Changqin NO. 1 inhibits neuronal apoptosis via suppressing GAS5 expression in a traumatic brain injury mice model

2019 ◽  
Vol 400 (6) ◽  
pp. 753-763 ◽  
Author(s):  
Xingping Dai ◽  
Min Yi ◽  
Dongsheng Wang ◽  
Yanyi Chen ◽  
Xia Xu
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Apoptosis ◽  
Apoptotic Cell ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Luciferase Reporter ◽  
Cell Detection ◽  
Neuroprotective Effects ◽  
Newborn Mice

Abstract The present study was designed to investigate the mechanism of the traditional Chinese medicine Changqin NO. 1 on the amelioration of traumatic brain injury (TBI). Adult male C57BL/6J mice and newborn mice were used to generate a mouse TBI model and harvest primary neurons, respectively. The localizations of specific neural markers neuropilin-1 (Nrp-1), growth-associated protein-43 (GAP-43) and microtubule-associated protein Tau (Tau) were examined in brain tissues by immunohistochemistry. Terminal deoxynucleotidyl transferase dUTP nick end labeling apoptotic cell detection in tissue sections and the CCK-8 cell viability assay were performed to examine neuronal apoptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were also carried out in this study. The association between long non-coding RNA (lncRNA) growth-arrest specific 5 (GAS5), miR-335 and RAS p21 GTPase activating protein 1 (Rasa1) was disclosed using the dual-luciferase reporter assay. Changqin NO. 1 inhibited TBI-induced neuronal apoptosis in vivo and in vitro. GAS5 functioned as a competing endogenous RNA (ceRNA) by sponging miR-335 to upregulate Rasa1 expression in mouse neuronal cells. Further investigations demonstrated that GAS5 promoted neuronal apoptosis following TBI via the miR-335/Rasa1 axis. In vivo experiments indicated that Changqin NO. 1 exerted neuroprotection during TBI via the GAS5/miR-335/Rasa1 axis. Changqin NO. 1 promoted neuroprotective effects by inhibiting neuronal apoptosis via the GAS5/miR-335/Rasa1 axis in TBI.

scholarly journals SHED-Derived Exosomes Regulate Microglial Polarization in the Treatment of Traumatic Brain Injury in Rats via miR-330-5p

2020 ◽  
Author(s):  
Ye Li ◽  
Xinxin Wang ◽  
Xiaoyu Cao ◽  
Na Li ◽  
Sun Meng ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Structural Damage ◽  
Inhibitory Effect ◽  
Deciduous Teeth ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Polarization ◽  
M1 Polarization

Abstract Background: Traumatic brain injury (TBI) causes structural damage and impairs motor and cognitive function of the brain. Our previous study suggested that exosomes (EXs) secreted by stem cells from human exfoliated deciduous teeth (SHED) extenuated motor damage in TBI rats by regulating microglia. The molecular mechanism of SHED-EXs was investigated in the present study. Methods: The miRNA array was performed to determine the differential miRNA expression in SHED-EXs treating microglia. The key miRNA was selected. Flow cytometry, immunofluorescence, enzyme linked immunosorbent assay (ELISA) and Griess assay were performed to detect the function of key miRNA. Real-time PCR, Western blotting and dual luciferase reporter assay were used to confirm the relationship between key miRNA and the target gene. Chromatin immunoprecipitation (ChIP) was performed to determine the downstream pathway of EXs-miRNA. Traumatic brain injury rat model was established and local injection of EXs-miRNA was performed to evaluate the effect.Results: SHED-EXs delivery of miR-330-5p was the key in the regulation of microglia polarization by inhibiting M1 polarization and promoting M2 polarization. Mechanistically, miR-330-5p had an inhibitory effect on Ehmt2, and miR-330-5p/Ehmt2 promoted the transcription of CXCL14 through H3K9me2. In vivo data showed that SHED-EXs/miR-330-5p reduced neuro-inflammation and repaired neurological function of TBI rats. Conclusions: SHED-EXs/miR-330-5p improved the motor function of rats after TBI by inhibiting M1 polarization and promoting M2 polarization of microglia through Ehmt2/H3K9me2/CXCL14 pathway.

scholarly journals Neuroprotective Effects of Geranylgeranylacetone in Experimental Traumatic Brain Injury

2013 ◽  
Vol 33 (12) ◽  
pp. 1897-1908 ◽  
Author(s):  
Zaorui Zhao ◽  
Alan I Faden ◽  
David J Loane ◽  
Marta M Lipinski ◽  
Boris Sabirzhanov ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Enhanced Recovery ◽  
Apoptotic Cell ◽  
Neuronal Loss ◽  
Lesion Size ◽  
Neuroprotective Effects ◽  
Stroke Models ◽  
Neuroprotective Actions ◽  
Experimental Traumatic Brain Injury

Geranylgeranylacetone (GGA) is an inducer of heat-shock protein 70 (HSP70) that has been used clinically for many years as an antiulcer treatment. It is centrally active after oral administration and is neuroprotective in experimental brain ischemia/stroke models. We examined the effects of single oral GGA before treatment (800 mg/kg, 48 hours before trauma) or after treatment (800 mg/kg, 3 hours after trauma) on long-term functional recovery and histologic outcomes after moderate-level controlled cortical impact, an experimental traumatic brain injury (TBI) model in mice. The GGA pretreatment increased the number of HSP70+ cells and attenuated posttraumatic α-fodrin cleavage, a marker of apoptotic cell death. It also improved sensorimotor performance on a beam walk task; enhanced recovery of cognitive/affective function in the Morris water maze, novel object recognition, and tail-suspension tests; and improved outcomes using a composite neuroscore. Furthermore, GGA pretreatment reduced the lesion size and neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex when compared with vehicle-treated TBI controls. Notably, GGA was also effective in a posttreatment paradigm, showing significant improvements in sensorimotor function, and reducing cortical neuronal loss. Given these neuroprotective actions and considering its longstanding clinical use, GGA should be considered for the clinical treatment of TBI.

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 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 Neuroprotective effects of progesterone in traumatic brain injury: blunted in vivo neutrophil activation at the blood-brain barrier

2013 ◽  
Vol 206 (6) ◽  
pp. 840-846 ◽  
Author(s):  
Jose L. Pascual ◽  
Mohammad A. Murcy ◽  
Shenghui Li ◽  
Wanfeng Gong ◽  
Rachel Eisenstadt ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Blood Brain Barrier ◽  
Neutrophil Activation ◽  
Brain Barrier ◽  
Neuroprotective Effects ◽  
Blood Brain

scholarly journals The neuroprotective effects of AMN082 on neuronal apoptosis in rats after traumatic brain injury

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chung-Che Lu ◽  
Tee-Tau Eric Nyam ◽  
Jinn-Rung Kuo ◽  
Yao-Lin Lee ◽  
Chung-Ching Chio ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Glutamate Receptor ◽  
Neuronal Apoptosis ◽  
Nitrosative Stress ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Motor Deficits ◽  
Sprague Dawley ◽  
Neuroprotective Effects

Abstract Background The aim of this study was to investigate whether AMN082 exerts its neuroprotective effect by attenuating glutamate receptor-associated neuronal apoptosis and improving functional outcomes after traumatic brain injury (TBI). Methods Anesthetized male Sprague–Dawley rats were divided into the sham-operated, TBI + vehicle, and TBI + AMN082 groups. AMN082 (10 mg/kg) was intraperitoneally injected 0, 24, or 48 h after TBI. In the 120 min after TBI, heart rate, mean arterial pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were continuously measured. Motor function, the infarct volume, neuronal nitrosative stress-associated apoptosis, and N-methyl-d-aspartate receptor 2A (NR2A) and NR2B expression in the pericontusional cortex were measured on the 3rd day after TBI. Results The results showed that the AMN082-treated group had a lower ICP and higher CPP after TBI. TBI-induced motor deficits, the increase in infarct volume, neuronal apoptosis, and 3-nitrotyrosine and inducible nitric oxide synthase expression in the pericontusional cortex were significantly improved by AMN082 therapy. Simultaneously, AMN082 increased NR2A and NR2B expression in neuronal cells. Conclusions We concluded that intraperitoneal injection of AMN082 for 3 days may ameliorate TBI by attenuating glutamate receptor-associated nitrosative stress and neuronal apoptosis in the pericontusional cortex. We suggest that AMN082 administration in the acute stage may be a promising strategy for TBI.

The Protective Effect of Sulfated Pachymaran on 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Neuronal Apoptosis in Mice

2017 ◽  
Vol 17 (1) ◽  
pp. 64-68
Author(s):  
Gao Gui-Zhen ◽  
Wu Chao ◽  
Zhai Ke-Feng ◽  
Shan Ling-Ling ◽  
Li Mei-Hong
Keyword(s):  
Tyrosine Hydroxylase ◽  
Protective Effect ◽  
Neuronal Apoptosis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Nigrostriatal Pathway ◽  
Neuroprotective Effects ◽  
Treatment Groups ◽  
Induced Apoptosis ◽  
Different Doses

Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were used to examine the neuroprotective effects of sulfated pachymaran. Male ICR mice were administered 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneally once a day for 7 days in model group. In sulfated pachymaran treatment groups, different doses of sulfated pachymaran (50, 100, and 150 mg/kg, respectively) were given consecutively after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in the following 7 days. The apoptosis of neurons in substantia nigra was observed by tyrosine hydroxylase immunostaining and TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Expression of Bcl-2, and Bax proteins in midbrain and striatum were detected by Western blot. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment significantly decreased the tyrosine hydroxylase-immunoreactive neurons (P < 0.01), increased the TUNEL-positive neurons (P < 0.05). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine markedly induced downregulation of Bcl-2 expression (P < 0.05, P < 0.01, respectively) and upregulation of Bax (P < 0.05, P < 0.01, respectively) expression in both midbrain and striatum. Sulfated pachymaran restored 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuronal death in the nigrostriatal pathway, and significantly elevated Bcl-2 expression and declined Bax expression, contributing to the balance between Bcl-2 and Bax proteins. These results indicated that sulfated pachymaran had protective effect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced apoptosis in striato-nigral system in vivo.

Drug Repurposing: Promises of Edaravone Target Drug in Traumatic Brain Injury

2020 ◽  
Vol 27 ◽  
Author(s):  
Zaynab Shakkour ◽  
Hawraa Issa ◽  
Helene Ismail ◽  
Ohanes Ashekyan ◽  
Karl John Habashy ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurological Disorders ◽  
Inflammatory Responses ◽  
Apoptotic Cell ◽  
Drug Repurposing ◽  
Biochemical Properties ◽  
Phase Iii ◽  
Radical Scavenger ◽  
Neuroprotective Effects

: Edaravone is a potent free-radical scavenger that has been in the market for more than 30 years. It was originally developed in Japan to treat strokes and has been used there since 2001. Aside from its anti-oxidative effects, edaravone demonstrated beneficial effects on pro-inflammatory responses, nitric oxide production, and apoptotic cell death. Interestingly, edaravone has shown neuroprotective effects in several animal models of diseases other than stroke. In particular, edaravone administration was found to be effective in halting amyotrophic lateral sclerosis (ALS) progression during the early stages. Accordingly, after its success in Phase III clinical studies, edaravone has been approved by the FDA as a treatment for ALS patients. Considering its promises in neurological disorders and its safety in patients, edaravone is a drug of interest that can be repurposed for traumatic brain injury (TBI) treatment. Drug repurposing is a novel approach in drug development that identifies drugs for purposes other than their original indication. This review presents the biochemical properties of edaravone along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.

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.

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