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

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.

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

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.

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

2017 ◽  
Vol 30 (4) ◽  
pp. 413-419 ◽  
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.

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

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.

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

2015 ◽  
Vol 290 ◽  
pp. 161-171 ◽  
Author(s):  
Devin W. McBride ◽  
Yuechun Wang ◽  
Prativa Sherchan ◽  
Jiping Tang ◽  
John H. Zhang
Keyword(s):  
Brain Injury ◽  
Water Content ◽  
Brain Water Content ◽  
Sensorimotor Deficits ◽  
Surgical Brain Injury ◽  
Brain Water

scholarly journals Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

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.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
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.

scholarly journals Tauroursodeoxycholic acid attenuates neuronal apoptosis via the TGR5/ SIRT3 pathway after subarachnoid hemorrhage in rats

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Huihui Wu ◽  
Nini Yu ◽  
Xia Wang ◽  
Yina Yang ◽  
Hui Liang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Water Content ◽  
Neuronal Apoptosis ◽  
Critical Event ◽  
Tunel Staining ◽  
Protective Effects ◽  
Brain Water Content ◽  
Sprague Dawley ◽  
Tauroursodeoxycholic Acid ◽  
Brain Water

Abstract Background Neuronal apoptosis plays a critical event in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). This study investigated the roles of Tauroursodeoxycholic acid (TUDCA) in attenuate neuronal apoptosis and underlying mechanisms after SAH. Methods Sprague–Dawley rats were subjected to model of SAH and TUDCA was administered via the internal carotid injection. Small interfering RNA (siRNA) for TGR5 were administered through intracerebroventricular injection 48 h before SAH. Neurological scores, brain water content, Western blot, TUNEL staining and immunofluorescence staining were evaluated. Results TUDCA alleviated brain water content and improved neurological scores at 24 h and 72 h after SAH. TUDCA administration prevented the reduction of SIRT3 and BCL-2 expressions, as well as the increase of BAX and cleaved caspase-3.Endogenous TGR5 expression were upregulated after SAH and treatment with TGR5 siRNA exacerbated neurological outcomes after SAH and the protective effects of TUDCA at 24 h after SAH were also abolished by TGR5 siRNA. Conclusions Our findings demonstrate that TUDCA could attenuated neuronal apoptosis and improve neurological functions through TGR5/ SIRT3 signaling pathway after SAH. TUDCA may be an attractive candidate for anti-apoptosis treatment in SAH.

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

1989 ◽  
Vol 559 (1 Arachidonie A) ◽  
pp. 431-432 ◽  
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

scholarly journals Sex Differences in Cerebral Edema after Experimental Traumatic Brain Injury

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.

Dexmedetomidine Inhibits Endoplasmic Reticulum Stress Response and Improves Neurological Function After Traumatic Brain Injury in Rats

2019 ◽  
Vol 9 (8) ◽  
pp. 1038-1044
Author(s):  
Hanqing Zang ◽  
Jing Li ◽  
Linxing Yang ◽  
Wendong Sun ◽  
Jing Han
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Water Content ◽  
Neuronal Apoptosis ◽  
Neurological Impairment ◽  
Endoplasmic Reticulum Stress Response ◽  
Brain Water Content ◽  
Caspase 12 ◽  
Group B ◽  
Brain Water

Dexmedetomidine (DEX) can inhibit neuronal apoptosis. There are multiple secondary lesions following traumatic brain injury (TBI). Our study evaluated the application of DEX in TBI by observing neurological impairment score, brain edema, nerve cells apoptosis, and endoplasmic reticulum stress response (ERS). SD rats were selected to establish TBI model using modified Feeney method and then randomly divided into sham operation group (A), TBI group (B), TBI + DEX group (C), and TBI + DEX + endoplasmic reticulum stress inducer 2-deoxyglucose (2-DG) group (D). The neurological injury severity score (mNSS) was measured on day 1, 3, and 7 after injury. The water content of brain tissue was measured. The pathology of brain tissue was observed on the 7th day after craniocerebral injury. Caspase-12 and IRE-1 were determined by Western blot. Apoptosis was assessed by TUNEL assay. CHOP and Glucose Regulatory Protein 78 (GRP78) expressions were detected by immunohistochemistry (IHC). Compared with group A, mNSS scores, brain water content, and neuronal apoptosis were increased, and caspase-12, IRE-1, CHOP, and GRP78 proteins were upregulated in groups B, C, and D (P < 0.05). Compared to group B, the neurological function was improved, brain water content and neuronal apoptosis were decreased, and caspase-12, IRE-1, CHOP, and GRP78 protein expressions were reduced in group C (P < 0.05). Neurological impairment was aggravated, brain water content and nerve cell apoptosis were increased, and caspase-12, IRE-1, CHOP, and GRP78 protein expressions were upregulated in group D compared to group C (P < 0.05). DEX treatment can alleviate brain edema after TBI and inhibit neuronal apoptosis, which has neuroprotective effects. Its mechanism may be related to ERS after TBI inhibition.

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