Glycerol Improves Intracerebral Hemorrhagic Brain Injury and Associated Kidney Dysfunction in Rats

In stroke patients, the development of acute kidney injury (AKI) is closely linked with worse outcomes and increased mortality. In this study, the interplay between post-stroke and AKI and treatment options was investigated in a rodent model of hemorrhagic stroke. Intrastriatal collagenase injection for 24 h caused neurological deficits, hematoma formation, brain edema, apoptosis, blood–brain barrier disruption, oxidative stress, and neuroinflammation in Sprague Dawley rats. Elevation of serum blood urea nitrogen, serum creatinine, urine cytokine-induced neutrophil chemoattractant-1, and urine Malondialdehyde, as well as moderate histological abnormality in the kidney near the glomerulus, indicated evidence of kidney dysfunction. The accumulation of podocalyxin DNA in urine further suggested a detachment of podocytes and structural deterioration of the glomerulus. Circulating levels of stress hormones, such as epinephrine, norepinephrine, corticosterone, and angiotensin II were elevated in rats with intracerebral hemorrhage. Osmotic agent glycerol held promising effects in alleviating post-stroke brain injury and kidney dysfunction. Although the detailed protective mechanisms of glycerol have yet to be determined, the intrastriatal collagenase injection hemorrhagic stroke model in rats allowed us to demonstrate the functional and structural integrity of glomerulus are targets that are vulnerable to post-stroke injury and stress hormones could be surrogates of remote communications.

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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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Fecal Microbiota Transplantation Is a Promising Method to Restore Gut Microbiota Dysbiosis and Relieve Neurological Deficits after Traumatic Brain Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5816837 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Donglin Du ◽

Wei Tang ◽

Chao Zhou ◽

Xiaochuan Sun ◽

Zhengqiang Wei ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Methionine Sulfoxide Reductase ◽

Neurological Deficits ◽

Sprague Dawley ◽

Rat Serum ◽

Gut Microbiota Dysbiosis

Background. Traumatic brain injury (TBI) can induce persistent fluctuation in the gut microbiota makeup and abundance. The present study is aimed at determining whether fecal microbiota transplantation (FMT) can rescue microbiota changes and ameliorate neurological deficits after TBI in rats. Methods. A controlled cortical impact (CCI) model was used to simulate TBI in male Sprague-Dawley rats, and FMT was performed for 7 consecutive days. 16S ribosomal RNA (rRNA) sequencing of fecal samples was performed to analyze the effects of FMT on gut microbiota. Modified neurological severity score and Morris water maze were used to evaluate neurobehavioral functions. Metabolomics was used to screen differential metabolites from the rat serum and ipsilateral brains. The oxidative stress indices were measured in the brain. Results. TBI induced significance changes in the gut microbiome, including the alpha- and beta-bacterial diversity, as well as the microbiome composition at 8 days after TBI. On the other hand, FMT could rescue these changes and relieve neurological deficits after TBI. Metabolomics results showed that the level of trimethylamine (TMA) in feces and the level of trimethylamine N-oxide (TMAO) in the ipsilateral brain and serum was increased after TBI, while FMT decreased TMA levels in the feces, and TMAO levels in the ipsilateral brain and serum. Antioxidant enzyme methionine sulfoxide reductase A (MsrA) in the ipsilateral hippocampus was decreased after TBI but increased after FMT. In addition, FMT elevated SOD and CAT activities and GSH/GSSG ratio and diminished ROS, GSSG, and MDA levels in the ipsilateral hippocampus after TBI. Conclusions. FMT can restore gut microbiota dysbiosis and relieve neurological deficits possibly through the TMA-TMAO-MsrA signaling pathway after TBI.

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Estrogen therapy for experimental intracerebral hemorrhage in rats

Journal of Neurosurgery ◽

10.3171/jns.2005.103.1.0097 ◽

2005 ◽

Vol 103 (1) ◽

pp. 97-103 ◽

Cited By ~ 41

Author(s):

Takehiro Nakamura ◽

Ya Hua ◽

Richard F. Keep ◽

Jung-Weon Park ◽

Guohua Xi ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Brain Edema ◽

Estrogen Therapy ◽

Female Rats ◽

Male Rats ◽

Neurological Deficits ◽

Sprague Dawley ◽

Autologous Whole Blood ◽

17Β Estradiol

Object The aims of this study were to determine the following: whether there are sex differences in intracerebral hemorrhage (ICH) induced brain injury in rats, whether delayed administration of 17β-estradiol can reduce ICH-induced brain damage, and whether these effects are estrogen receptor (ER)-dependent. Methods Male and female Sprague—Dawley rats received an infusion of 100 µl autologous whole blood into the right basal ganglia. Twenty-four hours later the rats were killed. The effects of 17β-estradiol on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Both ER-α and hemeoxygenase (HO)-1 were investigated through Western blot and immunohistochemical analysis. Brain edema was significantly less severe in female compared with that in male rats. The ER antagonist ICI 182,780 exacerbated ICH-induced brain edema in female but not in male rats, indicating that ER-α activation during ICH is protective in female rats. Administration of exogenous 17β-estradiol in male, but not in female, rats significantly attenuated brain edema, neurological deficits, and ICH-induced changes in HO-1 when given 2 hours after hemorrhage. The effects of exogenous 17β-estradiol occurred through an ER-independent mechanism. Conclusions Results in this study indicate that 17β-estradiol could be a potential therapeutic agent for ICH.

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Examining the Progressive Behavior and Neuropathological Outcomes Associated with Chronic Repetitive Mild Traumatic Brain Injury in Rats

Cerebral Cortex Communications ◽

10.1093/texcom/tgaa002 ◽

2020 ◽

Vol 1 (1) ◽

Cited By ~ 2

Author(s):

Eric Eyolfson ◽

Glenn R Yamakawa ◽

Yannick Griep ◽

Reid Collins ◽

Thomas Carr ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mild Traumatic Brain Injury ◽

Motor Behavior ◽

Functional Change ◽

Neurological Deficits ◽

Sprague Dawley ◽

Behavioral Impairment ◽

Motor Disturbance ◽

Ventricle Size

Abstract While the physical and behavioral symptomologies associated with a single mild traumatic brain injury (mTBI) are typically transient, repetitive mTBIs (RmTBI) have been associated with persisting neurological deficits. Therefore, this study examined the progressive changes in behavior and the neuropathological outcomes associated with chronic RmTBI through adolescence and adulthood in male and female Sprague Dawley rats. Rats experienced 2 mTBIs/week for 15 weeks and were periodically tested for changes in motor behavior, cognitive function, emotional disturbances, and aggression. Brain tissue was examined for neuropathological changes in ventricle size and presentation of Iba1 and GFAP. We did not see progressively worse behavioral impairments with the accumulation of injuries or time, but did find evidence for neurological and functional change (motor disturbance, reduced exploration, reduced aggression, alteration in depressive-like behavior, deficits in short-term working memory). Neuropathological assessment of RmTBI animals identified an increase in ventricle size, prolonged changes in GFAP, and sex differences in Iba1, in the corpus callosum, thalamus, and medial prefrontal cortex. Telomere length reduced exponentially as the injury load increased. Overall, chronic RmTBI did not result in accumulating behavioral impairment, and there is a need to further investigate progressive behavioral changes associated with repeated injuries in adolescence and young adulthood.

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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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Modeling traumatic brain injury combined with hemorrhagic shock in rats: Neurological assessment and PET imaging with 18F-fluorodeoxyglucaric acid

10.1101/2021.06.01.446662 ◽

2021 ◽

Author(s):

Hibah O Awwad ◽

Andria Hedrick ◽

Alex Mdzinarishvili ◽

Hailey Houson ◽

Kelly Standifer ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Hemorrhagic Shock ◽

Tissue Injury ◽

Brain Lesion ◽

Lesion Size ◽

Neurological Deficits ◽

Lesion Volume ◽

Sprague Dawley ◽

The Impact

Traumatic brain injury (TBI)is a major cause of death and disability worldwide. Hemorrhagic shock (HS) aggravates tissue injury and complicates TBI recovery. We studied the combined insult of mild TBI and HS and investigated the impact of varying loss of blood volume on neurologic deficit and brain lesion volume. A novel positron emission tomography (PET) technique was employed to monitor tissue injury. Male Sprague Dawley rats received mTBI by controlled cortical impact (CCI) followed by withdrawal of 0%, 30-40%, 45%, or 50% of blood (mTBI, mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, respectively). Neurological deficit (mNSS= 5.6, 7.6, and 12.3) and mortality (2/12, 2/6, and 7/12) were higher in mTBI+HS≤40%, mTBI+HS45%, and mTBI+HS50%, than in mTBI alone rats (no death; mNSS=3.3). Histologic lesion size increased 3.5-fold in mTBI+HS50% compared to mTBI alone and the infarct-avid PET agent 18F-fluorodeoxyglucaric acid (FGA) proportionately detected tissue necrosis in mTBI+HS50% rats. Based on these results, we conclude that HS aggravates mTBI-induced neurological deficits, tissue injury and mortality. PET using 18F-FGA as an imaging marker can detect the extent of injury in a non-invasive manner.

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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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IL-4/STAT6 signaling facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2018497117 ◽

2020 ◽

Vol 117 (51) ◽

pp. 32679-32690

Author(s):

Jing Xu ◽

Zhouqing Chen ◽

Fang Yu ◽

Huan Liu ◽

Cheng Ma ◽

...

Keyword(s):

Functional Recovery ◽

Hemorrhagic Stroke ◽

Brain Injuries ◽

Primary Cultures ◽

Young Female ◽

Neurological Deficits ◽

Beneficial Effects ◽

Collagenase Injection ◽

Enhanced Expression

Intracerebral hemorrhage (ICH) is a devastating form of stroke affecting millions of people worldwide. Parenchymal hematoma triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia and macrophages carry out hematoma clearance, thereby facilitating functional recovery after ICH. Here, we elucidate a pivotal role for the interleukin (IL)-4)/signal transducer and activator of transcription 6 (STAT6) axis in promoting long-term recovery in both blood- and collagenase-injection mouse models of ICH, through modulation of microglia/macrophage functions. In both ICH models, STAT6 was activated in microglia/macrophages (i.e., enhanced expression of phospho-STAT6 in Iba1+cells). Intranasal delivery of IL-4 nanoparticles after ICH hastened STAT6 activation and facilitated hematoma resolution. IL-4 treatment improved long-term functional recovery in young and aged male and young female mice. In contrast, STAT6 knockout (KO) mice exhibited worse outcomes than WT mice in both ICH models and were less responsive to IL-4 treatment. The construction of bone marrow chimera mice demonstrated that STAT6 KO in either the CNS or periphery exacerbated ICH outcomes. STAT6 KO impaired the capacity of phagocytes to engulf red blood cells in the ICH brain and in primary cultures. Transcriptional analyses identified lower level of IL-1 receptor-like 1 (ST2) expression in microglia/macrophages of STAT6 KO mice after ICH. ST2 KO diminished the beneficial effects of IL-4 after ICH. Collectively, these data confirm the importance of IL-4/STAT6/ST2 signaling in hematoma resolution and functional recovery after ICH. Intranasal IL-4 treatment warrants further investigation as a clinically feasible therapy for ICH.

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Collagen-Glycosaminoglycan Matrix Implantation Promotes Angiogenesis following Surgical Brain Trauma

BioMed Research International ◽

10.1155/2014/672409 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Kuo-Feng Huang ◽

Wei-Cherng Hsu ◽

Jong-Kai Hsiao ◽

Gunng-Shinng Chen ◽

Jia-Yi Wang

Keyword(s):

Brain Injury ◽

Functional Recovery ◽

Vascular Endothelial Cells ◽

Male Rats ◽

Neurological Deficits ◽

Neurosurgical Procedures ◽

Vascular Endothelial ◽

Sprague Dawley ◽

Angiogenic Growth Factors ◽

Surgical Brain Injury

Surgical brain injury (SBI) is unavoidable during many neurosurgical procedures intrinsically linked to postoperative neurological deficits. We have previously demonstrated that implantation of collagen glycosaminoglycan (CG) following surgical brain injury could significantly promote functional recovery and neurogenesis. In this study we further hypothesized that this scaffold may provide a microenvironment by promoting angiogenesis to favor neurogenesis and subsequent functional recovery. Using the rodent model of surgical brain injury as we previously established, we divided Sprague-Dawley male rats (weighting 300–350 g) into three groups: (1) sham (2) surgical injury with a lesion (L), and (3) L with CG matrix implantation (L + CG). Our results demonstrated that L + CG group showed a statistically significant increase in the density of vascular endothelial cells and blood vessels over time. In addition, tissue concentrations of angiogenic growth factors (such as VEGF, FGF2, and PDGF) significantly increased in L + CG group. These results suggest that implantation of a CG scaffold can promote vascularization accompanied by neurogenesis. This opens prospects for use of CG scaffolds in conditions such as brain injury including trauma and ischemia.

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Lesion-symptom mapping with NIHSS sub-scores in ischemic stroke patients

Stroke and Vascular Neurology ◽

10.1136/svn-2021-001091 ◽

2021 ◽

pp. svn-2021-001091

Author(s):

Deepthi Rajashekar ◽

Matthias Wilms ◽

M Ethan MacDonald ◽

Serena Schimert ◽

Michael D Hill ◽

...

Keyword(s):

Clinical Outcome ◽

Structure Function ◽

Structural Integrity ◽

Brain Regions ◽

Specific Structure ◽

Neurological Deficits ◽

Escape Trial ◽

Nihss Score ◽

Post Stroke ◽

Lesion Symptom Mapping

BackgroundLesion-symptom mapping (LSM) is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome. In clinical practice, patients are commonly evaluated using the National Institutes of Health Stroke Scale (NIHSS), an 11-domain clinical score to quantitate neurological deficits due to stroke. So far, LSM studies have mostly used the total NIHSS score for analysis, which might not uncover subtle structure–function relationships associated with the specific sub-domains of the NIHSS evaluation. Thus, the aim of this work was to investigate the feasibility to perform LSM analyses with sub-score information to reveal category-specific structure–function relationships that a total score may not reveal.MethodsEmploying a multivariate technique, LSM analyses were conducted using a sample of 180 patients with NIHSS assessment at 48-hour post-stroke from the ESCAPE trial. The NIHSS domains were grouped into six categories using two schemes. LSM was conducted for each category of the two groupings and the total NIHSS score.ResultsSub-score LSMs not only identify most of the brain regions that are identified as critical by the total NIHSS score but also reveal additional brain regions critical to each function category of the NIHSS assessment without requiring extensive, specialised assessments.ConclusionThese findings show that widely available sub-scores of clinical outcome assessments can be used to investigate more specific structure–function relationships, which may improve predictive modelling of stroke outcomes in the context of modern clinical stroke assessments and neuroimaging.Trial registration numberNCT01778335.

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