Correlation between subacute sensorimotor deficits and brain water content after surgical brain injury in rats

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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Inhibition of LRRK2-Rab10 Pathway Improves Secondary Brain Injury After Surgical Brain Injury in Rats

Frontiers in Surgery ◽

10.3389/fsurg.2021.749310 ◽

2022 ◽

Vol 8 ◽

Author(s):

Jie Li ◽

Muyao Wu ◽

Yating Gong ◽

Jiafeng Tang ◽

Jinchao Shen ◽

...

Keyword(s):

Brain Injury ◽

Water Content ◽

Neuronal Apoptosis ◽

Specific Inhibitor ◽

Secondary Brain Injury ◽

Brain Water Content ◽

Kinase Substrate ◽

Rab Protein ◽

Surgical Brain Injury ◽

Brain Water

Leucine-rich repeat kinase 2 (LRRK2) is considered as a potential target for the treatment of Parkinson's disease. This protein is expressed in the brain and has been associated with various diseases and lysosomal maintenance. Rab10 is a member of the Rab protein GTPase family that has been recently shown to be a kinase substrate of LRRK2. In addition, LRRK2 and its kinase substrate Rab10 constitute a key stress response pathway during lysosomal overload stress. This study aimed to investigate the potential role and mechanism underlying LRRK2 and its kinase substrate Rab10 involving surgical brain injury (SBI). One hundred and forty-four male Sprague-Dawley rats were examined using an SBI model, and some had received the LRRK2-specific inhibitor PF-06447475. Thereafter, western blotting, immunofluorescence, brain water content analysis, neuronal apoptosis assay, and neurological score analysis were conducted. The results showed that after SBI, LRRK2 and phosphorylated Rab10 (p-Rab10) expression in neuronal cells were upregulated, and administration of PF-06447475 significantly reduced neuronal apoptosis, neuroinflammation, and brain water content 12 h after SBI and improved neurological deficit 72 h after SBI, which is related to the decreased expression of LRRK2 and p-Rab10, and the lessening of lysosomal overload stress. Our research suggests that the inhibition of LRRK2 can effectively interfere with the role of p-Rab10 in promoting the secretion of lysosomal hydrolase in lysosomal overload stress after SBI, thereby reducing neuronal apoptosis and inflammation after SBI and playing a major role in brain protection.

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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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FGF10 Attenuates Experimental Traumatic Brain Injury through TLR4/MyD88/NF-κB Pathway

Cells Tissues Organs ◽

10.1159/000511381 ◽

2021 ◽

pp. 1-9

Author(s):

Qinhan Hou ◽

Hongmou Chen ◽

Quan Liu ◽

Xianlei Yan

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protein Expression ◽

Water Content ◽

Neurological Deficit ◽

Neuronal Apoptosis ◽

Neuronal Damage ◽

Intraventricular Injection ◽

Brain Water Content ◽

Brain Water

Traumatic brain injury (TBI) can induce neuronal apoptosis and neuroinflammation, resulting in substantial neuronal damage and behavioral disorders. Fibroblast growth factors (FGFs) have been shown to be critical mediators in tissue repair. However, the role of FGF10 in experimental TBI remains unknown. In this study, mice with TBI were established via weight-loss model and validated by increase of modified neurological severity scores (mNSS) and brain water content. Secondly, FGF10 levels were elevated in mice after TBI, whereas intraventricular injection of Ad-FGF10 decreased mNSS score and brain water content, indicating the remittance of neurological deficit and cerebral edema in TBI mice. In addition, neuronal damage could also be ameliorated by stereotactic injection of Ad-FGF10. Overexpression of FGF10 increased protein expression of Bcl-2, while it decreased Bax and cleaved caspase-3/PARP, and improved neuronal apoptosis in TBI mice. In addition, Ad-FGF10 relieved neuroinflammation induced by TBI and significantly reduced the level of interleukin 1β/6, tumor necrosis factor α, and monocyte chemoattractant protein-1. Moreover, Ad-FGF10 injection decreased the protein expression level of Toll-like receptor 4 (TLR4), MyD88, and phosphorylation of NF-κB (p-NF-κB), suggesting the inactivation of the TLR4/MyD88/NF-κB pathway. In conclusion, overexpression of FGF10 could ameliorate neurological deficit, neuronal apoptosis, and neuroinflammation through inhibition of the TLR4/MyD88/NF-κB pathway, providing a potential therapeutic strategy for brain injury in the future.

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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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Effects of Traumatic Brain Injury on Arachidonic Acid Metabolism and Brain Water Content in the Rat

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1989.tb22630.x ◽

1989 ◽

Vol 559 (1 Arachidonie A) ◽

pp. 431-432 ◽

Cited By ~ 5

Author(s):

PAUL DEMEDIUK ◽

ALAN I. FADEN ◽

ROBERT VINK ◽

ROBERT ROMHANYI ◽

TRACY K. McINTOSH

Keyword(s):

Traumatic Brain Injury ◽

Arachidonic Acid ◽

Brain Injury ◽

Water Content ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Brain Water Content ◽

Brain Water

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Sex Differences in Cerebral Edema after Experimental Traumatic Brain Injury

10.1101/2021.06.25.449932 ◽

2021 ◽

Author(s):

Heather M Minchew ◽

Sarah K Christian ◽

Paul Keselman ◽

Jinxiang Hu ◽

Brian T Andrews ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Sex Differences ◽

Brain Injury ◽

Water Content ◽

Cerebral Edema ◽

Contralateral Side ◽

Female Rats ◽

Male Rats ◽

Brain Water Content ◽

Brain Water

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Cerebral edema following TBI is known to play a critical role in injury severity and prognosis. In the current study we used multimodal magnetic resonance imaging (MRI) to assess cerebral edema 24 hours after unilateral contusive TBI in male and female rats. We then directly quantified brain water content in the same subjects ex vivo. We found that in male rats, the injured cortex had higher brain water content and lower apparent diffusion coefficient (ADC) values compared with the contralateral side. Females did not show hemispheric differences for these measures. However, both males and females had similarly elevated T2 values in the injured cortex compared with the contralateral side. A strong correlation was observed between brain water content and T2 values in the injured cortex in male rats, but not in females. These findings raise questions about the clinical interpretation of radiological findings pertinent to edema in female TBI patients. A more mechanistic understanding of sex differences and similarities in TBI pathophysiology will help improve patient management and the development of effective treatment strategies for TBI in men and women.

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Resuscitation with Pooled and Pathogen-Reduced Plasma Attenuates the Increase in Brain Water Content following Traumatic Brain Injury and Hemorrhagic Shock in Rats

Journal of Neurotrauma ◽

10.1089/neu.2016.4574 ◽

2017 ◽

Vol 34 (5) ◽

pp. 1054-1062 ◽

Cited By ~ 13

Author(s):

Gustav Folmer Genét ◽

Peter Bentzer ◽

Sisse Rye Ostrowski ◽

Pär Ingemar Johansson

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Hemorrhagic Shock ◽

Water Content ◽

Brain Water Content ◽

Brain Water

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The Antiedematous Effect of Exogenous Lactate Therapy in Traumatic Brain Injury: A Physiological and Mechanistic Approach

Neurocritical Care ◽

10.1007/s12028-021-01219-y ◽

2021 ◽

Author(s):

David Emmanuel Duhaut ◽

Catherine Heurteaux ◽

Carine Gandin ◽

Carole Ichai ◽

Hervé Quintard

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Water Content ◽

Oxygen Pressure ◽

Chloride Channels ◽

Brain Water Content ◽

Tissue Oxygen ◽

Cerebral Tissue ◽

Brain Water ◽

Tissue Oxygen Pressure

Abstract Background Sodium lactate (SL) has been described as an efficient therapy in treating raised intracranial pressure (ICP). However, the precise mechanism by which SL reduces intracranial hypertension is not well defined. An antiedematous effect has been proposed but never demonstrated. In this context, the involvement of chloride channels, aquaporins, or K–Cl cotransporters has also been suggested, but these mechanisms have never been assessed when using SL. Methods In a rat model of traumatic brain injury (TBI), we compared the effect of SL versus mannitol 20% on ICP, cerebral tissue oxygen pressure, and brain water content. We attempted to clarify the involvement of chloride channels in the antiedematous effects associated with lactate therapy in TBI. Results An equimolar single bolus of SL and mannitol significantly reduced brain water content and ICP and improved cerebral tissue oxygen pressure 4 h after severe TBI. The effect of SL on brain water content was much longer than that of mannitol and persisted at 24 h post TBI. Western blot and immunofluorescence staining analyses performed 24 h after TBI revealed that SL infusion is associated with an upregulation of aquaporin 4 and K–Cl cotransporter 2. Conclusions SL is an effective therapy for treating brain edema after TBI. This study suggests, for the first time, the potential role of chloride channels in the antiedematous effect induced by exogenous SL.

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Intracerebral Hemorrhage in Mice: Model Characterization and Application for Genetically Modified Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200405000-00002 ◽

2004 ◽

Vol 24 (5) ◽

pp. 487-494 ◽

Cited By ~ 84

Author(s):

Takehiro Nakamura ◽

Guohua Xi ◽

Ya Hua ◽

Timothy Schallert ◽

Julian T. Hoff ◽

...

Keyword(s):

Brain Injury ◽

Basal Ganglia ◽

Intracerebral Hemorrhage ◽

Water Content ◽

Gene Knockout ◽

Brain Water Content ◽

Male Mice ◽

Behavioral Deficits ◽

Autologous Whole Blood ◽

Brain Water

Gene knockout or transgenic animals may assist in elucidating the mechanisms of brain injury after intracerebral hemorrhage (ICH). However, almost all commercially available transgenic or knockout animals are mice. The purpose of this study was to develop an ICH model in mice and to investigate the influence of gender and complement C5 genetic differences on outcome after ICH. Male and female C57BL/6 mice and C5-deficient and -sufficient control mice were anesthetized and then received an injection of 30 μL autologous whole blood into the right basal ganglia. Brain water content was studied at 1 and 3 days after ICH. Behavioral tests (forelimb use asymmetry and corner turn test) were performed at 1, 3, 7, 14, 21, or 28 days after ICH. In male mice, brain water content was significantly increased in the ipsilateral basal ganglia 1 and 3 days after ICH, compared with saline injection controls ( P>0.01). There were marked neurological deficits 1 and 3 days after ICH, with progressive recovery over 28 days. In contrast, although brain edema and behavioral deficits were similar at 1 day after ICH in female and male mice, female mice showed reduced edema at 3 days and a faster recovery of behavioral deficits after ICH. 17β-estradiol treatment in male mice markedly reduced ICH-induced edema ( P>0.01). Brain water content was significantly increased in C5-deficient mice compared with C5-sufficient at 3 days after ICH ( P>0.05). These findings suggest that the mouse ICH model is a reproducible and feasible model. These results also suggest that gender and complement C5 are factors affecting brain injury after ICH.

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