lncRNA H19 Aggravates Brain Injury in Rats following Experimental Intracerebral Hemorrhage via NF-κB Pathway

Objective. To explore the effect of long noncoding RNA H19 (lncRNA H19) on brain injury in rats following experimental intracerebral hemorrhage (ICH). Methods. Rat ICH model was established with type IV collagenase. The neurological function scores were evaluated, and the water content in brain tissue was measured. The nerve injury indexes, inflammatory factors, and oxidative stress indexes were also measured. Moreover, the expression of lncRNA H19 was determined by qRT-PCR, and Western blot detected NF-κB pathway-related protein expression. Results. Compared with the sham group, the neurological function scores, the water content in brain tissue, and levels of injury indicators myelin basic protein (MBP), S-100B, and neuron-specific enolase (NSE) in the ICH rats were significantly increased. Meanwhile, the levels of TNF-α, IL-6, IL-1β, ROS, and MDA were significantly increased, but the levels of SOD were significantly decreased. In addition, the expression of lncRNA H19 in the brain tissue in the ICH group was significantly higher than that in the sham group. After further interference with lncRNA H19 expression (sh-H19 group), the levels of all the above indicators were reversed and the neurological damage was improved. Western blot results showed that the expression of NF-κBp65 and IKKβ was significantly higher, and IκBα expression was lower in the perivascular hematoma tissue in the ICH group compared with the sham group. Compared with the sh-NC group, NF-κBp65 and IKKβ expression were significantly lower and IκBα was significantly higher in the sh-H19 group. Conclusion. lncRNA H19 exacerbated brain injury in rats with ICH by promoting neurological impairment, brain edema, and releasing inflammatory responses and oxidative stress. This may be related to the activation of NF-κB signaling pathway.

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17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

ASN NEURO ◽

10.1177/17590914211038443 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110384

Author(s):

Han Xiao ◽

Jianyang Liu ◽

Jialin He ◽

Ziwei Lan ◽

Mingyang Deng ◽

...

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Mouse Model ◽

Intracerebral Hemorrhage ◽

Signaling Pathway ◽

Brain Edema ◽

Akt Signaling ◽

Neurological Deficits ◽

Akt Signaling Pathway ◽

And Oxidative Stress

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood–brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

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Depleting SOX2 improves ischemic stroke via lncRNA PVT1/microRNA-24-3p/STAT3 axis

Molecular Medicine ◽

10.1186/s10020-021-00346-8 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Zhongjun Chen ◽

Tieping Fan ◽

Xusheng Zhao ◽

Zhichen Zhang

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Brain Injury ◽

Water Content ◽

Artery Occlusion ◽

Neurological Deficits ◽

Neuron Survival ◽

Non Coding Rna ◽

Cerebral Artery Occlusion ◽

And Oxidative Stress

Abstract Objectives Studies have widely explored in the filed of ischemic stroke (IS) with their focus on transcription factors. However, few studies have pivoted on sex determining region Y-box 2 (SOX2) in IS. Thus, this study is launched to figure out the mechanisms of SOX2 in IS. Methods Rat middle cerebral artery occlusion (MCAO) was established as a stroke model. MCAO rats were injected with depleted SOX2 or long non-coding RNA plasmacytoma variant translocation 1 (PVT1) to explore their roles in neurological deficits, cerebral water content, neuron survival, apoptosis and oxidative stress. The relationship among SOX2, PVT1, microRNA (miR)-24-3p and signal transducer and activator of transcription 3 (STAT3) was verified by a series of experiments. Results SOX2, PVT1 and STAT3 were highly expressed while miR-24-3p was poorly expressed in cerebral cortex tissues of MCAO rats. Depleted SOX2 or PVT1 alleviated brain injury in MCAO rats as reflected by neuronal apoptosis and oxidative stress restriction, brain water content reduction, and neurological deficit and neuron survival improvements. Overexpression of PVT1 functioned oppositely. Restored miR-24-3p abolished PVT1 overexpression-induced brain injury in MCAO rats. SOX2 directly promoted PVT1 expression and further increased STAT3 by sponging miR-24-3p. Conclusion This study presents that depleting SOX2 improves IS via PVT1/miR-24-3p/STAT3 axis which may broaden our knowledge about the mechanisms of SOX2/PVT1/miR-24-3p/STAT3 axis and provide a reference of therapy for IS.

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Protective effects of epifriedelinol in a rat model of traumatic brain injury assessed with histological and hematological markers

Translational Neuroscience ◽

10.1515/tnsci-2018-0008 ◽

2018 ◽

Vol 9 (1) ◽

pp. 38-42 ◽

Cited By ~ 1

Author(s):

Shiping Li ◽

Qiaoying Zhang ◽

Peiwu Li

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Water Content ◽

Rat Model ◽

Protective Effects ◽

Hematological Markers ◽

Cytokine Levels ◽

Factor Α ◽

And Oxidative Stress

Abstract Background This study evaluated the protective effects of epifriedelinol (EFD) in a rat model of traumatic brain injury (TBI). Methodology TBI was induced by dropping a weight from a specific height. The animals were separated into control, TBI, and EFD 100 and 200 mg/kg groups. The latter received 100 and 200 mg/kg EFD, respectively, for 2 days beginning 30 min after inducing TBI. The neurological examination score, permeability of the blood–brain barrier (BBB), water content of the brain, cytokine levels, and oxidative stress parameters were measured in the rats. The effects of EFD on glial fibrillary acidic protein (GFAP)-positive cells were evaluated using immunohistochemistry. ResultThe EFD treatment significantly decreased the neurological score, permeability of the BBB, and water content of brain compared with the TBI group. The levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and oxidative stress were significantly decreased in the EFD-treated groups. The number of GFAP-positive cells was also significantly reduced in the EFD-treated groups. ConclusionEFD attenuates the secondary injury in TBI rats by reducing the serum cytokine levels and oxidative stress.

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Protective effects of quercetin on traumatic brain injury induced inflammation and oxidative stress in cortex through activating Nrf2/HO-1 pathway

Restorative Neurology and Neuroscience ◽

10.3233/rnn-201119 ◽

2021 ◽

Vol 39 (1) ◽

pp. 73-84

Author(s):

Jianqiang Song ◽

Guoliang Du ◽

Haiyun Wu ◽

Xiangliang Gao ◽

Zhen Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Western Blot ◽

Inflammatory Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Heme Oxygenase 1 ◽

The Brain ◽

And Oxidative Stress ◽

Quercetin Treatment

Background: Traumatic brain injury (TBI) has been a serious public health issue. Clinically, there is an urgent need for agents to ameliorate the neuroinflammation and oxidative stress induced by TBI. Our previous research has demonstrated that quercetin could protect the neurological function. However, the detailed mechanism underlying this process remains poorly understood. Objective: This research was designed to investigate the mechanisms of quercetin to protect the cortical neurons. Methods: A modified weight-drop device was used for the TBI model. 5, 20 or 50 mg/kg quercetin was injected intraperitoneally to rats at 0.5, 12 and 24 h post TBI. Rats were sacrificed three days post injury and their cerebral cortex was obtained from the injured side. The rats were randomly assigned into three groups of equal number: TBI and quercetin group, TBI group, and Sham group. The brain water content was calculated to estimate the brain damage induced by TBI. Immunohistochemical and Western blot assays were utilized to investigate the neurobehavioral status. Enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction were performed to evaluate the inflammatory responses. The cortical oxidative stress was measured by estimating the activities of malondialdehyde, superoxide dismutase, catalase and glutathione-Px. Western blot was utilized to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1). Results: Quercetin attenuated the brain edema and microgliosis in TBI rats. Quercetin treatment attenuated cortical inflammatory responses and oxidative stress induced by TBI insults. Quercetin treatment activated the cortical Nrf2/HO-1 pathway in TBI rats. Conclusions: Quercetin ameliorated the TBI-induced neuroinflammation and oxidative stress in the cortex through activating the Nrf2/HO-1 pathway.

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RNF34 overexpression exacerbates neurological deficits and brain injury in a mouse model of intracerebral hemorrhage by potentiating mitochondrial dysfunction-mediated oxidative stress

Scientific Reports ◽

10.1038/s41598-019-52494-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Xin Qu ◽

Ning Wang ◽

Wenjin Chen ◽

Meng Qi ◽

Yueqiao Xue ◽

...

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Transgenic Mice ◽

Intracerebral Hemorrhage ◽

Mitochondrial Dysfunction ◽

Neuronal Activity ◽

Neurological Deficits ◽

Protein Ubiquitination ◽

Stress Levels ◽

And Oxidative Stress

Abstract Intracerebral hemorrhage (ICH) is a common neurological condition associated with high disability and mortality. Alterations in protein ubiquitination have emerged as a key mechanism in the pathogenesis of neurological diseases. Here, we investigated the effects of the E3 ubiquitin ligase ring finger protein 34 (RNF34) on neurological deficits and brain injury in ICH mice. An ICH model was established via intracerebral injection of autologous blood into wild-type and RNF34 transgenic mice. Brain injury, neurological function, neuronal activity, and oxidative stress levels were measured, respectively. The underlying mechanisms were explored by molecular and cellular approaches. Our results showed that RNF34 overexpression in mice significantly aggravated the ICH-induced memory impairment, brain edema, infarction, hematoma volume, and loss of neuronal activity. RNF34 and oxidative stress levels gradually increased from 6 to 48 h after the ICH challenge and were positively correlated. The ICH-induced increase in intracellular ROS, superoxide anion, and mROS generation and the decrease in adenosine triphosphate production were exacerbated in RNF34 transgenic mice, but NADPH oxidase activity was unaffected. Moreover, RNF34 upregulation potentiated the ICH-induced decrease in PGC-1α, UCP2, and MnSOD expressions. RNF34 interacted with PGC-1α and targeted it for ubiquitin-dependent degradation. This study reveals that RNF34 exacerbates neurological deficits and brain injury by facilitating PGC-1α protein degradation and promoting mitochondrial dysfunction-mediated oxidative stress.

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Mechanism of Baicalein in Brain Injury After Intracerebral Hemorrhage by Inhibiting the ROS/NLRP3 Inflammasome Pathway

10.21203/rs.3.rs-609350/v1 ◽

2021 ◽

Author(s):

Xuan Chen ◽

Yue Zhou ◽

Shanshan Wang ◽

Wei Wang

Keyword(s):

Oxidative Stress ◽

Brain Injury ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Nlrp3 Inflammasome ◽

Inflammatory Factors ◽

Brain Water Content ◽

Ros Scavenger ◽

The Brain ◽

Brain Water

Abstract Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high disability/mortality. Baicalein has strong anti-inflammatory activity. This study aims to explore the mechanism of baicalein on brain injury after ICH. The model of brain injury after ICH was established by collagenase induction, followed by the evaluation of neurological severity, brain water content, the degenerated neurons, neuronal apoptosis and reactive oxygen species (ROS). The ICH model was treated with baicalein and silencing NLRP3 to detect brain injury. The expression of NLRP3 inflammasome was detected after treatment with ROS scavenger. The expression of oxidative stress markers and inflammatory factors were detected, and the levels of components in NLRP3 inflammasome were detected. Baicalein reduced the damage of nervous system, lesion surface, brain water content and apoptosis. Baicalein inhibited malondialdehyde and increased IL-10 by inhibiting ROS in brain tissue after ICH. Baicalein inhibited the high expression of NLRP3 inflammasome in ICH. ROS scavenger inhibited the NLRP3 inflammatory response by inhibiting ROS levels. Silencing NLRP3 alleviated the brain injury after ICH by inhibiting excessive oxidative stress and inflammatory factors. Overall, baicalein alleviated the brain injury after ICH by inhibiting ROS and NLRP3 inflammasome.

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Protective Effect of miR-340-5p against Brain Injury after Intracerebral Hemorrhage by Targeting PDCD4

Cerebrovascular Diseases ◽

10.1159/000508210 ◽

2020 ◽

Vol 49 (6) ◽

pp. 593-600

Author(s):

Wei Zhou ◽

Guandong Huang ◽

Jueming Ye ◽

Jiamei Jiang ◽

Qing Xu

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Target Gene ◽

Neurological Function ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Tnf Α ◽

Gene Assay ◽

The Brain

Objective: Intracerebral hemorrhage (ICH) is a common cerebrovascular disease. Increasing evidence has documented the crucial role of microRNAs in ICH. The present study aimed to investigate the role and underlying mechanism of miR-340-5p in ICH. Methods: The collagenase-induced ICH rat model was established. The neurological function of rats and the cerebral water content of rat brain tissue were measured to assess the brain injury. BV-2 cells were recruited and treated by LPS to mimic ICH-induced inflammatory response. qRT-PCR was used for the measurement of miR-340-5p. The protein levels of TNF-α, IL-6, and IL-1β were detected using ELISA. Luciferase reporter gene assay was performed to confirm the target gene. Results: Downregulation of miR-340-5p was detected in the serum of ICH patients and the brain tissues of ICH rats. Overexpression of miR-340-5p reversed the influence of ICH on the neurological function score and cerebral water content and inhibited the production of proinflammatory cytokines (TNF-α, IL-6, and IL-1β), which were induced by ICH in vivo. In in vitro study, levels of TNF-α, IL-6, and IL-1β were significantly enhanced in cells after LPS treatment, but these increases were eliminated by overexpression of miR-340-5p. PDCD4 was a direct target gene of miR-340-5p. Conclusion: miR-340-5p protects against brain injury after ICH. miR-340-5p might exert an anti-inflammatory effect during the occurrence of ICH via targeting PDCD4.

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Ameliorating Effects of Lithium on the Perinatal Ethanol-Induced Behavioral and Cognitive Dysfunction and Brain Oxidative Stress in Postnatal Developing Mice Pups

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200615170644 ◽

2020 ◽

Vol 21 (13) ◽

pp. 1325-1332

Author(s):

Mohammad Ahmad ◽

Gasem M. Abu Taweel

Keyword(s):

Oxidative Stress ◽

Brain Tissue ◽

Emotional Dysregulation ◽

Learning Capability ◽

Weaning Age ◽

Pregnant Mice ◽

Term Basis ◽

Significant Deficit ◽

Morphological Indices ◽

And Oxidative Stress

Background: Developmental ethanol (EtOH) exposure can cause lifelong behavioral hyperactivity, cognitive deficits, emotional dysregulation, and more. However, co-treatment with lithium (Li) on the day of EtOH exposure prevents many of the impairments. Methods: Experimental groups of pregnant mice were exposed to EtOH (20% v/v solution at a dose of 2.5 g/kg) in their drinking water and the animals were treated with Li (15 and 30 mg/kg) through IP injection on gestational days14, 16, 18, and 20, and post-natal days (PD) 3, 5, 7, and 9. All treatments with EtOH and exposure to Li doses to pregnant mice started on gestational day 14 and continued until post-natal day 9 (PD9). The effects on some developing morphological indices, nerve reflexes during weaning age, and various cognitive dysfunctions at adolescent ages and biochemical changes in the brain tissue indices of below-mentioned neurotransmitters and oxidative stress in post-natal developing offspring at adolescent age, were studied. Results: Perinatal exposure to EtOH in pregnant mice resulted in several postnatal developing and morphological indices in the developing male pups during their weaning period, like gain in their body weight, delay in appearance of their body hair fuzz and opening of their eyes, and disruptions in their developing motor reflexes. Discussion: During adolescent age, a significant deficit in their learning capability and cognitive behavior, decline in the neurochemical DA and 5-HT in their brain and some indices of oxidative stress TBARS, GSH, GST, CAT, and SOD was observed. Conclusion: These results indicate that Li ameliorates significantly and dose-dependently EtOH induced developmental toxicities like morphological developments and dysfunctions in cognitive retention and oxidative stress on a long-term basis in brain tissue. However, further detailed studies are required for the clinical use of as an ameliorating agent for perinatal EtOH induced dysfunctions.

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Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

Translational Neuroscience ◽

10.1515/tnsci-2021-0001 ◽

2020 ◽

Vol 12 (1) ◽

pp. 001-008

Author(s):

Ting Liu ◽

Xing-Zhi Liao ◽

Mai-Tao Zhou

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Western Blot ◽

Water Content ◽

Brain Edema ◽

Rat Model ◽

Neurosurgical Procedures ◽

Brain Water Content ◽

The Brain ◽

Brain Water

Abstract Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

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Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway

Human & Experimental Toxicology ◽

10.1177/09603271211036122 ◽

2021 ◽

pp. 096032712110361

Author(s):

Hai-Tao Zhang ◽

Xi-Zeng Wang ◽

Qing-Mei Zhang ◽

Han Zhao

Keyword(s):

Oxidative Stress ◽

Cerebral Ischemia ◽

Infarct Size ◽

Water Content ◽

Cell Apoptosis ◽

Ischemia Reperfusion ◽

Related Factor ◽

Nuclear Factor ◽

Cerebral Ischemia Reperfusion ◽

And Oxidative Stress

Objective To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. Methods The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress–related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. Results At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. Conclusion Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.

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