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

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

Biological Research ◽

10.1186/s40659-020-00323-1 ◽

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.

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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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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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Endoplasmic Reticulum Stress Response and Transcriptional Reprogramming

10.3389/978-2-88919-436-0 ◽

2015 ◽

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Endoplasmic Reticulum Stress ◽

Endoplasmic Reticulum Stress Response ◽

Transcriptional Reprogramming

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Faculty Opinions recommendation of The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718877833.793499944 ◽

2014 ◽

Author(s):

Alberto Luini

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Protein Kinase ◽

Endoplasmic Reticulum Stress ◽

Mitogen Activated Protein Kinase ◽

Signaling Cascades ◽

Endoplasmic Reticulum Stress Response ◽

Mitogen Activated Protein ◽

Protein Kinase Signaling ◽

Kdel Receptor

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Effects of Pharmacological Dose of Dexamethasone Given Postnatally on Blood-Brain Barrier Permeability and Brain Water Content

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2002.282.2.r632 ◽

2002 ◽

Vol 282 (2) ◽

pp. R632-R633

Author(s):

P. Temesvári k. Lazics f. Domoki f. Bari

Keyword(s):

Water Content ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Water Content ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Brain Water

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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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