scholarly journals Glymphatic Drainage Blocking Aggravates Brain Edema, Neuroinflammation via Modulating TNF-α, IL-10, and AQP4 After Intracerebral Hemorrhage in Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Xichang Liu ◽  
Gang Wu ◽  
Na Tang ◽  
Li Li ◽  
Cuimin Liu ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neurological Deficits ◽  
Protective Mechanism ◽  
Cervical Lymph Nodes ◽  
Glymphatic System ◽  
Tnf Α ◽  
Active Caspase

Objective: The “Glymphatic” system, a network of perivascular tunnels wrapped by astrocyte endfeet, was reported to be closely associated with the diseases of the central nervous system. Here, we investigated the role of the glymphatic system in intracerebral hemorrhage (ICH) and its protective mechanism.Method: Experimental ICH model was induced by type IV collagenase in rats. Cerebral lymphatic blockage was induced by ligation and removal of cervical lymph nodes. The experimental rats were divided into sham-operated (SO) group, ICH group, and cerebral lymphatic blocking and ICH (ICH + CLB) group. Neurological scores were measured using the Garcia scoring system on the third and seventh day after ICH. Active caspase-3 was immunostained to evaluate neuronal apoptosis. Brain water content was calculated using the dry-wet specific gravity method. The expression of inflammatory factors TNF-α, IL-1β, and IL-10 were detected using ELISA. Aquaporins-4 (AQP-4) and glial fibrillary acidic protein (GFAP) were detected using western blot analysis.Results: The neurological scores of rats in the CLB + ICH group were significantly lower than those in the in ICH group. The number of active caspase-3 neurons was significantly higher in the CLB + ICH group compared to the ICH group. CLB significantly aggravated ICH-induced brain edema 3 d after ICH. There was an increase in the expression of TNF-α, IL-1β, IL-10, AQP-4, GFAP after ICH. The expression of TNF-α was significantly higher in the CLB + ICH group compared to ICH group 3 d after ICH while there was no difference 7 d after ICH. There was no statistical difference in the expression of IL-1β between the ICH group and CLB + ICH group. However, the expression of IL-10 in the CLB + ICH group was significantly lower than that in the ICH group. Lastly, AQP-4 expression was significantly lower in the CLB + ICH group compared to the ICH group while the expression of GFAP was higher in the CLB + ICH group compared to the ICH group.Conclusion: CLB exacerbated cerebral edema, neuroinflammation, neuronal apoptosis and caused neurological deficits in rats with ICH via down-regulating AQP-4, up-regulating inflammatory TNF-α and inhibiting IL-10 expression. The glymphatic drainage system protects against neurologic injury after ICH induction in rats under normal physiological conditions.

scholarly journals Nrdp1 increases neuron apoptosis via downregulation of Bruce following intracerebral haemorrhage

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Changlong Zhou ◽  
Qingjun Liu ◽  
Wang Zhao ◽  
Ling Yang ◽  
Zhongyan Huang ◽  
...  
Keyword(s):  
Brain Edema ◽  
Cortical Neurons ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Neurological Injury ◽  
Apoptosis Protein ◽  
And Oxidative Stress ◽  
Active Caspase ◽  
Pro Inflammatory Cytokines

Abstract Background Neuregulin receptor degradation protein-1 (Nrdp1) is an E3 ubiquitin ligase that plays an important role in regulating cell growth, apoptosis and oxidative stress. However, the data regarding its expression and exact mechanism in neuronal injury following ICH has not been well identified. Methods In this study, primary cortical neurons from C57BL/6 mice were subjected to erythrocyte lysates. Nrdp1 expression, cell apoptosis, caspase-3 and BRUCE levels were detected. In addition, inflammatory response, brain edema, and neurological injury in ICH mice were also assessed. Results We found that the expression of Nrdp1 was significantly increased in neuron cells accompanied by up-regulation of active caspase-3 and decreased expression of BRUCE (an inhibitor of apoptosis protein). However, inhibiting Nrdp1 levels of neurons reduced caspase-3 activity but induced up-regulation of BRUCE. In vivo, inhibiting Nrdp1 levels increased pro-inflammatory cytokines, brain edema, and neurological injury following ICH. Conclusions Taken together, the data suggested that Nrdp1 might play a crucial role in neuronal apoptosis via inhibiting BRUCE following ICH.

scholarly journals 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

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.

Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal

2019 ◽  
Vol 19 (8) ◽  
pp. 597-604
Author(s):  
Li Pang ◽  
Shouqin Ji ◽  
Jihong Xing
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Caspase 3 ◽  
Global Ischemia ◽  
Neurological Deficits ◽  
Global Cerebral Ischemia ◽  
Caspase 9 ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Transient Global Ischemia

Background: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. Methods: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. Results: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1β, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. Conclusion: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

Gastrodin Attenuates Neuronal Apoptosis and Neurological Deficits after Experimental Intracerebral Hemorrhage

2020 ◽  
Vol 29 (1) ◽  
pp. 104483 ◽  
Author(s):  
Xi-chang Liu ◽  
Chang-zhu Wu ◽  
Xiao-fei Hu ◽  
Ting-ling Wang ◽  
Xiao-ping Jin ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Neuronal Apoptosis ◽  
Neurological Deficits

scholarly journals A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats

2017 ◽  
Vol 43 (2) ◽  
pp. 644-659 ◽  
Author(s):  
Azza H. Abd Elwahab ◽  
Basma K. Ramadan ◽  
Mona F. Schaalan  ◽  
Amina M. Tolba
Keyword(s):  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Cafeteria Diet ◽  
Control Group ◽  
Albino Rats ◽  
Protective Mechanism ◽  
Alcoholic Fatty Liver ◽  
Group I ◽  
Tnf Α

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the alarmingly rising clinical problems in the 21st century with no effective drug treatment until now. Taurine is an essential amino acid in humans that proved efficacy as a non-pharmacological therapy in a plethora of diseases; however, its impact on NAFLD remains elusive. The aim of the current study is to evaluate the protective mechanism of taurine in experimental steatohepatitis induced by junk food given as cafeteria-diet (CAF-D) in male albino rats. Methods: Forty adult male albino rats of local strain between 8-10 weeks old, weighing 150 ± 20 g, were divided into four equal groups: Group I (control group), Group II (Taurine group), Group III (CAF-D for 12 weeks) and Group IV (CAF-D +Taurine). CAF-D was given in addition to the standard chow for 12 weeks, where each rat was given one piece of beef burger fried in 15 g of sunflower oil, one teaspoonful of mayonnaise, and one piece of petit pan bread, weighing 60g/ piece. In the serum, liver function tests; ALT, AST, ALP, GGT and the lipid profile; TG, TC, HDL-C added to reduced glutathione (GSH) were assessed colorimetrically, while fibroblast growth factor (FGF)-21, adiponectin & interleukin (IL)-6 via ELISA. The same technique was used for the assays of the hepatic levels of FGF-21, silent information regulator (SIRT1), malondialdehyde (MDA),IL-10, tumor necrosis factor-α (TNF-α) as well as the apoptotic markers; caspase-3 and B-cell lymphoma (Bcl-2). Results: The cafeteria-diet induced steatohepatitis was reflected by significantly increased body and liver weight gain, elevation of liver enzymes; ALT, AST, ALP and GGT added to the dyslipidemic panel, presented as increased TC, TG, LDL-C and decreased HDL-C levels. The steatosis-induced inflammatory milieu, marked by elevated serum levels of FGF-21, IL-6, hepatic TNF-α, as well as reduced IL-10 and adiponectin, was associated with steatosis- induced hepatic oxidative stress, reflected by increased hepatic MDA and decreased GSH levels, along with stimulated caspase-3 and decline in BcL-2 hepatic levels. These pathological disturbances were significantly ameliorated by taurine supplementation and evidenced histopathologically. The cross talk between hepatic FGF-21 and SIRT1 and their association to the induced perturbations are novel findings in this study. Taurine's efficacy in restoration of hepatic structure and function is partially via the increase in SIRT1 and associated reduction of FGF-21. Conclusion: The findings of the current study prove the protective role of taurine in NAFLD via a novel role in the amelioration of FGF-21/ SIRT1 axis, which could be considered a new therapeutic target.

scholarly journals 17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110384
Author(s):  
Han Xiao ◽  
Jianyang Liu ◽  
Jialin He ◽  
Ziwei Lan ◽  
Mingyang Deng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Akt Signaling ◽  
Neurological Deficits ◽  
Akt Signaling Pathway ◽  
And Oxidative Stress

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood–brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

scholarly journals miR-7-5p Affects Brain Edema After Intracerebral Hemorrhage and Its Possible Mechanism

2020 ◽  
Vol 8 ◽  
Author(s):  
Xiqian Chen ◽  
Shuwen Deng ◽  
Qiang Lei ◽  
Qiang He ◽  
Yijun Ren ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Blue Staining ◽  
Akt Pathway ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Aqp4 Expression ◽  
Neutrophil Lymphocyte Ratio ◽  
Reactive Protein ◽  
Tnf Α

Objective: To explore the relationship between miR-7-5p and brain edema after intracerebral hemorrhage and the role of butylphthalide (NBP) in brain edema after intracerebral hemorrhage.Method: Routine blood testing, C-reactive protein results, and computed tomography data were collected 1, 7, and 14 days after intracerebral hemorrhage in six patients. Levels of MMP-9, ZO-1, occludin, IL-6, TNF-α, and miR-7-5p were detected in each patient's serum. Sixty male Sprague–Dawley rats were randomly divided into sham operation, intracerebral hemorrhage, and NBP treatment groups. Dry–wet weight was used to assess brain edema, and Evans blue staining was used to assess the permeability of the blood–brain barrier. Expression levels of IL-6, TNF-α, ZO-1 and occludin, PI3K, AKT, p-AKT, AQP4, and miR-7-5p were analyzed in the rat brains.Result: The blood neutrophil–lymphocyte ratio (NLR) on day 1 was associated with the area of brain edema on day 7. The expression of miR-7-5p decreased after intracerebral hemorrhage, and as a result, the inhibition of the PI3K/AKT pathway was weakened. The decreased inhibition of the PI3K/AKT pathway resulted in an increase in AQP4 expression, which further aggravated brain edema. NBP can upregulate the expression of miR-7-5p, affecting these pathways to reduce brain edema.Conclusion: After intracerebral hemorrhage, miR-7-5p expression in brain tissue is reduced, which may increase the expression of AQP4 by activating the PI3K/AKT pathway. NBP can inhibit this process and reduce brain edema.

scholarly journals The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiaowei Fei ◽  
Yeting He ◽  
Jia Chen ◽  
Weitao Man ◽  
Chen Chen ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Knockout Mice ◽  
Neuronal Apoptosis ◽  
Inflammatory Factors ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Tnf Α ◽  
Apoptotic Effect

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

Paricalcitol pretreatment attenuates renal ischemia/reperfusion injury by inhibiting p38 MAPK and activating PI3K/Akt signaling pathways

2019 ◽  
Vol 44 (4) ◽  
pp. 452-461
Author(s):  
Zahide Cavdar ◽  
Cemre Ural ◽  
Ayse Kocak ◽  
Sevki Arslan ◽  
Sibel Ersan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Albino Rats ◽  
Sod Activity ◽  
Interstitial Inflammation ◽  
Tnf Α ◽  
Active Caspase

Abstract Objective This study aimed to investigate the renoprotective effects of paricalcitol, a synhetic vitamin D analog, through its possible roles on p38 MAPK and PI3K/Akt signaling pathways to prevent oxidative stress, inflammation and apoptosis during renal I/R. Materials and methods Total 20 kidney tissues of sham (n = 6), subjected to renal I/R bilaterally for 45 min ischemia followed by 24 h reperfusion (n = 7) and paricalcitol (0.3 μg/kg, ip) pretreated Wistar albino rats (n =7) were used in this study. Interstitial inflammation and active caspase-3 expression were evaluated histologically. TNF-α, IL-1β, kidney injury molecule-1 (KIM-1), MDA and SOD activity in kidneys were analysed biochemically. Furthermore, activation of p38 MAPK, PI3K/Akt signaling pathways and NFκB p65 were evaluated by western blot. Results Paricalcitol pretreatment significantly reduced interstitial inflammation during renal I/R, which was consistent with decreased tumor TNF-α, IL-1β, active caspase-3 and KIM-1 expression. Paricalcitol also reduced MDA level and attenuated the reduction of SOD activity in the kidney during I/R. Moreover, paricalcitol could suppress the p38 MAPK and NFκB p65, and also activate PI3K/Akt signaling pathway during renal I/R. Conclusion All these findings indicate that paricalcitol may be an effective practical strategy to prevent renal I/R injury.

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