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

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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NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice

Journal of Neuroinflammation ◽

10.1186/s12974-019-1591-4 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 6

Author(s):

Xuan Wu ◽

Siming Fu ◽

Yun Liu ◽

Hansheng Luo ◽

Feng Li ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Water Content ◽

Autologous Blood ◽

Neurological Deficits ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Protective Mechanisms ◽

Neuroprotective Effects ◽

Melanocortin 1 Receptor ◽

Brain Water

Abstract Background Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Recently, melanocortin-1 receptor (Mc1r) activation by Nle4-D-Phe7-α-MSH (NDP-MSH) was shown to play a neuroprotective role in an experimental autoimmune encephalomyelitis (EAE) mouse model. This study aimed to investigate whether NDP-MSH could alleviate neuroinflammation and BBB disruption after experimental ICH, as well as the potential mechanisms of its neuroprotective roles. Methods Two hundred and eighteen male C57BL/6 mice were subjected to autologous blood-injection ICH model. NDP-MSH, an agonist of Mc1r, was administered intraperitoneally injected at 1 h after ICH insult. To further explore the related protective mechanisms, Mc1r small interfering RNA (Mc1r siRNA) and nuclear receptor subfamily 4 group A member 1 (Nr4a1) siRNA were administered via intracerebroventricular (i.c.v) injection before ICH induction. Neurological test, BBB permeability, brain water content, immunofluorescence staining, and Western blot analysis were implemented. Results The Expression of Mc1r was significantly increased after ICH. Mc1r was mainly expressed in microglia, astrocytes, and endothelial cells following ICH. Treatment with NDP-MSH remarkably improved neurological function and reduced BBB disruption, brain water content, and the number of microglia in the peri-hematoma tissue after ICH. Meanwhile, the administration of NDP-MSH significantly reduced the expression of p-NF-κB p65, IL-1β, TNF-α, and MMP-9 and increased the expression of p-CREB, Nr4a1, ZO-1, occludin, and Lama5. Inversely, the knockdown of Mc1r or Nr4a1 abolished the neuroprotective effects of NDP-MSH. Conclusions Taken together, NDP-MSH binding Mc1r attenuated neuroinflammation and BBB disruption and improved neurological deficits, at least in part through CREB/Nr4a1/NF-κB pathway after ICH.

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Role of flunarizine hydrochloride in secondary brain injury following intracerebral hemorrhage in rats

International Journal of Immunopathology and Pharmacology ◽

10.1177/0394632017742224 ◽

2017 ◽

Vol 30 (4) ◽

pp. 413-419 ◽

Cited By ~ 4

Author(s):

Jianping Niu ◽

Rui Hu

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Cell Apoptosis ◽

Akt Pathway ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Hematoma Volume ◽

Brain Water

This study aimed to explore the role and mechanism(s) of flunarizine hydrochloride in the intracerebral hemorrhage (ICH) rats. The 32 adult male Sprague Dawley (SD) rats were randomly assigned into four groups: control group, sham group, ICH group, and FLU + ICH group. The effects of flunarizine hydrochloride were assessed on the basis of hematoma volume, blood–brain barrier (BBB) integrity, and brain water content in the ICH rat models. The role of flunarizine hydrochloride in cell recovery was assessed by behavioral scores, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot assay. Involvement of PI3K/AKT pathway in exerting the effect of flunarizine hydrochloride was also determined. Results showed that the hematoma volume, BBB integrity, and brain water content were significantly decreased in the FLU + ICH group. Cell apoptosis significantly increased in the ICH model group, while flunarizine hydrochloride decreased this increase. The expressions of glial cell line-derived neurotrophic factor (GDNF), neuroglobin (NGB), and p-AKT were increased after flunarizine hydrochloride treatment in ICH rats. In conclusion, flunarizine hydrochloride has protective effects against ICH by reducing brain injury, cell apoptosis, and the activation of P13K/AKT pathway. These findings provide a theoretical basis for the treatment of flunarizine hydrochloride in ICH.

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Rehmannia and Rhubarb Decoction Exerts Neuroprotective Effects on the Blood-brain barrier during Acute Intracerebral Hemorrhage by Downregulating the HMGB1/TLR4/MMP9 signaling pathway

10.21203/rs.3.rs-41479/v1 ◽

2020 ◽

Author(s):

Shan Jiang ◽

Chun-Mei Li ◽

Ding-Fang Cai ◽

Jing-Si Zhang ◽

Xiao-Fei Yu

Keyword(s):

Intracerebral Hemorrhage ◽

Protective Effect ◽

Water Content ◽

Signaling Pathway ◽

Blood Brain Barrier ◽

Evans Blue ◽

Brain Barrier ◽

Brain Water Content ◽

Acute Intracerebral Hemorrhage ◽

Brain Water

Abstract Background Blood-brain barrier (BBB) is a gate-keeping system with selective permeability that serves to protect the central nervous system. The underlying neuroprotective mechanism of the BBB during acute intracerebral hemorrhage (ICH) remains poorly understood. Rehmannia and rhubarb decoction (RRD) is a classic traditional Chinese medicine formula that has been extensively applied for hemorrhagic diseases in China. In the present study, the potential protective effects of RRD on the BBB during acute ICH and the underlying mechanism were investigated. Methods The ICH model was established by injection of autologous blood (100 µl) into spontaneously hypertensive rats, which were randomly divided into the following groups: i) Sham; ii) ICH; iii) RRD; iv) TAK-242; v) TAK-242 + RRD; vi) high mobility group box 1 protein (HMGB1) inhibitor ethyl pyruvate (EP); and vii) EP + RRD. Neurological deficits, pathological examination, brain water content, Evans blue(EB) extravasation, immunofluorescence staining and the expression levels of HMGB1, toll-like receptor 4 (TLR4), matrix metalloproteinase 9 (MMP-9), Claudin-5, Occludin and zona occludens − 1 (Zo-1) were subsequently examined in each group on day 3 following operation. In addition, MRI and transmission electron microscopy were also performed to observe the BBB structure. Results RRD treatment markedly improved neurological functions, reduced brain water content and Evans blue extravasation, ameliorated the disruption of BBB and downregulated HMGB1, TLR4 and MMP-9 expression whilst upregulating the expression of Claudin-5, Occludin and Zo-1. Conclusion These results demonstrate that RRD has a protective effect on the BBB in rats during ICH and this protective effect is related to the down-regulation of HMGB1/TLR4/MMP9 signaling pathway.

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Abstract TP350: Escin Attenuates the Impairment of Neurological Function by Ameliorating Systemic Inflammation in Intracerebral Hemorrhagic Mice

Stroke ◽

10.1161/str.51.suppl_1.tp350 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Fenghua Fu ◽

Tian Wang

Keyword(s):

Water Content ◽

Signaling Pathway ◽

Systemic Inflammation ◽

Evans Blue ◽

Test Scores ◽

Neurological Function ◽

Brain Water Content ◽

Evans Blue Extravasation ◽

Brain Water ◽

Water Contents

Background and Purpose: Escin could attenuate cerebral ischemia-induced brain injury. The present study aimed to investigate whether Escin may attenuate the impairment of neurological function by ameliorating systemic inflammation in ICH mice. Methods: The ICH model was prepared by intrastriatal injection of collagenase. At 0.5 h, 2 h, 6 h and 12 h after Escin injection, the concentration of Escin in the serum and brain were detected. The effects of Escin on the Garcia test were evaluated. Brain water content was observed via a wet/dry weight method. Evans blue extravasation in the cerebrums were also assayed. The serum IL-1β level was detected with the ELISA kit. The ICH mice were further treated with Escin plus IL-1β. At 24 h of the ICH, Garcia test, and brain water content, the Evans blue extravasation and serum IL-1β levels were evaluated. Additionally, the expression of RhoA, ROCK1, IκBα, nuclear NF-κB, cytosolic NF-κB, Occludin and Claudin-5 in mice brain tissue were investigated with the Western blot. Results: Escin was detected in the serum of the Control group and ICH group at 0.5 h, 2 h, 6 h and 12 h after Escin administration. Escin was not detected in brain tissues at any time points in the animals. At 24 h and 72 h of ICH, the Garcia test scores in the Escin groups were significantly increased ( P < 0.05 or P < 0.01). Brain water contents and Evans blue extravasation of the right basal ganglia in the Escin groups were significantly reduced ( P < 0.05 or P < 0.01). Escin abated the increase of IL-1β induced by ICH ( P < 0.05 or P < 0.01). IL-1β administration reversed the effect of Escin on Garcia test scores, the brain water contents, and the Evans blue extravasation ( P < 0.01). In the ICH group, the levels of RhoA, ROCK1, nuclear NF-κB were increased while the expression of IκBα, cytosolic NF-κB, Occludin, Claudin-5 were reduced ( P < 0.05 or P < 0.01). However, Escin abated RhoA, ROCK1, nuclear NF-κB and augmented IκBα, cytosolic NF-κB, Occludin, and Claudin-5. IL-1β administration partially blocked the Escin-mediated regulation of IL-1β/RhoA/NF-κB signaling pathway. Conclusion: Escin cannot penetrate the blood brain barrier (BBB). Escin improves neurological function and by inhibiting systemic inflammation, and then regulating IL-1β/RhoA/NF-κB signaling pathway in BBB.

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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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Abstract TP349: Recombinant Slit2 Reduces Brain Water Content and Attenuates Neurobehavioral Deficits Following Intracerebral Hemorrhage in a Murine Model

Stroke ◽

10.1161/str.48.suppl_1.tp349 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Sherrefa R Burchell ◽

Cesar Reis ◽

Lingyan Yu ◽

Ningbo Xu ◽

John H Zhang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Water Content ◽

Time Course ◽

Leukocyte Migration ◽

Neurological Deficits ◽

Brain Water Content ◽

Stroke Subtype ◽

Western Blots ◽

Improved Outcomes ◽

Brain Water

Introduction and Hypothesis: Intracerebral hemorrhage (ICH) remains the least treatable and most fatal stroke subtype, being associated with significant vascular disruption, which leads to edema development and the recruitment of inflammatory agents. Slit2, one of a family of three large secreted proteins, has been found to regulate cell proliferation, adhesion, and migration through its receptor, roundabout (Robo)1. We have previously found that administration of recombinant Slit2 (rSlit2) improved outcomes after surgical brain injury. Thus, we hypothesized that Slit2, through the Robo1 receptor, could mitigate ICH-induced neuroinflammation by reducing leukocyte migration, thereby decreasing brain water content (BWC), and improving neurobehavior. Methods: ICH was induced in CD-1 mice by collagenase infusion, as previously established. To determine the expression of Slit2 and Robo1 after ICH, a time course profile (3, 6, 12, 24, and 72 hours) of both proteins was developed by Western Blotting. Then, animals were randomly divided into 5 groups: sham, vehicle, 3μg/kg rSlit2, 10μg/kg rSlit2, and 30μg/kg rSlit2. rSlit2 was administered 1h after ICH, and BWC and neurobehavior assessed at 24 and 72 hours. Western blots and immunohistochemistry will be done to evaluate leukocyte infiltration and other inflammatory markers. Results: Endogenous Slit2 and Robo1 were initially decreased, and then increased after ICH, in comparison to sham. Treatment with rSlit2 significantly reduced brain water content at 24 hours and improved neurological scores. At 72h, there was a tendency for improved brain water content and neurobehavior. We further anticipate that rSlit2 treatment will attenuate leukocyte migration to the injury site, as well as inhibit other pro-inflammatory signals, and these through its action on Robo1. Conclusions: Recombinant Slit2 improved outcomes after murine ICH (BWC and neurological deficits). We expect that this occurs through the inhibition of inflammatory signaling.

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Activation of the Melanocortin-1 Receptor by NDP-MSH Attenuates Oxidative Stress and Neuronal Apoptosis through PI3K/Akt/Nrf2 Pathway after Intracerebral Hemorrhage in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8864100 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Siming Fu ◽

Xu Luo ◽

Xuan Wu ◽

Tongyu Zhang ◽

Linggui Gu ◽

...

Keyword(s):

Oxidative Stress ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Neuronal Apoptosis ◽

Caspase 3 ◽

Neurological Deficits ◽

Enzyme Linked Immunosorbent Assay ◽

Brain Water Content ◽

Melanocortin 1 Receptor ◽

Brain Water

Oxidative stress and neuronal apoptosis play crucial roles in secondary brain injury (SBI) after intracerebral hemorrhage (ICH). Recently, Nle4-D-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), a synthetic agonist of the melanocortin-1 receptor (Mc1r), has been proved to inhibit neuroinflammatory in several diseases. This study is aimed at exploring if NDP-MSH could reduce oxidative stress and neuronal apoptosis following ICH, as well as the potential mechanism. A mouse ICH model was induced by autologous blood injection. NDP-MSH was intraperitoneally injected at 1 h after ICH. Mc1r siRNA and PI3K inhibitor LY294002 were administrated to inhibit the expression of Mc1r and phosphorylation of PI3K, respectively. Neurological test, brain water content, enzyme-linked immunosorbent assay (ELISA), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), immunofluorescence, and Western blot analysis were utilized in this study. The results exhibited that Mc1r was mainly expressed in neurons, and its level in the ipsilateral hemisphere was significantly elevated after ICH. NDP-MSH treatment significantly attenuated the neurological deficits and brain water content 24 hours after ICH, which was accompanied by the inhibition of oxidative stress and neuronal apoptosis. The administration of NDP-MSH after ICH significantly promoted the expression of Mc1r, p-PI3K, p-Akt, and p-Nrf2, followed by an increase of Bcl-2 and reduction of cleaved caspase-3. Conversely, downregulating the expression of Mc1r and phosphorylation of PI3K aggravated the neurological deficits and brain edema at 24 hours after ICH, meanwhile, the effect of NDP-MSH on the expression of Mc1r, p-PI3K, p-Akt, p-Nrf2, Bcl-2, and cleaved caspase 3 was also abolished. In conclusion, our data suggest that the activation of Mc1r by NDP-MSH ameliorates oxidative stress and neuronal apoptosis through the PI3K/Akt/Nrf2 signaling pathway after ICH in mice.

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Role for Target of Rapamycin (mTOR) Signal Pathway in Regulating Neuronal Injury after Intracerebral Hemorrhage

Cellular Physiology and Biochemistry ◽

10.1159/000455983 ◽

2017 ◽

Vol 41 (1) ◽

pp. 145-153 ◽

Cited By ~ 16

Author(s):

Jie-Ping Wang ◽

Meng-Yu Zhang

Keyword(s):

Protein Kinase ◽

Intracerebral Hemorrhage ◽

Protein Expression ◽

Water Content ◽

Caspase 3 ◽

Signal Pathway ◽

Target Of Rapamycin ◽

Neurological Deficits ◽

Brain Water Content ◽

Brain Water

Background/Aims: Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and activation of its signal pathway plays an important role in regulating protein growth and synthesis as well as cell proliferation and survival. In the present study, we examined the contribution of mTOR signal and its downstream products to brain injuries induced by intracerebral hemorrhage (ICH) in rats. Methods: Western Blot analysis was employed to examine the protein expression of mTOR and its downstream pathway and Caspase-3. ELISA was used to measure pro-inflammatory cytokines (PICs) and vascular endothelial growth factor (VEGF). Additionally, neurological Severity Score and brain water content were used to indicate neurological function and brain edema. Results: The protein expression of p-mTOR, mTOR-mediated phosphorylation of 4E–binding protein 4 (4E-BP1), p70 ribosomal S6 protein kinase 1 (S6K1) pathways were amplified in ICH rats compared with controls. Blocking mTOR using rapamycin significantly attenuated upregulation of PICs, namely IL-1β, IL-6 and TNF-α, and Caspase-3 indicating cell apoptosis, and promoted the levels of VEGF and its subtype receptor VEGFR-2 in brain tissues. Moreover, the effects of rapamycin were linked to improvement of neurological deficits and increased brain water content observed in ICH rats. Conclusion: Activation mTOR signal is engaged in pathophysiological process during ICH and blocking mTOR pathway plays a beneficial role in regulating neuronal tissues via PIC, apoptotic Caspase-3 and VEGF mechanisms. This has pharmacological implications to target specific mTOR and its downstream signal pathway for neuronal dysfunction and vulnerability related to ICH.

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Metabolic Insight Into the Neuroprotective Effect of Tao-He-Cheng-Qi (THCQ) Decoction on ICH Rats Using Untargeted Metabolomics

Frontiers in Pharmacology ◽

10.3389/fphar.2021.636457 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rui-Pei Yang ◽

Da-Ke Cai ◽

Yu-Xing Chen ◽

Hai-Ning Gang ◽

Mei Wei ◽

...

Keyword(s):

Lipid Metabolism ◽

Amino Acid ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Sham Group ◽

Neuroprotective Effect ◽

Treated Group ◽

Brain Water Content ◽

Model Group ◽

Brain Water

Tao-He-Cheng-Qi decoction (THCQ) is an effective traditional Chinese medicine used to treat intracerebral hemorrhage (ICH). This study was performed to investigate the possible neuroprotective effect of THCQ decoction on secondary brain damage in rats with intracerebral hemorrhage and to elucidate the potential mechanism based on a metabolomics approach. Sprague-Dawley (SD) rats were randomly divided into five groups: the sham group, collagenase-induced ICH model group, THCQ low-dose (THCQ-L)-treated group, THCQ moderate-dose (THCQ-M)-treated group and THCQ high-dose (THCQ-H)-treated group. Following 3 days of treatment, behavioral changes and histopathological lesions in the brain were estimated. Untargeted metabolomics analysis with multivariate statistics was performed by using ultrahigh-performance liquid chromatography–mass spectrometry (UPLC-Q-Exactive Orbitrap MS). THCQ treatment at two dosages (5.64 and 11.27 g/kg·d) remarkably improved behavior (p < 0.05), brain water content (BMC) and hemorheology (p < 0.05) and improved brain nerve tissue pathology and inflammatory infiltration in ICH rats. Moreover, a metabolomic analysis demonstrated that the serum metabolic profiles of ICH patients were significantly different between the sham group and the ICH-induced model group. Twenty-seven biomarkers were identified that potentially predict the clinical benefits of THCQ decoction. Of these, 4 biomarkers were found to be THCQ-H group-specific, while others were shared between two clusters. These metabolites are mainly involved in amino acid metabolism and glutamate-mediated cell excitotoxicity, lipid metabolism-mediated oxidative stress, and mitochondrial dysfunction caused by energy metabolism disorders. In addition, a correlation analysis showed that the behavioral scores, brain water content and hemorheology were correlated with levels of serum metabolites derived from amino acid and lipid metabolism. In conclusion, the results indicate that THCQ decoction significantly attenuates ICH-induced secondary brain injury, which could be mediated by improving metabolic disorders in cerebral hemorrhage rats.

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Brain edema formation and neurological impairment after subarachnoid hemorrhage in rats

Journal of Neurosurgery ◽

10.3171/2009.3.jns08412 ◽

2009 ◽

Vol 111 (5) ◽

pp. 988-994 ◽

Cited By ~ 31

Author(s):

Serge C. Thal ◽

Sonja Sporer ◽

Mariusz Klopotowski ◽

Simone E. Thal ◽

Johannes Woitzik ◽

...

Keyword(s):

Water Content ◽

Brain Edema ◽

Neuronal Cell ◽

Cell Loss ◽

Neurological Deficits ◽

Brain Water Content ◽

Edema Formation ◽

Neuronal Cell Loss ◽

Brain Water ◽

Brain Edema Formation

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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