Sestrin2 protects against traumatic brain injury by reinforcing the activation of Nrf2 signaling

2020 ◽  
pp. 096032712098422
Author(s):  
Xiaobin Liu ◽  
Min Li ◽  
Jiabao Zhu ◽  
Weidong Huang ◽  
Jinning Song
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
In Vitro Models ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Nuclear Levels

Sestrin2 (SESN2) is stress-inducible protein that confers cytoprotective effects against various noxious stimuli. Accumulating evidence has documented that SESN2 has potent anti-apoptosis and anti-oxidative stress functions. However, whether it provides neuroprotection in traumatic brain injury (TBI) models remains unexplored. The purpose of this study was to explore the regulatory effect of SESN2 on TBI using in vivo and in vitro models. We found that TBI resulted in a marked induction of SESN2 in the cerebral cortex tissues of mice. SESN2 overexpression in the brain by in vivo gene transfer significantly decreased neurological deficit, brain edema, and neuronal apoptosis of mice with TBI. Moreover, the overexpression of SESN2 significantly decreased the oxidative stress induced by TBI in mice. In vitro studies of TBI demonstrated that SESN2 overexpression decreased apoptosis and oxidative stress in scratch-injured cortical neurons. Notably, SESN2 overexpression increased the nuclear levels of nuclear factor-erythroid 2-related factor 2 (Nrf2) and enhanced the activation of Nrf2 antioxidant signaling in in vivo and in vitro models of TBI. In addition, the inhibition of Nrf2 significantly abolished SESN2-mediated neuroprotective effects in vivo and in vitro. In conclusion, these results of our work demonstrate that SESN2 protects against TBI by enhancing the activation of Nrf2 antioxidant signaling.

scholarly journals Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

2020 ◽  
Author(s):  
Han Wang ◽  
Xiaoming Zhou ◽  
Lingyun Wu ◽  
Guangjie Liu ◽  
Weidong Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tunel Staining ◽  
Related Factor ◽  
Mice Model ◽  
Anti Inflammatory

Abstract Background: Aucubin (Au), an iridoid glycoside from natural plants, has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods: In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml or 200 μg/ml) were added in culture medium at 0h and 6h after neurons stimulated by H 2 O 2 (100μM). After exposed for 12 hours, neurons were collected for western blot (WB), immunofluorescence and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. Results: Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

scholarly journals Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

2020 ◽  
Author(s):  
Han Wang ◽  
Xiaoming Zhou ◽  
Lingyun Wu ◽  
Guangjie Liu ◽  
Weidong Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Neurological Deficits ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tunel Staining ◽  
Related Factor ◽  
Mice Model ◽  
Anti Inflammatory

Abstract Background: Aucubin (Au) has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H2O2-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model.Methods: Neuronal apoptosis, brain water content, histological damages and neurological deficits and cognitive functions were measured. We performed western blot, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA). RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with intraperitoneal injection of Au.Results: We found that Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au.Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

scholarly journals WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury

2020 ◽  
Vol 21 (4) ◽  
pp. 1463 ◽  
Author(s):  
Chu-Yuan Chang ◽  
Min-Zong Liang ◽  
Ching-Chih Wu ◽  
Pei-Yuan Huang ◽  
Hong-I Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Ex Vivo ◽  
Neuronal Regeneration ◽  
Functional Behavior ◽  
Functional Behavior Analysis ◽  
Positive Effect

The treatment of traumatic brain injury (TBI) remains a challenge due to limited knowledge about the mechanisms underlying neuronal regeneration. This current study compared the expression of WNT genes during regeneration of injured cortical neurons. Recombinant WNT3A showed positive effect in promoting neuronal regeneration via in vitro, ex vivo, and in vivo TBI models. Intranasal administration of WNT3A protein to TBI mice increased the number of NeuN+ neurons without affecting GFAP+ glial cells, compared to control mice, as well as retained motor function based on functional behavior analysis. Our findings demonstrated that WNT3A, 8A, 9B, and 10A promote regeneration of injured cortical neurons. Among these WNTs, WNT3A showed the most promising regenerative potential in vivo, ex vivo, and in vitro.

scholarly journals N-arachidonoyl-L-serine (AraS) Possesses Proneurogenic Properties in Vitro and in Vivo after Traumatic Brain Injury

2013 ◽  
Vol 33 (8) ◽  
pp. 1242-1250 ◽  
Author(s):  
Ayelet Cohen-Yeshurun ◽  
Dafna Willner ◽  
Victoria Trembovler ◽  
Alexander Alexandrovich ◽  
Raphael Mechoulam ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cannabinoid Receptor ◽  
Fold Increase ◽  
Lesion Volume ◽  
Post Injury ◽  
Neuroprotective Effects ◽  
Neurobehavioral Function

N-arachidonoyl-L-serine (AraS) is a novel neuroprotective endocannabinoid. We aimed to test the effects of exogenous AraS on neurogenesis after traumatic brain injury (TBI). The effects of AraS on neural progenitor cells (NPC) proliferation, survival, and differentiation were examined in vitro. Next, mice underwent TBI and were treated with AraS or vehicle. Lesion volumes and clinical outcome were evaluated and the effects on neurogenesis were tested using immunohistochemistry. Treatment with AraS led to a dose-dependent increase in neurosphere size without affecting cell survival. These effects were partially reversed by CB1, CB2, or TRPV1 antagonists. AraS significantly reduced the differentiation of NPC in vitro to astrocytes or neurons and led to a 2.5-fold increase in expression of the NPC marker nestin. Similar effects were observed in vivo in mice treated with AraS 7 days after TBI. These effects were accompanied by a reduction in lesion volume and an improvement in neurobehavioral function compared with controls. AraS increases proliferation of NPCs in vitro in cannabinoid-receptor-mediated mechanisms and maintains NPC in an undifferentiated state in vitro and in vivo. Moreover, although given at 7 days post injury, these effects are associated with significant neuroprotective effects leading to an improvement in neurobehavioral functions.

scholarly journals Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

2020 ◽  
Author(s):  
Han Wang ◽  
Xiaoming Zhou ◽  
Lingyun Wu ◽  
Guangjie Liu ◽  
Weidong Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Neurological Deficits ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tunel Staining ◽  
Related Factor ◽  
Mice Model ◽  
Anti Inflammatory

Abstract Background: Aucubin (Au) has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods: Neuronal apoptosis, brain water content, histological damages and neurological deficits and cognitive functions were measured. We performed western blot, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA). RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with intraperitoneal injection of Au. Results: We found that Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

scholarly journals Neuroprotective Effects Of The Inert Gas Argon Onexperimental Traumatic Brain Injury In Vivo With The Controlled Cortical Impact Model In Mice

2021 ◽  
Author(s):  
Fritz I. Schneider ◽  
Sandro M Krieg ◽  
Ute Lindauer ◽  
Michael Stoffel ◽  
Yu-Mi Ryang
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Neurological Outcome ◽  
Primary Outcome ◽  
Secondary Outcome ◽  
Outcome Parameter ◽  
Neuroprotective Effects

Abstract BACKGROUND: Argon has shown neuroprotective effects after traumatic brain injury (TBI) and cerebral ischemia in vitro and in focal cerebral ischemia in vivo. The purpose of this study is to show if Argon beneficially impacts brain contusion volume (BCV) as the primary outcome parameter as well as secondary outcome parameters such as brain edema, intracranial pressure (ICP), neurological outcome, and cerebral blood flow (CBF) in an in vivo model.METHODS: Subjects were randomly assigned to either argon treatment or room air. After applying controlled cortical impact (CCI) onto the dura with 8 m/s (displacement 1 mm, impact duration 150 ms), treatment was administered by a recovery chamber with 25%, 50%, or 75% argon and the rest being oxygen for 4 h after trauma. Two control groups received room air for 15 min and 24 h, respectively. Neurological testing and ICP measurements were performed 24 h after trauma, and brains were removed to measure secondary brain damage. RESULTS: The primary outcome parameter BCV and the secondary outcome parameter brain edema were not significantly reduced by argon treatment at any concentration, respectively. There was a highly significant decrease in ICP at 50% argon (p=0.001), and significant neurological improvement (beamwalk missteps) at 25% and 50% argon (p=0.01; p=0.049 respectively) compared to control.CONCLUSIONS: Similar to prior in vitro studies argon exerts its best neuroprotective effects with regard to neurological outcome and ICP at a concentration of 50%. Furthermore, a significant improvement in neurological outcome was observed at an argon concentration of 25%. There was no significant reduction of BCV as the primary outcome parameter.

scholarly journals Lycopene Exerts Neuroprotective Effects After Hypoxic–Ischemic Brain Injury in Neonatal Rats via the Nuclear Factor Erythroid-2 Related Factor 2/Nuclear Factor-κ-Gene Binding Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Changchang Fu ◽  
Yihui Zheng ◽  
Jinjin Zhu ◽  
Binwen Chen ◽  
Wei Lin ◽  
...  
Keyword(s):  
Brain Injury ◽  
Cortical Neurons ◽  
Infarct Volume ◽  
Perinatal Asphyxia ◽  
Related Factor ◽  
Nuclear Factor ◽  
Primary Cortical Neurons ◽  
Study Results

Neonatal hypoxic-ischemic encephalopathy (HIE) is a brain injury caused by perinatal asphyxia and is the main cause of neonatal death and chronic neurological diseases. Protection of neuron after hypoxic-ischemic (HI) brain injury is considered as a potential therapeutic target of HI brain injury. To date, there are no effective medicines for neonatal HI brain injury. Lycopene (Lyc), a member of the carotenoids family, has been reported to have anti-oxidative and anti-inflammatory effects. However, its effects and potential mechanisms in HI brain injury have not yet to be systematically evaluated. In this study, we investigated whether Lyc could ameliorate HI brain injury and explored the associated mechanism both in vivo and in vitro experiments. In vivo study, Lyc significantly reduced infarct volume and ameliorated cerebral edema, decreased inflammatory response, promoted the recovery of tissue structure, and improved prognosis following HI brain injury. In vitro study, results showed that Lyc reduced expression of apoptosis mediators in oxygen-glucose deprivation (OGD)-induced primary cortical neurons. Mechanistically, we found that Lyc-induced Nrf2/NF-κB pathway could partially reversed by Brusatol (an Nrf2 inhibitor), indicated that the Nrf2/NF-κB pathway was involved in the therapy of Lyc. In summary, our findings indicate that Lyc can attenuated HI brain injury in vivo and OGD-induced apoptosis of primary cortical neurons in vitro through the Nrf2/NF-κB signaling pathway.

scholarly journals 6′-O-Galloylpaeoniflorin Attenuates Cerebral Ischemia Reperfusion-Induced Neuroinflammation and Oxidative Stress via PI3K/Akt/Nrf2 Activation

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Zhongmei Wen ◽  
Weichen Hou ◽  
Wei Wu ◽  
Yang Zhao ◽  
Xuechao Dong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pc12 Cells ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Phosphorylated Akt

6′-O-galloylpaeoniflorin (GPF), a galloylated derivative of paeoniflorin isolated from peony root, has been proven to possess antioxidant potential. In this present study, we revealed that GPF treatment exerted significant neuroprotection of PC12 cells following OGD, as evidenced by a reduction of oxidative stress, inflammatory response, cellular injury, and apoptosis in vitro. Furthermore, treatment with GPF increased the levels of phosphorylated Akt (p-Akt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as promoted Nrf2 translocation in PC12 cells, which could be inhibited by Ly294002, an inhibitor of phosphoinositide 3-kinase (PI3K). In addition, Nrf2 knockdown or Ly294002 treatment significantly attenuated the antioxidant, anti-inflammatory, and antiapoptotic activities of GPF in vitro. In vivo studies indicated that GPF treatment significantly reduced infarct volume and improved neurological deficits in rats subjected to CIRI, as well as decreased oxidative stress, inflammation, and apoptosis, which could be inhibited by administration of Ly294002. In conclusion, these results revealed that GPF possesses neuroprotective effects against oxidative stress, inflammation, and apoptosis after ischemia-reperfusion insult via activation of the PI3K/Akt/Nrf2 pathway.

scholarly journals Vitamin D confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

2021 ◽  
Author(s):  
Changmeng Cui ◽  
Changshui Wang ◽  
Feng Jin ◽  
Mengqi Yang ◽  
Lingsheng Kong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Brain Injury ◽  
Neurological Deficits ◽  
Autophagic Flux ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Nrf2 Activation ◽  
Autophagic Process

Abstract Background: Traumatic brain injury (TBI) initiates an oxidative cascade that contributes to the delayed progressive damage, whereas autophagy is critical in maintaining homeostasis during stressful challenge. We previously demonstrated that vitamin D (VitD) shows strong neuroprotective and anti-oxidative properties in the animal models of TBI. Therefore, the present study aimed to further explore the potential interrelationship between oxidative stress and autophagy in the progression of TBI and therapeutic mechanism of VitD. Methods: Neuroprotective effects of calcitriol, the active form of VitD, were examined following TBI. We further evaluated the impacts of TBI and VitD treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling. To confirm the mechanism, chloroquine (CQ) treatment and Nrf2−/− mice were used to block autophagy and Nrf2 pathway, respectively. Results: We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. To further confirm whether autophagy was responsible for Keap1 degradation and Nrf2 activation, the lysosomal inhibitor, CQ, was used to block autophagy. Our data suggested that CQ treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of VitD against both TBI-induced neurological deficits and neuronal apoptosis. Conclusions: Therefore, our work demonstrated a neuroprotective role of VitD in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

scholarly journals Vitamin D confers neuroprotective effects in traumatic brain injury by activating Nrf2 signaling through an autophagy-mediated mechanism

2021 ◽  
Author(s):  
Changmeng Cui ◽  
Changshui Wang ◽  
Feng Jin ◽  
Mengqi Yang ◽  
Lingsheng Kong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Brain Injury ◽  
Neurological Deficits ◽  
Autophagic Flux ◽  
Related Factor ◽  
Neuroprotective Effects ◽  
Nrf2 Activation ◽  
Autophagic Process

Abstract Background: Traumatic brain injury (TBI) initiates an oxidative cascade that contributes to the delayed progressive damage, whereas autophagy is critical in maintaining homeostasis during stressful challenge. We previously demonstrated that vitamin D (VitD) shows strong neuroprotective and anti-oxidative properties in the animal models of TBI. Therefore, the present study aimed to further explore the potential interrelationship between oxidative stress and autophagy in the progression of TBI and therapeutic mechanism of VitD. Methods: Neuroprotective effects of calcitriol, the active form of VitD, were examined following TBI. We further evaluated the impacts of TBI and VitD treatment on autophagic process and nuclear factor E2-related factor 2 (Nrf2) signaling. To confirm the mechanism, chloroquine (CQ) treatment and Nrf2 −/− mice were used to block autophagy and Nrf2 pathway, respectively. Results: We found that treatment of calcitriol markedly ameliorated the neurological deficits and histopathological changes following TBI. The brain damage impaired autophagic flux and impeded Nrf2 signaling, the major regulator in antioxidant response, consequently leading to uncontrolled and excessive oxidative stress. Meanwhile, calcitriol promoted autophagic process and activated Nrf2 signaling as evidenced by the reduced Keap1 expression and enhanced Nrf2 translocation, thereby mitigating TBI-induced oxidative damage. To further confirm whether autophagy was responsible for Keap1 degradation and Nrf2 activation, the lysosomal inhibitor, CQ, was used to block autophagy. Our data suggested that CQ treatment abrogated calcitriol-induced autophagy and compromised Nrf2 activation with increased Keap1 accumulation and reduced expression of Nrf2-targeted genes. Additionally, both CQ treatment and Nrf2 genetic knockout abolished the protective effects of VitD against both TBI-induced neurological deficits and neuronal apoptosis. Conclusions: Therefore, our work demonstrated a neuroprotective role of VitD in TBI by triggering Nrf2 activation, which might be mediated by autophagy.

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