Long Course Hyperbaric Oxygen Stimulates Neurogenesis and Attenuates Inflammation after Ischemic Stroke

Several studies have provided evidence with regard to the neuroprotection benefits of hyperbaric oxygen (HBO) therapy in cases of stroke, and HBO also promotes bone marrow stem cells (BMSCs) proliferation and mobilization. This study investigates the influence of HBO therapy on the migration of BMSCs, neurogenesis, gliosis, and inflammation after stroke. Rats that sustained transient middle cerebral artery occlusion (MCAO) were treated with HBO three weeks or two days. The results were examined using a behavior test (modified neurological severity score, mNSS) and immunostaining to evaluate the effects of HBO therapy on migration of BMSCs, neurogenesis, and gliosis, and expression of neurotrophic factors was also evaluated. There was a lower mNSS score in the three-week HBO group when compared with the two-day HBO group. Mobilization of BMSCs to an ischemic area was more improved in long course HBO treatments, suggesting the duration of therapy is crucial for promoting the homing of BMSCs to ischemic brain by HBO therapies. HBO also can stimulate expression of trophic factors and improve neurogenesis and gliosis. These effects may help in neuronal repair after ischemic stroke, and increasing the course of HBO therapy might enhance therapeutic effects on ischemic stroke.

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Abstract WP134: 3K3A-APC Protects Pericyte-deficient Mice From Ischemic Brain Injury

Stroke ◽

10.1161/str.51.suppl_1.wp134 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yaoming Wang ◽

Mikko Huuskonen ◽

Axel Montagne ◽

Berislav Zlokovic

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Activated Protein C ◽

Artery Occlusion ◽

Ischemic Brain Injury ◽

Neuroprotective Effects ◽

Ischemic Brain ◽

Functional Deficits ◽

Favorable Safety ◽

Cerebral Artery Occlusion

Pericytes play a key role in maintaining the blood-brain barrier (BBB) integrity. BBB disruption occurs during early stages after ischemic stroke. However, the role of pericytes in the pathogenesis of ischemic stroke remains still understudied. 3K3A-APC, a recombinant variant of activated protein C, has shown benefits in preclinical models of ischemic stroke and has favorable safety profile and reduces hemorrhage in Phase 2 study in ischemic stroke patients (RHAPSODY). In the present study, we used PDGFRβ heterozygous knockout (PDGFRβ+/-) mice to investigate the effects of pericyte deficiency on ischemic brain injury using transient proximal middle cerebral artery occlusion (tMCAO). Additionally, we investigated the effects of 3K3A-APC therapy (0.2mg/kg i.v. 4h after stroke) in this model. Compared to controls, pericyte deficiency in PDGFRβ+/- mice resulted in ~35% increase in the infarct and edema volumes, reduction in pericyte coverage from 58% to 25%, and increased IgG and fibrin deposition suggesting accelerated BBB breakdown 24h after stroke. Additionally, PDGFRβ+/- mice showed by 36% more degenerating Fluoro-Jade+ neurons and exhibited accelerated neurobehavioral abnormalities. 3K3A-APC improved neuropathological changes and functional deficits. Our results suggest that pericyte deficiency worsens brain damage and functional outcome after ischemic stroke in mice suggesting that pericytes may play an important role in protecting brain from post-ischemic. We also suggests that 3K3A-APC protects pericyte function in stroked mice which could contribute to its overall neuroprotective effects.

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Silencing of lncRNA XLOC_035088 Protects Middle Cerebral Artery Occlusion-Induced Ischemic Stroke by Notch1 Signaling

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa129 ◽

2020 ◽

Vol 80 (1) ◽

pp. 60-70

Author(s):

Miao Chen ◽

Feng Wang ◽

Hairong Wang

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Hippocampal Neurons ◽

Artery Occlusion ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Cerebral Artery Occlusion

Abstract Ischemic stroke represents one of the leading causes of mortality worldwide and especially in developing countries. It is crucial for finding effective therapeutic targets that protect the brain against ischemic injury. Long noncoding RNAs (lncRNAs) have emerged as major regulators of neurological diseases, and clarifying their roles in cerebral ischemic injury may provide novel targets for the treatment of ischemic stroke. We aimed to investigate the role of lncRNA-XLOC_035088 in middle cerebral artery occlusion (MCAO)-induced rat brain injury and oxygen-glucose deprivation (OGD)-reperfusion treated hippocampal neurons. In our findings, we found that XLOC_035088 expression was significantly upregulated in OGD-reperfusion treated hippocampal neurons and in different brain regions of MCAO-treated rats. XLOC_035088 silencing protected against MCAO-induced ischemic brain injury in vivo and OGD-induced hippocampal neuronal apoptosis in vitro. Intrahippocampal silencing of XLOC_035088 significantly decreased brain XLOC_035088 expression, reduced brain infarct size, and improved neurological function through inhibiting NOTCH1 following derepression of presenilin 2 (PSEN2). Taken together, this study provides evidence that the lncRNA XLOC_035088/PSEN2/Notch1 axis is involved in the pathogenesis of ischemic brain injury, and presents a promising therapeutic route for ischemic stroke.

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Phospholipase D1 and D2 Synergistically Regulate Thrombus Formation

International Journal of Molecular Sciences ◽

10.3390/ijms21186954 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6954

Author(s):

Li-Ming Lien ◽

Wan-Jung Lu ◽

Ting-Yu Chen ◽

Tzu-Yin Lee ◽

Hsueh-Hsiao Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Thrombus Formation ◽

Artery Occlusion ◽

Pulmonary Thrombosis ◽

Neurological Severity Score ◽

Phospholipase D1 ◽

Redundant Functions ◽

Cerebral Artery Occlusion ◽

Increase Survival Rate

Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.

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Platelet lysates stimulate angiogenesis, neurogenesis and neuroprotection after stroke

Thrombosis and Haemostasis ◽

10.1160/th12-11-0875 ◽

2013 ◽

Vol 110 (08) ◽

pp. 323-330 ◽

Cited By ~ 22

Author(s):

Yael Hayon ◽

Olga Dashevsky ◽

Ela Shai ◽

David Varon ◽

Ronen Leker

Keyword(s):

Subventricular Zone ◽

Tissue Repair ◽

Artery Occlusion ◽

Therapeutic Effects ◽

Brain Ischaemia ◽

Neuroprotective Effects ◽

Lateral Ventricles ◽

Neurological Severity Score ◽

Ischaemic Brain ◽

Cerebral Artery Occlusion

SummaryPlatelets contain chemo-attractants and mitogens that have a major role in tissue repair. Therefore we hypothesised that tissue regeneration secondary to activation of endogenous neural stem cells (eNSC) can be enhanced by delivering platelets to the ischaemic brain. To examine these potential therapeutic effects we injected platelet-poor plasma (PPP), fibroblast growth factor (FGF2) and platelet lysate (PLT) to the lateral ventricles after permanent middle cerebral artery occlusion (PMCAO) in rats. The animals were tested with the neurological severity score, and infarct volumes were measured at 90 days post–PMCAO. Immunohistochemistry was used to determine the fate of newborn cells and to count blood vessels in the ischaemic brain. Platelets significantly increased eNSC proliferation and angiogenesis in the subventricular zone (SVZ) and in the peri-lesion cortex. Functional outcome was significantly improved and injury size was significantly reduced in rats treated with PLT suggesting additional neuroprotective effects. In conclusion, local delivery of PLT to the lateral ventricles induces angiogenesis, neurogenesis and neuroprotection and reduces behavioural deficits after brain ischaemia.

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Hyperglycemia primes NETosis, which exacerbates ischemic brain damage

10.21203/rs.2.18044/v1 ◽

2019 ◽

Author(s):

Jiangshan Deng ◽

Fei Zhao ◽

Yunlong Zhang ◽

Yajun Zhou ◽

Xiaofeng Xu ◽

...

Keyword(s):

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Brain Damage ◽

Artery Occlusion ◽

Wild Type ◽

Stroke Patients ◽

Acute Hyperglycemia ◽

Ischemic Brain ◽

Infarction Volume ◽

Cerebral Artery Occlusion

Abstract Background：Hyperglycemia is common and associated with poor outcomes in acute ischemic stroke patients. It is not well understood how hyperglycemia exacerbates brain damage in ischemic stroke. Neutrophil extracellular traps (NETs) have shown an emerging role in noninfectious diseases. We aimed to determine the role of NETs in acute ischemic stroke with hyperglycemia. Methods: NETs were immunostained using NET markers (citrullinated histone H3 (H3Cit)) and quantified in thrombi retrieved from ischemic stroke patients undergoing endovascular treatment. BKS-db/db and wild-type mice were used to establish the permanent middle cerebral artery occlusion (pMCAO) model. Wild-type mice were injected with glucose to simulate acute hyperglycemia after middle cerebral artery occlusion. NETs were detected in the peri-ischemic brain tissue. After inhibition of NET formation, infarction volume, neurological function and inflammatory factors in pMCAO mice were evaluated. Results: H3Cit, a marker of NETs, was observed in almost all thrombi. H3Cit was much more abundant in thrombi from diagnosed diabetic patients and acute hyperglycemic patients compared with those in normglycemic patients. In pMCAO mice, NETs were induced by chronic diabetes and acute hyperglycemia. Inhibition of NET formation with the peptidylarginine deiminase 4 (PAD4) inhibitor Cl-amidine decreased the infarction volume both in db/db and wild-type mice with hyperglycemia. Neurological function deficits were alleviated by blocking NET formation, as shown in the grip strength and rotarod tests. The levels of TNF-α and IL-1β but not IL-6 coincided with NET formation. Conclusions: Hyperglycemia may exacerbate brain damage in ischemic stroke through NETs. The underlying mechanisms deserve to be further studied.

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Abstract TP77: New treatment

Stroke ◽

10.1161/str.48.suppl_1.tp77 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Munehisa Shimamura ◽

Hironori Nakagami ◽

Kouji Wakayama ◽

Tomohiro Kawano ◽

Hideki Mochizuki ◽

...

Keyword(s):

Infarct Volume ◽

Artery Occlusion ◽

Therapeutic Effects ◽

Systemic Injection ◽

Ischemic Brain ◽

Trap Staining ◽

Osteoclast Activation ◽

New Treatment ◽

Cerebral Artery Occlusion ◽

Radial Bone

Background and purpose: We previously showed that stimulation of RANKL (receptor activator of nuclear factor-B ligand)/ RANK (receptor for RANKL) signal with novel RANKL-based partial peptide, MHP1, worked as anti-inflammatory in microglia and macrophages without induction of osteoclast activation, but the effects of systemic injection of MHP1 in ischemic brain is still unclear. Here, we examined the effects of systemically injected MHP1 in ischemic brain. Methods: FITC-conjugated MHP1 was injected via jugular vein 4 hrs after transient middle cerebral artery occlusion (tMCAo) in C57BL6J mice to check whether MHP1 could penetrate into infarct parenchyma. To examine whether MHP1 has therapeutic effects, MHP1 was injected intravenously (IV) followed by successive subcutaneous injection with Alzet pump beginning at 4 or 6 hrs after tMCAo. The effects of MHP1 for osteoclast activation in the radial bone in paralyzed upper arm were examined by TRAP staining. Results: Immunohistochemistry for FITC showed that MHP1 could successfully penetrated into infarct parenchyma 5 min after IV injection of MHP1, but the penetrated MHP1 was not observed 1 hr after injection. These results indicated that MHP1 should be administered continuously to achieve successive penetration into infarct parenchyma. The mice treated with MHP1 showed less neurological severity score and infarct volume at 48 hrs after tMCAo even when the treatment was started at 6 hrs after MCAo. TRAP staining showed that osteoclast activation in paralyzed radial bone was inhibited in MHP1-treated mice, suggesting that MHP1 could prevent osteoclast activation as well as ischemic injury. Conclusion: Systemically injected MHP1 could successfully penetrated into infarct parenchyma and prevent exacerbation of paralysis and infarct size after tMCAo. Although further studies for improvement of its stability are needed, MHP1 might be a novel agent to treat ischemic brain.

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A Microarray Study of Middle Cerebral Occlusion Rat Brain with Acupuncture Intervention

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/496932 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Chao Zhang ◽

Yan Wen ◽

Xiaonong Fan ◽

Sha Yang ◽

Guang Tian ◽

...

Keyword(s):

Ischemic Stroke ◽

Rat Brain ◽

Microarray Analysis ◽

Quantitative Polymerase Chain Reaction ◽

Artery Occlusion ◽

Pathological Process ◽

Ischemic Brain ◽

Acupuncture Intervention ◽

Polymerase Chain ◽

Cerebral Artery Occlusion

Microarray analysis was used to investigate the changes of gene expression of ischemic stroke and acupuncture intervention in middle cerebral artery occlusion (MCAo) rat brain. Results showed that acupuncture intervention had a remarkable improvement in neural deficit score, cerebral blood flow, and cerebral infarction volume of MCAo rats. Microarray analysis showed that a total of 627 different expression genes were regulated in ischemic stroke. 417 genes were upregulated and 210 genes were downregulated. A total of 361 different expression genes were regulated after acupuncture intervention. Three genes were upregulated and 358 genes were downregulated. The expression of novel genes after acupuncture intervention, includingTph1andOlr883, was further analyzed by Real-Time Quantitative Polymerase Chain Reaction (RT-PCR). Upregulation ofTph1and downregulation ofOlr883indicated that the therapeutic effect of acupuncture for ischemic stroke may be closely related to the suppression of poststroke depression and regulation of olfactory transduction. In conclusion, the present study may enrich our understanding of the multiple pathological process of ischemic brain injury and indicate possible mechanisms of acupuncture on ischemic stroke.

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Endothelial S1P 1 Signaling Counteracts Infarct Expansion in Ischemic Stroke

Circulation Research ◽

10.1161/circresaha.120.316711 ◽

2020 ◽

Author(s):

Anja Nitzsche ◽

Marine Poittevin ◽

Ammar Benarab ◽

Philippe Bonnin ◽

Giuseppe Faraco ◽

...

Keyword(s):

Ischemic Stroke ◽

Protective Role ◽

Artery Occlusion ◽

Spatial Modulation ◽

Ischemic Brain ◽

Cerebrovascular Function ◽

Sphingosine 1 Phosphate ◽

Infarct Expansion ◽

Transient Models ◽

Cerebral Artery Occlusion

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular-protective pathways may provide therapeutic targets for neurological disorders. Sphingosine 1-phosphate (S1P) signaling coordinates vascular functions in other organs, and S1P receptor-1 (S1P 1 ) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P 1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P 1 modulation in stroke. Objective: To address roles and mechanisms of engagement of endothelial cell (EC) S1P 1 in the naïve and ischemic brain and its potential as a target for cerebrovascular therapy. Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P 1 in the mouse brain. With an S1P 1 signaling reporter, we reveal that abluminal polarization shields S1P 1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar ECs. S1P 1 signaling sustains hallmark endothelial functions in the naïve brain, and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by EC-selective deficiency in S1P production, export, or the S1P 1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P 1 provides modest protection only in the context of reperfusion. In the ischemic brain, EC S1P 1 supports blood-brain barrier (BBB) function, microvascular patency, and the rerouting of blood to hypo-perfused brain tissue through collateral anastomoses. Selective S1P 1 agonism counteracts cortical infarct expansion after middle cerebral artery occlusion by engaging the endothelial receptor pool after BBB penetration. Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with BBB-penetrating S1P 1 agonists.

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GC-MS-Based Metabolomics to Reveal the Protective Effect of Gross Saponins of Tribulus terrestris Fruit against Ischemic Stroke in Rat

Molecules ◽

10.3390/molecules24040793 ◽

2019 ◽

Vol 24 (4) ◽

pp. 793 ◽

Cited By ~ 5

Author(s):

Yang Wang ◽

Hongyu Zhao ◽

Yue Liu ◽

Wenjun Guo ◽

Yanru Bao ◽

...

Keyword(s):

Ischemic Stroke ◽

Protective Effect ◽

Human Life ◽

Artery Occlusion ◽

Tribulus Terrestris ◽

Therapeutic Effects ◽

Triphenyltetrazolium Chloride ◽

Fatty Acids Metabolism ◽

Neuroprotective Treatment ◽

Cerebral Artery Occlusion

Stroke is one of the most common neurological disorders and seriously threatens human life. Gross saponins of Tribulus terrestris fruit (GSTTF) are used for neuroprotective treatment on convalescents of ischemic stroke. However, the therapeutic effects and mechanisms have not yet well understood, especially from the metabolic perspective. In this study, the protective effect of GSTTF on ischemic stroke in a middle cerebral artery occlusion (MCAO) rat model was investigated by the GC-MS-based metabolomics approach. 2,3,5-triphenyltetrazolium chloride (TTC) staining of brain tissues showed that GSTTF significantly reduced the infarct area after MCAO surgery. Metabolomic profiling showed a series of metabolic perturbation occurs in ischemic stroke compared with sham group. GSTTF can reverse the MCAO-induced serum metabolic deviations by regulating multiple metabolic pathways including fatty acids metabolism, amino acids metabolism, and carbohydrates metabolism. The current study provided a useful approach for understanding the mechanism of MCAO-induced ischemic stroke and a reliable basis for evaluating the efficacy of GSTTF in the treatment of ischemic stroke.

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Antineuroinflammatory effects of dl-3-n-butylphthalide conferred by stimulation of Foxp3 and Ki-67 in an ischemic stroke model

10.21203/rs.3.rs-22724/v1 ◽

2020 ◽

Author(s):

Xi Liu ◽

Runzhe Liu ◽

Dongxu Fu ◽

Hao Wu ◽

Xin Zhao ◽

...

Keyword(s):

Ischemic Stroke ◽

Artery Occlusion ◽

Neurological Deficits ◽

Stroke Model ◽

Ki 67 ◽

Ischemic Brain ◽

Caspase 1 ◽

And Function ◽

Cerebral Artery Occlusion ◽

First Time

Abstract Background Dl-3-n-butylphthalide (NBP) has been widely used for the treatment of ischemic stroke in China. However, its mechanisms of action have not been fully elucidated. Methods We established a permanent middle cerebral artery occlusion (pMCAO) rat model and administered 4 mg/kg/d NBP by tail vein injection for 9 days. Changes in some molecules related to neuroinflammation, neovascularization and nerve regeneration were observed, such as MALDI-TOF MSI to study the distribution of phospholipids in the brain, LA-ICP MSI to observe the changes of Foxp3, Ki-67 and pCREB, immunohistochemistry to investigate NLRP3 and its downstream inflammatory products Caspase-1 and IL-1β. Results These results showed that NBP attenuated ischemic damage in pMCAO rats, accompanied by improving neurological deficits. It was revealed for the first time in an animal stroke model that NBP decreased the levels of PE (18:0), NLRP3, Caspase-1 and IL-1β, while increasing the levels of several phospholipids, such as PA (16:0/18:1), PA (18:0/22:6), PE (16:0/22:6), PE (P-18:0/22:6), PE (18:0/22:6), PS (18:0/22:6), PI (18:0/20:4), Foxp3, Ki-67 and pCREB, in the ischemic brain region. Conclusion These results provide evidence that NBP can reduce neuroinflammation in brain tissue and promote the regeneration of nerves and blood vessels, thus exerting a protective effect on neuromorphology and function.

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