Moderate Ethanol Pre-treatment Mitigates ICH-Induced Injury via ER Stress Modulation in Rats

Intracerebral hemorrhage (ICH) is a life-threatening type of stroke that disrupts the normal neurological function of the brain. Clinical studies have reported a non-linear J-shaped association between alcohol consumption levels and the occurrence of cerebral stroke. Specifically, alcohol intoxication increases stroke incidence, while moderate alcohol pre-conditioning decreases stroke frequency and improves outcomes. Although alcohol pre-consumption is likely a crucial player in ICH, the underlying mechanism remains unclear. We performed 1-h alcohol pre-conditioning followed by ICH induction in Sprague-Dawley (SD) rats to investigate the role of alcohol pre-conditioning in ICH. Interestingly, behavioral test analysis found that ethanol intoxication (3 g/kg) aggravated ICH-induced neurological deficits, but moderate ethanol pre-conditioning (0.75 g/kg) ameliorated ICH-induced neurological deficits by reducing the oxidative stress and proinflammatory cytokines release. Moreover, we found that moderate ethanol pretreatment improved the striatal endoplasmic reticulum (ER) homeostasis by increasing the chaperone protein expression and reducing oxidative stress and apoptosis caused by ICH. Our findings show that the mechanism regulated by moderate ethanol pre-conditioning might be beneficial for ICH, indicating the importance of ER homeostasis, oxidative stress, and differential cytokines release in ICH.

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Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01169.2003 ◽

2004 ◽

Vol 286 (6) ◽

pp. H2442-H2451 ◽

Cited By ~ 92

Author(s):

Ikuyo Kusaka ◽

Gen Kusaka ◽

Changman Zhou ◽

Mami Ishikawa ◽

Anil Nanda ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Brain Injury ◽

Cerebral Ischemia ◽

Cerebral Infarction ◽

Focal Cerebral Ischemia ◽

Lipid Hydroperoxide ◽

Neurological Deficits ◽

Sprague Dawley

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT1-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT1-R antagonist candesartan (0.5 mg·kg−1·day−1) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats ( n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91phox and p22phox mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91phox and p22phox mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91phox and p22phox, decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT1-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.

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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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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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Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage

Neurosurgical FOCUS ◽

10.3171/foc.2003.15.4.10 ◽

2003 ◽

Vol 15 (4) ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Takehiro Nakamura ◽

Richard F. Keep ◽

Ya Hua ◽

Timothy Schallert ◽

Julian T. Hoff ◽

...

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Intracerebral Hemorrhage ◽

Brain Edema ◽

Iron Chelator ◽

Iron Accumulation ◽

Neurological Deficits ◽

Sprague Dawley ◽

Autologous Whole Blood ◽

The Right

Object In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. Methods Male Sprague–Dawley rats received an infusion of 100 μl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor–1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis. Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1. Conclusions Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

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Kidney Ischemia-Reperfusion Decreases Hydrogen Sulfide and Increases Oxidative Stress in the Heart

Biomolecules ◽

10.3390/biom10111565 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1565

Author(s):

Charith U. B. Wijerathne ◽

Susara Madduma Hewage ◽

Yaw L. Siow ◽

Karmin O

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Hydrogen Sulfide ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Underlying Mechanism ◽

Sprague Dawley ◽

Increased Risk ◽

H2s Production ◽

Kidney Ischemia

Patients with acute kidney injury (AKI) have an increased risk of cardiovascular disease. The underlying mechanism of AKI-induced heart injury is not well-understood. Hydrogen sulfide (H2S), at physiological concentrations, has been implicated in cardiovascular protection through redox balance and vessel relaxation. Cystathionine gamma-lyase (CSE) plays an essential role in H2S production in the heart. The present study investigated the effect of AKI on H2S production and oxidative stress in the heart. AKI was induced by kidney ischemia-reperfusion in male and female Sprague-Dawley rats, which led to an increase in plasma creatinine and blood urea nitrogen levels. There was a significant increase in lipid peroxidation and a decrease in glutathione (antioxidant) levels in the plasma and heart, indicating systemic and cardiac oxidative stress. Kidney ischemia-reperfusion reduced CSE expression and H2S production in the heart. There was a decrease in antioxidant transcription factor Nrf2 level in the nucleus and an increase in inflammatory cytokine (IL-6, TNF-α) expression in the heart. These results suggest that AKI can down-regulate CSE-mediated H2S production, reduce glutathione levels and increase oxidative stress in the heart. This may contribute to an increased risk of cardiovascular disease in AKI.

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IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5913424 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Shengpeng Liu ◽

Jerry J. Flores ◽

Bo Li ◽

Shuixiang Deng ◽

Gang Zuo ◽

...

Keyword(s):

Blood Clot ◽

Scavenger Receptor ◽

Underlying Mechanism ◽

Neurological Deficits ◽

Long Term Results ◽

Primary Role ◽

Sprague Dawley ◽

Rat Pups ◽

Cd163 Expression ◽

Nrf2 Signaling Pathway

Aims. Blood clots play the primary role in neurological deficits after germinal matrix hemorrhage (GMH). Previous studies have shown a beneficial effect in blood clot clearance after hemorrhagic stroke. The purpose of this study is to investigate interleukin-19’s role in hematoma clearance after GMH and its underlying mechanism of IL-20R1/ERK/Nrf2 signaling pathway. Methods. A total of 240 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. rIL-19 was administered intranasally 1 hour post-GMH. IL-20R1 CRISPR was administered intracerebroventricularly, or Nrf2 antagonist ML385 was administered intraperitoneally 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, immunohistochemistry, histology, and hemoglobin assay were used to evaluate treatment regiments in the short- and long-term. Results. Endogenous IL-19, IL-20R1, IL-20R2, and scavenger receptor CD163 were increased after GMH. rIL-19 treatment improved neurological deficits, reduced hematoma volume and hemoglobin content, reduced ventriculomegaly, and attenuated cortical thickness loss. Additionally, treatment increased ERK, Nrf2, and CD163 expression, whereas IL-20R1 CRISPR-knockdown plasmid and ML385 inhibited the effects of rIL-19 on CD163 expression. Conclusion. rIL-19 treatment improved hematoma clearance and attenuated neurological deficits induced by GMH, which was mediated through the upregulation of the IL-20R1/ERK/Nrf2 pathways. rIL-19 treatment may provide a promising therapeutic strategy for the GMH patient population.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6966394 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Ran Gu ◽

Lu Wang ◽

Hao Zhou ◽

Xike Wang ◽

Cameron Lenahan ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Western Blot ◽

Underlying Mechanism ◽

Immunofluorescence Staining ◽

Neurological Deficits ◽

High Morbidity ◽

Sprague Dawley ◽

Neuroprotective Effects ◽

Bv2 Cells

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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Deletion of MicroRNA-144/451 Cluster Aggravated Brain Injury in Intracerebral Hemorrhage Mice by Targeting 14-3-3ζ

Frontiers in Neurology ◽

10.3389/fneur.2020.551411 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaohong Wang ◽

Yin Hong ◽

Lei Wu ◽

Xiaochun Duan ◽

Yue Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Intracerebral Hemorrhage ◽

Gene Knockout ◽

Underlying Mechanism ◽

Neurological Deficits ◽

Tnf Α ◽

Collagenase Injection ◽

Factor Α ◽

The Brain ◽

Necrosis Factor

This study aims at evaluating the importance and its underlying mechanism of the cluster of microRNA-144/451 (miR-144/451) in the models with intracerebral hemorrhage (ICH). A model of collagenase-induced mice with ICH and a model of mice with simple miR-144/451 gene knockout (KO) were used in this study. Neurodeficits and the water content of the brain of the mice in each group were detected 3 days after collagenase injection. The secretion of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β), as well as certain biomarkers of oxidative stress, was determined in this study. The results revealed that the expression of miR-451 significantly decreased in the mice with ICH, whereas miR-144 showed no significant changes. KO of the cluster of miR-144/451 exacerbated the neurological deficits and brain edema in the mice with ICH. Further analyses demonstrated that the KO of the cluster of miR-144/451 significantly promoted the secretion of TNF-α and IL-1β and the oxidative stress in the perihematomal region of the mice with ICH. In addition, the miR-144/451's depletion inhibited the regulatory axis' activities of miR-451-14-3-3ζ-FoxO3 in the mice with ICH. In conclusion, these data demonstrated that miR-144/451 might protect the mice with ICH against neuroinflammation and oxidative stress by targeting the pathway of miR-451-14-3-3ζ-FoxO3.

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Attenuation of Remifentanil-Induced Hyperalgesia by Betulinic Acid Associates with Inhibiting Oxidative Stress and Inflammation in Spinal Dorsal Horn

Pharmacology ◽

10.1159/000493144 ◽

2018 ◽

Vol 102 (5-6) ◽

pp. 300-306 ◽

Cited By ~ 2

Author(s):

Chang-Cheng Lv ◽

Man-Li Xia ◽

Shu-Juan Shu ◽

Fei Chen ◽

Li-Shan Jiang

Keyword(s):

Oxidative Stress ◽

Dorsal Horn ◽

Betulinic Acid ◽

Spinal Dorsal Horn ◽

Manganese Superoxide Dismutase ◽

Visceral Pain ◽

Sprague Dawley ◽

Spinal Dorsal ◽

Pre Treatment ◽

Factor Α

Remifentanil-induced hyperalgesia (RIH) is known to be associated with oxidative stress and inflammation. Betulinic acid (BA) was reported to reduce visceral pain owing to its anti-oxidative and anti-inflammatory potential. Here, we explored whether BA can attenuate RIH through inhibiting oxidative stress and inflammation in spinal dorsal horn. Sprague-Dawley rats were randomly divided into 4 groups: Control, Incision, RIH, and RIH pre-treated with BA. After pretreated with BA (25 mg/kg, i.g.) for 7 days, rats were subcutaneously infused with remifentanil (40 μg/kg) for 30 min during right plantar incision surgery to induce RIH. The paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), spinal oxidative stress and inflammatory mediators were determined. Intraoperative remifentanil infusion induced postoperative hyperalgesia, as evidenced by the significant decrease in PWMT and PWTL (p < 0.01), and the significant increase in oxidative stress and inflammation evidenced by up-regulations of malondialdehyde, 3-nitrotyrosine, interleukin-1β and tumour necrosis factor-α (p < 0.01) in spinal dorsal horn and matrix metalloproteinase-9 (MMP-9) activity (p < 0.01) in dorsal root ganglion, as well as a decrease in manganese superoxide dismutase activity (p < 0.01) compared with control and incision groups. All these results mentioned above were markedly reversed by pre-treatment with BA (p < 0.01) compared with RIH group. These findings demonstrated that BA can effectively attenuate RIH, which associates with potentially inhibiting oxidative stress and subsequently down-regulating MMP-9-related pro-inflammatory cyokines in spinal dorsal horn.

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Huayu Tongluo Recipe Attenuates Renal Oxidative Stress and Inflammation through the Activation of AMPK/Nrf2 Signaling Pathway in Streptozotocin- (STZ-) Induced Diabetic Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5873007 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yachun Li ◽

Shuai Guo ◽

Fan Yang ◽

Lifei Liu ◽

Zhiqiang Chen

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Total Protein ◽

Inflammatory Markers ◽

Underlying Mechanism ◽

Renal Tissue ◽

Diabetic Rats ◽

Sprague Dawley ◽

Sod Activity ◽

Nrf2 Signaling Pathway

Diabetic nephropathy (DN), a severe microvascular complication of diabetes, is one of the leading causes of end-stage renal disease. Huayu Tongluo Recipe (HTR) has been widely used in the clinical treatment of DN in China, and its efficacy is reliable. This study aimed to explore the renoprotective effect of HTR and the underlying mechanism. Male Sprague-Dawley rats were fed with high sugar and fat diet combined with an intraperitoneal injection of STZ to establish the diabetic model. Rats in each group were respectively given drinking water, HTR, and irbesartan by gavage for 16 weeks. 24-hour urine samples were collected every 4 weeks to detect the content of total protein and 8-OHdG. Blood samples were taken to detect biochemical indicators and inflammatory markers at the end of 16th week. Renal tissue was collected to investigate pathological changes and to detect oxidative stress and inflammatory markers. AMPK/Nrf2 signaling pathway and fibrosis-related proteins were detected by immunohistochemistry, immunofluorescence, real-time PCR, and western blot. 24h urine total protein (24h UTP), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), and triglyceride (TG) were decreased in the rats treated with HTR, while there was no noticeable change of blood glucose. HTR administration decreased malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in kidneys, complying with reduced 8-OHdG in the urine. The levels of TNF-α, IL-1β, and MCP1 and the expression of nuclear NFκB were also lower after HTR treatment. Furthermore, HTR alleviated pathological renal injury and reduced the accumulation of extracellular matrix (ECM). Besides, HTR enhanced the AMPK/Nrf2 signaling and increased the expression of HO-1 while it inhibited the Nox4/TGF-β1 signaling in the kidneys of STZ-induced diabetic rats. HTR can inhibit renal oxidative stress and inflammation to reduce ECM accumulation and protect the kidney through activating the AMPK/Nrf2 signaling pathway in DN.

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