Rh-CXCL-12 Attenuates Neuronal Pyroptosis after Subarachnoid Hemorrhage in Rats via Regulating the CXCR4/NLRP1 Pathway

Subarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides neuroprotective effects, which can alleviate brain injury and inflammation induced by stroke. Previous studies have suggested that CXCR4 reduces the pyroptosis of LPS-stimulated BV2 cells. The purpose of this study was to evaluate the antipyroptosis effects and mechanisms of CXCR4 after SAH. SAH animal model was induced via endovascular perforation. A total of 136 male Sprague-Dawley rats were used. Recombinant human cysteine-X-cysteine chemokine ligand 12 (rh-CXCL-12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitor of CXCR4, AMD3100, was administered intraperitoneally at 1 h before SAH. The neurobehavior tests were assessed, followed by performing Western blot and immunofluorescence staining. The Western blot results suggested that the expressions of endogenous CXCL-12, CXCR4, and NLRP1 were increased and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on neurons, microglia, and astrocytes. Rh-CXCL-12 treatment improved the neurological deficits and reduced the number of FJC-positive cells, IL-18-positive neurons, and cleaved caspase-1(CC-1)-positive neurons after SAH. Meanwhile, rh-CXCL-12 treatment increased the levels of CXCL-12 and CXCR4, and reduced the levels of NLRP1, IL-18, IL-1β, and CC-1. Moreover, the administration of AMD3100 abolished antipyroptosis effects of CXCL-12 and its regulation of CXCR4 post-SAH. The CXCR4/NLRP1 signaling pathway may be involved in CXCL-12-mediated neuronal pyroptosis after SAH. Early administration of CXCL-12 may be a preventive and therapeutic strategy against brain injury after SAH.

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CXCL-12 Attenuates Neuroinflammation via the CXCR4/PI3K/Akt Signaling Pathway in a Rat Model of SAH

10.21203/rs.3.rs-126753/v1 ◽

2020 ◽

Author(s):

Gang Zuo ◽

Ran Gu ◽

Lu Wang ◽

Cameron Lenahan ◽

Hao Qu ◽

...

Keyword(s):

Brain Injury ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Akt Signaling ◽

Immunofluorescence Staining ◽

Neurological Deficits ◽

High Morbidity ◽

Sprague Dawley ◽

Short And Long Term

Abstract BackgroundSubarachnoid hemorrhage (SAH) is a cerebrovascular disease associated with high morbidity and mortality. CXCR4 provides a neuroprotective effect, which can alleviate brain injury and inflammation induced by stroke. The purpose of this study was to evaluate the anti-inflammatory effects and mechanisms of CXCR4 after SAH. Methods: SAH was induced via endovascular perforation. 185 male Sprague-Dawley rats were used. Recombinant human cysteine-X-cysteine chemokine ligand 12 (rh-CXCL-12) was administered intranasally at 1 h after SAH induction. To investigate the underlying mechanism, the inhibitors of CXCR4 and P13K, AMD3100 and LY294002, respectively, were administered intraperitoneally at 1 h before SAH. The short- and long-term neurobehavior were assessed, followed by performing western blot and immunofluorescence staining. ResultsWestern blotting suggested that the expressions of endogenous CXCL-12 and CXCR4 were increased, and peaked at 24 h following SAH. Immunofluorescence staining showed that CXCR4 was expressed on microglia. Rh-CXCL-12 treatment reduced the number of M1 macrophages and improved the short- and long-term neurological deficits after SAH. Meanwhile, rh-CXCL-12 treatment increased the levels of CXCL-12, CXCR4, PI3K, and p-Akt, and reduced the levels of IL-1β, IL-6, and TNF-α. Moreover, the administration of AMD3100 and LY294002 abolished the post-SAH neurobehavioral and neuroinflammatory improvements of CXCL-12 and its regulation of PI3K and p-Akt protein levels.ConclusionsThe CXCR4/PI3K/Akt signaling pathway may be involved in CXCL-12-mediated reduction of post-SAH neuroinflammation. Early administration of CXCL-12 may be a preventive and therapeutic strategy against delayed brain injury after SAH.

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Taurine Protects against Postischemic Brain Injury via the Antioxidant Activity of Taurine Chloramine

Antioxidants ◽

10.3390/antiox10030372 ◽

2021 ◽

Vol 10 (3) ◽

pp. 372

Author(s):

Song-I Seol ◽

Hyun Jae Kim ◽

Eun Bi Choi ◽

In Soon Kang ◽

Hye-Kyung Lee ◽

...

Keyword(s):

Antioxidant Enzymes ◽

Brain Injury ◽

Antioxidant Enzyme ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Neurological Deficits ◽

Heme Oxygenase 1 ◽

Taurine Chloramine ◽

Neuroprotective Effects ◽

Bv2 Cells

Taurine is ubiquitously distributed in mammalian tissues and is highly concentrated in the heart, brain, and leukocytes. Taurine exerts neuroprotective effects in various central nervous system diseases and can suppress infarct formation in stroke. Taurine reacts with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) to produce taurine chloramine (Tau-Cl). We investigated the neuroprotective effects of taurine using a rat middle cerebral artery occlusion (MCAO) model and BV2 microglial cells. Although intranasal administration of taurine (0.5 mg/kg) had no protective effects, the same dose of Tau-Cl significantly reduced infarct volume and ameliorated neurological deficits and promoted motor function, indicating a robust neuroprotective effect of Tau-Cl. There was neutrophil infiltration in the post-MCAO brains, and the MPO produced by infiltrating neutrophils might be involved in the taurine to Tau-Cl conversion. Tau-Cl significantly increased the levels of antioxidant enzymes glutamate–cysteine ligase, heme oxygenase-1, NADPH:quinone oxidoreductase 1, and peroxiredoxin-1 in BV2 cells, whereas taurine slightly increased some of them. Antioxidant enzyme levels were increased in the post-MCAO brains, and Tau-Cl further increased the level of MCAO-induced antioxidant enzymes. These results suggest that the neutrophils infiltrate the area of ischemic injury area, where taurine is converted to Tau-Cl, thus protecting from brain injury by scavenging toxic HOCl and increasing antioxidant enzyme expression.

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Neuroprotective Effects of Magnesium Lithospermate B against Subarachnoid Hemorrhage in Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500647 ◽

2018 ◽

Vol 46 (06) ◽

pp. 1225-1241 ◽

Cited By ~ 1

Author(s):

Yucong Peng ◽

Pingyou He ◽

Linfeng Fan ◽

Hangzhe Xu ◽

Jianru Li ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Salvia Miltiorrhiza ◽

Neurological Deficits ◽

Sprague Dawley ◽

Chinese Medicinal Herb ◽

Neuroprotective Effects ◽

Sprague Dawley Rats ◽

Apoptotic Protein ◽

Magnesium Lithospermate B

Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with few effective pharmacotherapies available. Salvia miltiorrhiza, a traditional Chinese medicinal herb, has been widely used to treat cardiovascular diseases for centuries. Recent studies have demonstrated that magnesium lithospermate B (MLB), a bioactive ingredient extracted from Salvia miltiorrhiza, exerts neuroprotective effects in several central nervous system insults. However, little is known about the role of MLB in SAH-induced brain injury and the exact molecular mechanism. In the current study, we studied the neuroprotective effects of MLB in SAH and explored the potential mechanism. Adult male Sprague–Dawley rats were subjected to an endovascular perforation process to produce an SAH model. MLB was administrated intraperitoneally at 30[Formula: see text]min after SAH with a dose of 25[Formula: see text]mg/kg or 50[Formula: see text]mg/kg. We found that administration of MLB significantly attenuated brain edema and neurological deficits after SAH. In addition, immunofluorescence staining demonstrated that MLB dose-dependently inhibited the activation of microglia and reduced neuronal apoptosis. Western blot analysis showed that MLB decreased the expression of inflammatory cytokine TNF-[Formula: see text] and pro-apoptotic protein cleaved caspase-3. More importantly, MLB increased the expression of SIRT1, while inhibited the acetylation of NF-[Formula: see text]B. Furthermore, pretreatment with sirtinol (a selective inhibitor of SIRT1) reversed all the aforementioned effects of MLB after SAH. In conclusion, our results indicated that MLB exerted robust neuroprotective effects against SAH via suppressing neuroinflammation and apoptosis. These neuroprotective effects of MLB against SAH might be exerted via regulating the SIRT1/NF-[Formula: see text]B pathway. MLB or the SIRT1/NF-[Formula: see text]B pathway could be a novel and promising therapeutic strategy for SAH management.

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Electroacupuncture at GV20 and ST36 Exerts Neuroprotective Effects via the EPO-Mediated JAK2/STAT3 Pathway in Cerebral Ischemic Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/6027421 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Hong Xu ◽

Ya-min Zhang ◽

Hua Sun ◽

Su-hui Chen ◽

Ying-kui Si

Keyword(s):

Tyrosine Kinases ◽

Neuroprotective Effect ◽

Score Test ◽

Underlying Mechanism ◽

Male Rats ◽

Neurological Deficits ◽

Sprague Dawley ◽

Triphenyltetrazolium Chloride ◽

Neuroprotective Effects ◽

Cerebral Ischemic

Background. While electroacupuncture (EA) in cerebral ischemia has been used to promote functional recovery, the underlying mechanism of its protective effect remains poorly understood.Objective. We investigated the effects of EA stimulation at GV20 and ST36 to observe the changes in erythropoietin- (EPO-) mediated Janus family tyrosine kinases 2 (JAK2) signal transducers and activators of the transcription 3 (STAT3) cell pathway.Methods. Thirty-six specific pathogen-free Sprague-Dawley (SD) male rats were randomly assigned to three groups: the sham-operated group (S group), the middle cerebral artery occlusion (MCAO) group (M group), and the EA group. Neurological deficits were assessed through the Ludmila Belayev 12-score test and 2,3,5-triphenyltetrazolium chloride (TTC) staining was shown. The protein and mRNA expression levels of EPO, the EPO receptor (EpoR), p-JAK2, JAK2, p-STAT3, and STAT3 were examined to explore the EA effect on rats with cerebral ischemic reperfusion injury (CIRI).Results. EA significantly decreased infarct size and improved neurological function. Furthermore, target EPO, EpoR, JAK2, and STAT3 mRNA and protein levels significantly increased in the EA group.Conclusions. EA exerts a neuroprotective effect, possibly via the regulation of the EPO-mediated JAK2/STAT3 cell pathway and downstream apoptotic pathways in a rat CIRI model.

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2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats

Cells ◽

10.3390/cells11020242 ◽

2022 ◽

Vol 11 (2) ◽

pp. 242

Author(s):

Chieh-Hsin Wu ◽

Hung-Pei Tsai ◽

Yu-Feng Su ◽

Cheng-Yu Tsai ◽

Ying-Yi Lu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Vasospasm ◽

Neuronal Apoptosis ◽

Neurological Deficits ◽

Neuroprotective Effects ◽

Tnf Α ◽

Amino Phenol ◽

Group 5 ◽

Neuro Inflammation

A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood–brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1β and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway.

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TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-020-03278-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yan Zhou ◽

Tao Tao ◽

Guangjie Liu ◽

Xuan Gao ◽

Yongyue Gao ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Therapeutic Target ◽

Cortical Neurons ◽

Neuronal Apoptosis ◽

Early Brain Injury ◽

Neurological Deficits ◽

Human Brain Tissue

AbstractNeuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

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White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage

Cell Transplantation ◽

10.1177/0963689718812054 ◽

2018 ◽

Vol 28 (1) ◽

pp. 26-35 ◽

Cited By ~ 5

Author(s):

Jinwei Pang ◽

Jianhua Peng ◽

Ping Yang ◽

Li Kuai ◽

Ligang Chen ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

White Matter ◽

Early Brain Injury ◽

Therapeutic Strategies ◽

White Matter Injury ◽

High Morbidity ◽

Normal Brain ◽

Neurological Outcomes ◽

Multiple Substrates

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment.

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Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2016-012925 ◽

2017 ◽

Vol 9 (7) ◽

pp. 659-663 ◽

Cited By ~ 8

Author(s):

Markus Bruder ◽

Sae-Yeon Won ◽

Sepide Kashefiolasl ◽

Marlies Wagner ◽

Nina Brawanski ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Favorable Outcome ◽

Matched Pair ◽

Control Group ◽

High Morbidity ◽

Secondary Brain Injury ◽

Heparin Group ◽

Vasomotor Function

ObjectiveSecondary brain injury leads to high morbidity and mortality rates in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, evidence-based treatment strategies are sparse. Since heparin has various effects on neuroinflammation, microthromboembolism and vasomotor function, our objective was to determine whether heparin can be used as a multitarget prophylactic agent to ameliorate morbidity in SAH.MethodsBetween June 1999 and December 2014, 718 patients received endovascular treatment after rupture of an intracranial aneurysm at our institution; 197 of them were treated with continuous unfractionated heparin in therapeutic dosages after the endovascular procedure. We performed a matched pair analysis to evaluate the effect of heparin on cerebral vasospasm (CVS), cerebral infarction (CI), and outcome.ResultsThe rate of severe CVS was significantly reduced in the heparin group compared with the control group (14.2% vs 25.4%; p=0.005). CI and multiple ischemic lesions were less often present in patients with heparin treatment. These effects were enhanced if patients were treated with heparin for >48 hours, but the difference was not significant. Favorable outcome at 6-month follow-up was achieved in 69% in the heparin group and in 65% in the control group.ConclusionsPatients receiving unfractionated continuous heparin after endovascular aneurysm occlusion have a significant reduction in the rate of severe CVS, have CI less often, and tend to have a favorable outcome more often. Our findings support the potential beneficial effects of heparin as a multitarget therapy in patients with SAH, resulting in an additional ‘H’ therapy in vasospasm treatment.

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IM-12 activates the Wnt–β-catenin signaling pathway and attenuates rtPA-induced hemorrhagic transformation in rats after acute ischemic stroke

Biochemistry and Cell Biology ◽

10.1139/bcb-2018-0384 ◽

2019 ◽

Vol 97 (6) ◽

pp. 702-708 ◽

Cited By ~ 3

Author(s):

Ting Wang ◽

Yu-Mei Duan ◽

Qiao Fu ◽

Tao Liu ◽

Jin-Cheng Yu ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Hemorrhagic Transformation ◽

Neurological Deficits ◽

Control Group ◽

High Morbidity ◽

Sprague Dawley ◽

Gsk 3Β

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt–β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague–Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke, and then were either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood–brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of β-catenin and downstream proteins while suppressing the expression of GSK-3β. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt–β-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.

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Neuroprotective Effects of Bone Marrow Mononuclear Cells Therapy in a Rat Model of Ischemia Stroke

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2256 ◽

2020 ◽

Vol 10 (3) ◽

pp. 346-351

Author(s):

Jianfeng Liu ◽

Yamei Hu ◽

Gang Li ◽

Qianlin Zhang ◽

Jiewen Zhang

Keyword(s):

Bone Marrow ◽

Caspase 3 ◽

Mononuclear Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neurological Deficits ◽

Bone Marrow Mononuclear Cells ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Rat Models

Objective: Bone marrow mononuclear cells (BMMCs) are considered a potential approach to promote the recovery of stroke-induced neurological deficit. However, the exact mechanism of BMMCs in nerve function recovery is still unclear. Methods: Adult Sprague-Dawley (SD) rat models of cerebral ischemia-reperfusion injury was established by using thread method. BMMCs were transplanted into rat models. Neurological deficits were evaluated by Longa score scale. Immunohistochemistry assay were employed to examine the expression of GFAP and Nogo-A around the ischemic foci in the right frontal lobe. Caspase-3 activity was examined by Western Blot. Results: Rats in BMMCs group had lessened neurological deficits and cleaved Caspase-3 expression on day 21 after reper-fusion, as well as higher expression of GFAP [(37.62±2.45) vs. (27.62±1.69) and (38.00±1.85) vs. (27.25±1.83), P < 0.05] and lower expression of Nogo-A [(28.88±2.64) vs. (32.50±1.60) and (23.87±2.36) vs. (32.00±1.85), P < 0.05] on day 14 and 21 after reperfusion. Meanwhile, the expression of Nogo-A on day 21 was lower than that on day 14 after reperfusion [(23.87±2.36) vs. (28.88±2.64), P < 0.05] in BMMCs group. Conclusion: These findings suggested that BMMCs treatment could improve the functional recovery of neurological deficits in rats with MCAO, which was probably related to enhanced expression of GFAP and reduced Nogo-A expression and Caspase-3 activity in the ischemic brain tissues.

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