Brain edema formation and neurological impairment after subarachnoid hemorrhage in rats

Object Global cerebral edema is an independent risk factor for early death and poor outcome after subarachnoid hemorrhage (SAH). In the present study, the time course of brain edema formation, neurological deficits, and neuronal cell loss were investigated in the rat filament SAH model. Methods Brain water content and neurological deficits were determined in rats randomized to sham (1-, 24-, or 48-hour survival), SAH by endovascular perforation (1-, 24-, or 48-hour survival), or no surgery (control). The neuronal cell count (CA1–3) was quantified in a separate set of SAH (6-, 24-, 48-, or 72-hour survival) and shamoperated animals. Results Brain water content increased significantly 24 (80.2 ± 0.4% [SAH] vs 79.2 ± 0.1% [sham]) and 48 hours (79.8 ± 0.2% [SAH] vs 79.3 ± 0.1% [sham]) after SAH. The neuroscore was significantly worse after SAH (33 ± 15 [24 hours after SAH] vs 0 ± 0 points [sham]) and correlated with the extent of brain edema formation (r = 0.96, p < 0.001). No hippocampal damage was present up to 72 hours after SAH. Conclusions Brain water content and neurological dysfunction reached a maximum at 24 hours after SAH. This time point, therefore, seems to be optimal to test the effects of therapeutic interventions on brain edema formation. Neuronal cell loss was not present in CA1–3 up to 72 hours of SAH. Therefore, morphological damage needs to be evaluated at later time points.

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Microvascular Changes during the Early Phase of Experimental Bacterial Meningitis

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1990.148 ◽

1990 ◽

Vol 10 (6) ◽

pp. 914-922 ◽

Cited By ~ 94

Author(s):

H.-W. Pfister ◽

U. Koedel ◽

R. L. Haberl ◽

U. Dirnagl ◽

W. Feiden ◽

...

Keyword(s):

Free Radicals ◽

Bacterial Meningitis ◽

Water Content ◽

Brain Edema ◽

Early Phase ◽

Brain Water Content ◽

Edema Formation ◽

Oxygen Derived Free Radicals ◽

Brain Water ◽

Brain Edema Formation

We investigated the temporal profile of the changes in regional CBF (rCBF) and intracranial pressure (ICP) during the early phase of pneumococcal meningitis in the rat. rCBF, as measured by laser-Doppler flowmetry, and ICP were continuously monitored during 6 h post infection (p.i.). Brain edema formation was assessed by brain water content determinations. Meningitis was induced by intracisternal injection of 75 μl of 107 colony-forming units/ml pneumococci (n = 7). In control animals (n = 6), saline was injected. There was no change in the rCBF or ICP of controls throughout the experiment. However, there was a dramatic increase in rCBF and ICP associated with brain edema formation in untreated meningitis animals. rCBF increased to 135.3 ± 33.8% (mean ± SD) in the untreated animals at 1 h p.i, and reached 211.1 ± 40.5% at 6 h p.i. (p < 0.05 compared with controls). ICP increased from 2.9 ± 1.4 to 10.4 ± 4.7 mm Hg at 6 h p.i. (p < 0.05 compared with controls). Brain water content was significantly elevated (79.69 ± 0.24 compared with 78.94 ± 0.16% in the control group, p < 0.05). We investigated the effect of dexamethasone (3 mg/kg i.p.), which was given prior to the induction of meningitis (n = 3) or at 2 h after pneumococcal injection (n = 5), indomethacin (10 mg/kg i.V., n = 5), and superoxide dismutase (SOD; 132,000 U/kg i.v. per 6 h, n = 6). The increases in rCBF and ICP were prevented by the pretreatment with dexamethasone and the administration of SOD, delayed and attenuated by pretreatment with indomethacin, and reversed by administration of dexamethasone 2 h p.i. These findings suggest that oxygen-derived free radicals are involved as mediators in the increases of rCBF and ICP and brain edema formation during the early phase of experimental bacterial meningitis. Arachidonic acid metabolites of the cyclooxygenase pathway are partially involved in the observed changes and are one possible source for the generation of oxygen-derived free radicals in bacterial meningitis.

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Brain edema after intracerebral hemorrhage in rats: the role of iron overload and aquaporin 4

Journal of Neurosurgery ◽

10.3171/2008.4.jns17512 ◽

2009 ◽

Vol 110 (3) ◽

pp. 462-468 ◽

Cited By ~ 54

Author(s):

Wang Gai Qing ◽

Yang Qi Dong ◽

Tang Qing Ping ◽

Li Guang Lai ◽

Li Dong Fang ◽

...

Keyword(s):

Iron Overload ◽

Water Content ◽

Brain Edema ◽

Time Course ◽

Iron Chelator ◽

Brain Water Content ◽

Edema Formation ◽

Aqp4 Expression ◽

The Right ◽

Brain Water

Object Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. An increase of brain water content was associated with an increase of brain iron, which is an erythrocyte degradation product. Expression of AQP4 is highly modified in several brain disorders, and it can play a key role in cerebral edema formation. However, the question whether AQP4 is regulated by drugs lacks reliable evidence, and the interacting roles of iron overload and AQP4 in brain edema after ICH are unknown. The goal of this study was to clarify the relationship between iron overload and AQP4 expression and to characterize the effects of the iron chelator deferoxamine (DFO) on delayed brain edema after experimental ICH. Methods A total of 144 Sprague-Dawley rats weighing between 250 and 300 g were used in this work. The animals were randomly divided into 4 groups. The ICH models (Group C) were generated by injecting 100 μl autologous blood stereotactically into the right caudate nucleus; surgical control rats (Group B) were generated in a similar fashion, by injecting 100 μl saline into the right caudate nucleus. Intervention models (Group D) were established by intraperitoneal injection of DFO into rats in the ICH group. Healthy rats (Group A) were used for normal control models. Brain water content, iron deposition, and AQP4 in perihematomal brain tissue were evaluated over the time course of the study (1, 3, 7, and 14 days) in each group. Results Iron deposition was found in the perihematomal zone as early as the 1st day after ICH, reaching a peak after 7 days and remaining at a high level thereafter for at least 14 days following ICH. Rat brain water content around the hematoma increased progressively over the time course, reached its peak at Day 3, and still was evident at Day 7 post-ICH. Immunohistochemical analysis showed that AQP4 was richly expressed over glial cell processes surrounding microvessels in the rat brain; there was upregulation of the AQP4 expression in perihematomal brain during the observation period, and it reached maximum at 3 to 7 days after ICH. The changes of brain water content were accompanied by an alteration of AQP4. The application of the iron chelator DFO significantly reduced iron overload, brain water content, and AQP4 level in the perihematomal area compared with the control group. Conclusions Iron overload and AQP4 may play a critical role in the formation of brain edema after ICH. In addition, AQP4 expression was affected by iron concentration. Importantly, treatment with DFO significantly reduced brain edema in rats and inhibited the AQP4 upregulation after ICH. Deferoxamine may be a potential therapeutic agent for treating ICH.

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Glibenclamide does not improve outcome following severe collagenase-induced intracerebral hemorrhage in rats

PLoS ONE ◽

10.1371/journal.pone.0252584 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252584

Author(s):

Tiffany F. C. Kung ◽

Cassandra M. Wilkinson ◽

Christine A. Dirks ◽

Glen C. Jickling ◽

Frederick Colbourne

Keyword(s):

Intracerebral Hemorrhage ◽

Water Content ◽

Transient Receptor Potential ◽

Neurological Deficits ◽

Brain Water Content ◽

Adult Rats ◽

Edema Formation ◽

Improve Outcome ◽

Transient Receptor Potential Melastatin ◽

Brain Water

Intracerebral hemorrhage (ICH) is a devastating insult with few effective treatments. Edema and raised intracranial pressure contribute to poor outcome after ICH. Glibenclamide blocks the sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) channel implicated in edema formation. While glibenclamide has been found to improve outcome and reduce mortality in animal models of severe ischemic stroke, in ICH the effects are less clear. In our previous study, we found no benefit after a moderate-sized bleed, while others have reported benefit. Here we tested the hypothesis that glibenclamide may only be effective in severe ICH, where edema is an important contributor to outcome. Glibenclamide (10 μg/kg loading dose, 200 ng/h continuous infusion) was administered 2 hours post-ICH induced by collagenase injection into the striatum of adult rats. A survival period of 24 hours was maintained for experiments 1–3, and 72 hours for experiment 4. Glibenclamide did not affect hematoma volume (~81 μL) or other safety endpoints (e.g., glucose levels), suggesting the drug is safe. However, glibenclamide did not lessen striatal edema (~83% brain water content), ionic dyshomeostasis (Na+, K+), or functional impairment (e.g., neurological deficits (median = 10 out of 14), etc.) at 24 hours. It also did not affect edema at 72 h (~86% brain water content), or overall mortality rates (25% and 29.4% overall in vehicle vs. glibenclamide-treated severe strokes). Furthermore, glibenclamide appears to worsen cytotoxic edema in the peri-hematoma region (cell bodies were 46% larger at 24 h, p = 0.0017), but no effect on cell volume or density was noted elsewhere. Overall, these findings refute our hypothesis, as glibenclamide produced no favorable effects following severe ICH.

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Pial Arterial Pressure Contribution to Early Ischemic Brain Edema

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.85 ◽

1989 ◽

Vol 9 (5) ◽

pp. 597-602 ◽

Cited By ~ 17

Author(s):

Shuhei Yamaguchi ◽

Shotai Kobayashi ◽

Kazuya Yamashita ◽

Mitsuhiro Kitani

Keyword(s):

Arterial Pressure ◽

Water Content ◽

Brain Edema ◽

Peripheral Region ◽

Core Region ◽

Brain Water Content ◽

Edema Formation ◽

The Core ◽

Mca Occlusion ◽

Brain Water

The effect of pial arterial pressure (PAP) on brain edema was examined in cats with middle cerebral artery (MCA) occlusion. Measurements of PAP and regional CBF (rCBF) were collected in the central core and the peripheral margin of the MCA territory over 180 min post MCA occlusion. Brain water content in each region was determined at the end of the experiment. MCA occlusion resulted in decreased PAP and rCBF in both the core (PAP = 13 mm Hg, rCBF = 9 ml/100 g/min) and the peripheral region (PAP = 15 mm Hg, rCBF = 18 ml/100 g/min). Brain edema developed in both the core and the peripheral region. Brain water content was correlated inversely with PAP in the core region and positively in the peripheral region. The results indicate that decreased blood flow contributes to cytotoxic edema in the core, and a hydrostatic pressure gradient preferentially enhances edema formation in the peripheral region. Maintenance of high perfusion pressure early after ischemia onset may suppress brain edema in the core region.

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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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Expression of IL-1β, IL-6 and TNF-α in rats with thioacetamide-induced acute liver failure and encephalopathy: correlation with brain edema

Asian Biomedicine ◽

10.5372/1905-7415.0502.026 ◽

2011 ◽

Vol 5 (2) ◽

pp. 205-215 ◽

Cited By ~ 2

Author(s):

Li-Qing Wang ◽

Heng-Jun Zhou ◽

Cai-Fei Pan ◽

Sheng-Mei Zhu ◽

Lin-Mei Xu

Keyword(s):

Hepatic Encephalopathy ◽

Motor Activity ◽

Water Content ◽

Brain Edema ◽

Proinflammatory Cytokines ◽

Enzyme Linked Immunosorbent Assay ◽

Brain Water Content ◽

Tnf Α ◽

The Relationship ◽

Brain Water

Abstract Background: Secondary brain edema is a serious complication of hepatic encephalopathy (HE). Recently, it has been reported that proinflammatory cytokines are involved in the pathogenesis of brain edema during HE. Objectives: Observe the dynamic expressions of brain and plasma proinflammatory cytokines in encephalopathy rats, and evaluate the relationship between proinflammatory cytokines and brain edema. Methods: Acute HE rats were induced by intraperitoneal injection of thioacetamide (TAA) in 24 hours intervals for two consecutive days. Then, clinical symptom and stages of hepatic encephalopathy, motor activity counts, index of liver function, and brain water content were observed. The dynamic expressions of IL-1β, IL-6, and TNF-α in plasma and brain tissues were measured with enzyme-linked immunosorbent assay. Results: Typical clinical performances of hepatic encephalopathy were occurred in all TAA-administrated rats. The TAA rats showed lower motor activity counts and higher the index of alanine aminotransferase, aspartate aminotransferase, total bilirubin and ammonia than those in control rats. Brain water content was significantly enhanced in TAA rats compared with the control. The expressions of IL-1β, IL-6, and TNF- α in plasma and brain significantly increased in TAA rats. In addition, the expressions of cerebral proinflammatory cytokines were positively correlated with brain water content but negatively correlated with motor activity counts.Conclusion: Inflammation was involved in the pathogenesis of brain edema during TAA-induced HE.

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Sheng-Di-Da-Huang Decoction Inhibited Inflammation Expressed in Microglia after Intracerebral Hemorrhage in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6470534 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Min Cai ◽

Zhonghai Yu ◽

Wen Zhang ◽

Li Yang ◽

Jun Xiang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Water Content ◽

Evans Blue ◽

Microglial Activation ◽

Critical Role ◽

Neurological Deficits ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Evans Blue Extravasation ◽

Brain Water

Objects. Sheng-Di-Da-Huang Decoction was used as an effective hemostatic agent in ancient China. However, its therapeutic mechanism is still not clear. Inflammatory injury plays a critical role in ICH-induced secondary brain injury. After hemolysis, hematoma components are released, inducing microglial activation via TLR4, which initiates the activation of transcription factors (such as NF-κB) to regulate expression of proinflammatory cytokine genes. This study aimed to verify the anti-inflammatory effects of Sheng-Di-Da-Huang Decoction on ICH rats. Materials and Methods. Intracerebral hemorrhage was induced by injection of bacterial collagenase (0.2 U) in rats. Neurological deficits, brain water content, Evans blue extravasation, expression of TLR4, NF-κB, Iba-1 positive cells (activated microglia), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were examined 1, 3, 7, and 14 days after collagenase injection. MR images were also studied. Results. Sheng-Di-Da-Huang Decoction remarkably improved neurological function, reduced brain water content as well as Evans blue extravasation, downregulated expression of TLR4, NF-κB, TNF-α, and IL-1β, and inhibited microglial activation. Conclusions. Sheng-Di-Da-Huang Decoction reduced inflammation reaction after ICH through inhibited inflammation expressed in microglia.

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Seizures induced by intracerebral injection of thrombin: a model of intracerebral hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1997.87.1.0073 ◽

1997 ◽

Vol 87 (1) ◽

pp. 73-78 ◽

Cited By ~ 72

Author(s):

Kevin R. Lee ◽

Ivo Drury ◽

Elizabeth Vitarbo ◽

Julian T. Hoff

Keyword(s):

Intracerebral Hemorrhage ◽

Electrical Activity ◽

Brain Edema ◽

Seizure Activity ◽

Neurological Deficits ◽

Coagulation Cascade ◽

Thrombin Inhibitor ◽

Eeg Monitoring ◽

Edema Formation ◽

Brain Edema Formation

✓ The coagulation cascade plays an important role in brain edema formation caused by intracerebral blood. In particular, thrombin produces brain injury via direct brain cell toxicity. Seizures and increased cerebral electrical activity are commonly associated with intracerebral blood and are possible effects of thrombin leading to cell injury in the brain. In this study, artificial clots containing concentrations of thrombin found in hematomas were infused intracerebrally in rats. The animals were observed clinically for seizure activity, behavior, and neurological deficits. Several animals underwent video electroencephalographic (EEG) monitoring during intracerebral infusion and for 30 minutes postinfusion. All animals were killed 24 hours after injection, and brain water and ion contents were measured to determine the amount of brain edema. Clinically, thrombin produced focal motor seizures in all animals. None of the control animals or those receiving Nα-(2-Naphthalenesulfonyl-glycyl)-4-amidino-DL-phenylalanine-piperidide (α-NAPAP), a thrombin inhibitor added to the thrombin, showed clinical evidence of seizures. Of the rats undergoing EEG monitoring, all animals receiving thrombin showed electrical evidence of seizure activity, whereas none of the control animals exhibited seizure activity. There was no evidence of seizure activity on EEG monitoring when α-NAPAP was injected along with the thrombin. In addition, the artificial clots containing thrombin produced agitation and a circling tendency in the rats, along with brain edema. These results indicate that the coagulation cascade is involved in seizure production and increased brain electrical activity, which contribute to the neurological deficits and brain edema formation that are seen with intracerebral hemorrhage.

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The Activation of Phosphatidylserine/CD36/TGF-β1 Pathway prior to Surgical Brain Injury Attenuates Neuroinflammation in Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4921562 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Lei Huang ◽

Hailiang Tang ◽

Prativa Sherchan ◽

Cameron Lenahan ◽

Warren Boling ◽

...

Keyword(s):

Brain Injury ◽

Water Content ◽

Neurological Deficits ◽

Preventive Strategy ◽

Neurosurgical Procedures ◽

Brain Water Content ◽

Protein Levels ◽

Surgical Brain Injury ◽

Brain Water ◽

Brain Tissues

Neuroinflammation plays an important pathological role in experimental surgical brain injury (SBI). Apoptotic associated with phosphatidylserine (PS) externalization promotes anti-inflammatory mediator TGF-β1 release. In the present study, we investigated the anti-neuroinflammation effect of PS liposome or isoflurane pretreatment via PS/CD36/TGF-β1 signaling in a rat model of SBI. A total of 120 male Sprague-Dawley rats (weighing 280-330 gms) were used. SBI was induced by partial right frontal lobe corticotomy. Intranasal PS liposome or isoflurane inhalation was administered prior to SBI induction. CD36 small interfering RNA (siRNA) was administered intracerebroventricularly. Recombinant Annexin V protein (rAnnexin V) was delivered intranasally. Post-SBI assessments included neurological tests, brain water content, Western blot, and immunohistochemistry. Endogenous CD36 protein levels but not TGF-β1 was significantly increased within peri-resection brain tissues over 72 h after SBI. SBI rats were associated with increased brain water content surrounding corticotomy and neurological deficits. PS liposome pretreatment significantly reduced brain water content and improved some neurological deficits at 24 hours and 72 hours after SBI. PS liposome increased CD36 and TGF-β1 protein levels, but decreased IL-1β and TNFα protein levels in peri-resection brain tissues at 24 hours after SBI. CD36 siRNA or rAnnexin V partially countered the protective effect of PS liposome. Isoflurane pretreatment produced similar antineuroinflammation and neurological benefits in SBI rats partially by upregulating CD36/Lyn/TGF-β1 signaling. Collectively, our findings suggest that the activation of PS/CD36/TGF-β1 pathway by PS liposome or isoflurane prior to SBI could attenuate neuroinflammation and improve neurological outcomes in rats. PS liposome or isoflurane pretreatment may serve as an effective preventive strategy to minimize the brain injury caused by neurosurgical procedures in patients.

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Neuroprotection of Sanhua Decoction against Focal Cerebral Ischemia/Reperfusion Injury in Rats through a Mechanism Targeting Aquaporin 4

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/584245 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Lin Lu ◽

Hui-qin Li ◽

Ji-huang Li ◽

Ai-ju Liu ◽

Guo-qing Zheng

Keyword(s):

Cerebral Ischemia ◽

Water Content ◽

Brain Edema ◽

Focal Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Aquaporin 4 ◽

Brain Water Content ◽

Aqp4 Expression ◽

Cerebral Ischemia Reperfusion ◽

Brain Water

Sanhua decoction (SHD) is a famous classic Chinese herbal prescription for ischemic stroke, and aquaporin 4 (AQP4) is reported to play a key role in ischemic brain edema. This study aimed to investigate neuroprotection of SHD against focal cerebral ischemia/reperfusion (I/R) injury in rats and explore the hypothesis that AQP4 probably is the target of SHD neuroprotection against I/R rats. Lentiviral-mediated AQP4-siRNA was inducted into adult male Sprague-Dawley rats via intracerebroventricular injection. The focal cerebral ischemia/reperfusion model was established by occluding middle cerebral artery. Neurological examinations were performed according to Longa Scale. Brain water content, was determined by wet and dry weight measurement. Western blot was adopted to test the AQP4 expression in ipsilateral hippocampus. After the treatment, SHD alleviated neurological deficits, reduced brain water content and downregulated the expression of AQP4 at different time points following I/R injury. Furthermore, neurobehavioral function and brain edema after I/R were significantly attenuated via downregulation of AQP4 expression when combined with AQP4-siRNA technology. In conclusion, SHD exerted neuroprotection against focal cerebral I/R injury in rats mainly through a mechanism targeting AQP4.

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