scholarly journals Induction of the Vitamin D Receptor Attenuates Autophagy Dysfunction-Mediated Cell Death Following Traumatic Brain Injury

2017 ◽  
Vol 42 (5) ◽  
pp. 1888-1896 ◽  
Author(s):  
Changmeng Cui ◽  
Jianzhong Cui ◽  
Feng Jin ◽  
Ying Cui ◽  
Ran Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Cell Death ◽  
Brain Injury ◽  
Protein Expression ◽  
Rat Brain ◽  
Male Rats ◽  
Autophagic Flux ◽  
Sham Operation ◽  
Protective Effects

Background/Aims: Traumatic brain injury (TBI) is a major public health problem in the world and causes high rates of mortality and disability. Recent evidence suggests that vitamin D (VD) has neuroprotective actions and can promote function recovery after TBI. In vitro and in vivo studies have demonstrated that autophagy could be enhanced following supplementation with an active metabolite of VD (calcitriol). However, it is unclear whether autophagy participates in the protective effects of calcitriol after TBI. To test this hypothesis, we examined the protective effects of calcitriol on TBI-induced neurological impairment and further investigated whether calcitriol could modulate autophagy dysfunction-mediated cell death in the cortex region of rat brain. Methods: Eighty-five male rats (250-280 g) were randomly assigned to sham (n=15), TBI model (TBI, n=35) and calcitriol treatment (calcitriol, n=35) groups. Rats were injected intraperitoneally with calcitriol (1 µg/kg) at 30 min, 24 h and 48 h post-TBI in the calcitriol group. The lysosomal inhibitor, chloroquine (CQ), was used to evaluate autophagic flux in the TBI and calcitriol groups. Neurological functions were evaluated via the modified neurological severity score test at 1-7 days after TBI or sham operation, and the terminal deoxynucleotidyl transferase-mediated FITC-dUTP nick-end labeling method was used to evaluate the ability of calcitriol to inhibit apoptosis. The expression of VDR, LC3 and p62 proteins was measured by western blot analysis at 1, 3 and 7 days post-injury Results: Calcitriol treatment attenuated mNSS at 2-7 days post-TBI (P < 0.05 versus TBI group). Calcitriol dramatically increased VDR protein expression compared with the untreated counterparts at 1, 3 and 7 days post-TBI (P < 0.05). The rate of apoptotic cells in calcitriol-treated rats was significantly reduced compared to that observed in the TBI group (P < 0.05). The LC3II/LC3I ratio was decreased in the cortex region at 1, 3 and 7 days post-TBI in rats treated with calcitriol (p < 0.05 versus TBI group), and the p62 expression was also attenuated (p < 0.05 versus TBI group). The LC3II/LC3I ratio in the calcitriol group was significantly increased when pretreated with CQ (P < 0.05). Conclusion: Calcitriol treatment activated VDR protein expression and attenuated neurological deficits in this rat TBI model. The protective effects might be associated with the restoration of autophagy flux and the decrease in apoptosis in the cortex region of rat brain.

Protective effects of zinc chelation in traumatic brain injury correlate with upregulation of neuroprotective genes in rat brain

2004 ◽  
Vol 355 (3) ◽  
pp. 221-225 ◽  
Author(s):  
Helen L Hellmich ◽  
Christopher J Frederickson ◽  
Douglas S DeWitt ◽  
Ricardo Saban ◽  
Margaret O Parsley ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Rat Brain ◽  
Protective Effects ◽  
Zinc Chelation

scholarly journals Beneficial Effects of Ethyl Pyruvate through Inhibiting High-Mobility Group Box 1 Expression and TLR4/NF-κB Pathway after Traumatic Brain Injury in the Rat

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Xingfen Su ◽  
Handong Wang ◽  
Jinbing Zhao ◽  
Hao Pan ◽  
Lei Mao
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Ethyl Pyruvate ◽  
Apoptotic Cell ◽  
High Mobility ◽  
High Mobility Group ◽  
Male Rats ◽  
Vehicle Group ◽  
Secondary Brain Injury ◽  
Protective Effects

Ethyl pyruvate (EP) has demonstrated neuroprotective effects against acute brain injury through its anti-inflammatory action. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from dying cells. This study was designed to investigate the protective effects of EP against secondary brain injury in rats after Traumatic Brain Injury (TBI). Adult male rats were randomly divided into three groups: (1) Sham + vehicle group, (2) TBI + vehicle group, and (3) TBI + EP group (n=30per group). Right parietal cortical contusion was made by using a weight-dropping TBI method. In TBI + EP group, EP was administered intraperitoneally at a dosage of 75 mg/kg at 5 min, 1 and 6 h after TBI. Brain samples were harvested at 24 h after TBI. We found that EP treatment markedly inhibited the expressions of HMGB1 and TLR4, NF-κB DNA binding activity and inflammatory mediators, such as IL-1β, TNF-αand IL-6. Also, EP treatment significantly ameliorated beam walking performance, brain edema, and cortical apoptotic cell death. These results suggest that the protective effects of EP may be mediated by the reduction of HMGB1/TLR4/NF-κB-mediated inflammatory response in the injured rat brain.

scholarly journals Vitamin D Receptor Activation Influences NADPH Oxidase (NOX2) Activity and Protects against Neurological Deficits and Apoptosis in a Rat Model of Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Changmeng Cui ◽  
Sixin Song ◽  
Jianzhong Cui ◽  
Yan Feng ◽  
Junling Gao ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Vitamin D ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Neurological Diseases ◽  
Receptor Activation ◽  
Neurological Deficits ◽  
Protective Effects ◽  
Ca1 Region ◽  
Neurobehavioral Deficits

Traumatic brain injury (TBI) is a worldwide phenomenon which results in significant neurological and cognitive deficits in humans. Vitamin D (VD) is implicated as a therapeutic strategy for various neurological diseases now. Recently, inhibition of the NADPH oxidase (NOX2) was reported to protect against oxidative stress (ROS) production. However, whether alterations in NOX2expression and NOX activity are associated with calcitriol (active metabolite of VD) treatment following TBI remains unclear. In the present study, rats were randomly assigned to the sham, TBI, and calcitriol-treated groups. Calcitriol was administered intraperitoneally (2 μg/kg) at 30 min, 24 h, and 48 h after TBI insult. We observed that calcitriol treatment alleviated neurobehavioral deficits and brain edema following TBI. At the molecular levels, administration of calcitriol activated the expression of VDR and downregulated NOX2as well as suppressed apoptosis cell rate in the hippocampus CA1 region of TBI rats. In conclusion, our findings indicate that the protective effects of calcitriol may be related to the modulation of NADPH oxidase and thereby ultimately inhibited the progression of apoptosis. Calcitriol may be promising as a protective intervention following TBI, and more study is warranted for its clinical testing in the future.

scholarly journals FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

2021 ◽  
Vol 11 ◽  
Author(s):  
Jun Chen ◽  
Xue Wang ◽  
Jian Hu ◽  
Jingting Du ◽  
Confidence Dordoe ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Protein Expression ◽  
Microvascular Endothelial Cell ◽  
Potential Candidate ◽  
Protective Effects ◽  
Junction Protein

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro, rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.

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.

Protective effects of icariin on traumatic brain injury

2021 ◽  
Vol 19 ◽  
Author(s):  
Anni Du ◽  
Rui Cai ◽  
Jingshan Shi ◽  
Qin Wu
Keyword(s):  
Traumatic Brain Injury ◽  
Cerebral Cortex ◽  
Brain Injury ◽  
Protein Expression ◽  
Chinese Herb ◽  
Inflammatory Factors ◽  
Therapeutic Drug ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Expression Levels

Background: Neuroinflammation is central to the pathology of traumatic brain injury (TBI). Icariin (ICA) is a flavonoid derived from the genus Epimedium which is a traditional Chinese herb, a potential therapeutic drug for TBI. This study aims to explore the protective effect of ICA on TBI and its mechanism Methods: Sprague-Dawley rats were exposed to controlled cortical impact to produce a neuroinflammatory response. The treatment groups received ICA (15 mg/kg, 30 mg/kg and 60 mg/kg), while the sham group was gavaged with equal volumes of saline. The beam-balance testing and prehensile traction test were used for neurological scoring. Pathological changes were observed by H&E staining. The protein expression levels of inflammatory factors were measured by Western blot analysis Results: It was found that ICA significantly improved the neuroethology function and alleviated the pathological injury in TBI rats. The protein expression levels of inflammatory factors COX-2, IL-1β, and TNF-α and its regulatory proteins p-NF-κB-p65, p-ERK1/2, p-JNK, and p-p38 were increased in the cerebral cortex injured by TBI. The protein expression levels of inflammatory cytokines were markedly decreased in cerebral cortex of TBI rats when administrated with ICA. Conclusion: The present study demonstrates that ICA may be a promising therapeutic strategy for reducing inflammation in TBI.

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 Enriching neural stem cell and anti‐inflammatory glial phenotypes with electrical stimulation after traumatic brain injury in male rats

2021 ◽  
Author(s):  
Eunyoung Park ◽  
Johnathan G. Lyon ◽  
Melissa Alvarado‐Velez ◽  
Martha I. Betancur ◽  
Nassir Mokarram ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cell ◽  
Electrical Stimulation ◽  
Brain Injury ◽  
Neural Stem Cell ◽  
Male Rats ◽  
Anti Inflammatory
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