrated by their performance in the rotarod test. Therefore, both in vitro and in vivo data presented strongly support the conclusion that MOAP-1 is an important apoptotic modulator in ischemic injury. These results may suggest that a reduction of MOAP-1 function in the brain could be a potential therapeutic approach in the treatment of acute stroke.

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