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Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage

Neural Regeneration Research 2023年第6期18卷 1308-1315页

作者： Zi-Xian Zhou Qi Cui Ying-Mei Zhang Jia-Xin Yang Wen-Jing Xiang Ning Tian Yan-Lin Jiang Mei-Ling Chen Bin Yang Qing-Hua Li Ru-Jia Liao Laboratory of Neuroscience Affiliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxi Zhuang Autonomous RegionChina Department of Neurology Affiliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxi Zhuang Autonomous RegionChina Guangxi Clinical Research Center for Neurological Diseases Affiliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxi Zhuang Autonomous RegionChina Department of Pharmacology Affiliated Hospital of Guilin Medical UniversityGuilin Medical UniversityGuilinGuangxi Zhuang Autonomous RegionChina

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage(ICH).Withaferin A(WFA),a natural compound,exhibits a positive effect on a number of neurological diseases.However,the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown.In this study,we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis.We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH.WFA was injected intracerebroventricularly at 0.1,1 or 5μg/kg once daily for 7 days,starting immediately after ICH operation.WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage.Through in vitro experiments,cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury.Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde,an oxidative stress marker,and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH.Western blot assay,quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling axis,promoted translocation of Nrf2 from the cytoplasm to nucleus,and increased HO-1 expression.Silencing Nrf2 with siRNA completely reversed HO-1 expression,oxidative stress and protective effects of WFA.Furthermore,WFA reduced hemin-induced ferroptosis.However,after treatment with an HO-1 inhibitor,the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened.MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell inj

关键词： behavior brain injuries hemorrhagic stroke ferroptosis heme oxygenase-1 neuroprotection nuclear factor E2-related factor 2 nuclear translocator oxidative stress stroke

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Efficacy of acupuncture on repair of glial scars in rats with traumatic brain injury

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Journal of Traditional Chinese Medicine 2023年第2期43卷 329-336页

作者： ZENG Hai CAO Luxi PANG Zhao ZHAO Sisi WANG Shiqi LIN Zhuowen CHEN Minan LIN Shujun ZHANG Yimin Department of Acupuncture and Moxibustion College of Traditional Chinese MedicineJinan UniversityGuangzhou 510632China Medical Administration Division the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China Medical College of Acupuncture-Moxibustion and Rehabilitation Guangzhou University of Chinese MedicineGuangzhou 510006China

OBJECTIVE:To explore the underlying mechanism of acupuncture on nerve repair by investigating its effect on the differentiation of glial cells and the repair of glial scars.METHODS:Sprague-Dawley rats were randomly allocated to three groups:normal group,model group,and acupuncture group.Acupuncture was applied at Renzhong(GV26),Baihui(GV20),Fengfu(GV16),Yamen(GV15)and Hegu(LI4)within 12 h after TBI modeling with a frequency of one session per day for 4 weeks.Neurobehavioral assessment,hematoxylin and eosin staining,immunofluorescence detection,and magnetic resonance imaging scanning were performed on days 3,7,14,and 28 after modeling of traumatic brain injury(TBI).RESULTS:Acupuncture promoted the proliferation of glial cells and glial scars at an early stage but inhibited the proliferation of glial cells and glial scars at a late stage.Morphological observations and immunofluorescence histochemistry showed that the morphology of the perilesional cortex in the acupuncture group was improved and the number of neurons was increased when compared with the model group.The lesion size of ipsilateral brain parenchyma in the acupuncture group was smaller than in the model group on days 7,14,and 28(P<0.05)after TBI modeling.CONCLUSIONS:Acupuncture might have a bidirectional regulatory effect on glial scar repair after TBI by promoting the proliferation of glial cells and glial scars to limit the injured area and relieve nerve injury during the early stages,and by inhibiting glial scar hyperplasia to benefit the regeneration and repair of neurons and axons and promote neurological function recovery during the later stages.

关键词： acupuncture astrocytes microglia gliosis brain injuries traumatic

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Acupuncture on intrauterine growth restriction associated brain injury:case study including use of magnetic resonance imaging

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Journal of Traditional Chinese Medicine 2023年第3期43卷 602-605页

作者： XIN Zhixiong LI Jiyuan XU Yanni LING Jing JIANG Min YU Yutian Department of Pediatrics People's Hospital of Sanshui DistrictFoshan 528000China Department of MRI Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China Ninth School of Clinical Medicine Peking UniversityBeijing 100038China Foshan Minfound Medical Imaging Diagnostic Center Foshan 528000China Department of Gynecology Shenzhen Traditional Chinese Medicine HospitalShenzhen 518033China Acupuncture Department Beijing Shijitan HospitalCapital Medical UniversityBeijing 100038China

brain injury due to intrauterine growth restriction(IUGR) is a thorny clinical problem that often leads to permanent neurological deficits such as cerebral palsy.Few practical therapies can treat an IUGR-associated brain injury.We employed acupuncture to treat a 6-month-old male patient with severe hypoxic-ischemic encephalopathy(HIE) due to IUGR,as confirmed by magnetic resonance imaging(MRI).Three courses of acupuncture treatment significantly improved some of the patient’s clinical characteristics,such as his insensitive responsiveness and motor deficits,with remarkably reversed HIE features on MRI at 1-year of age.This case suggests that acupuncture is a potential treatment option for an IUGRassociated brain injury and warrants further investigation.

关键词： acupuncture fetal growth retardation brain injuries hypoxia-ischemia brain magnetic resonance imaging neuronal plasticity

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Could Intrathymic Injection of Myelin Basic Protein Suppress Inflammatory Response After Co-culture of T Lymphocytes and BV-2 Microglia Cells？

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Chinese Medical Journal 2016年第7期129卷 831-837页

作者： Zhan-Qun Cui Bao-Long Liu Qiao-Li Wu Ying Cai Wei-Jia Fan Ming-Chao Zhang Wei-Liang Ding Department of Neurosurgery Graduate School of Tianjin Medical University Tianjin 300070 China Department of Neurosurgery Tianjin Huanhu Hospital Tianjin 300060 China Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases 'Tianjin Huanhu Hospital Tianjin 300060 China

Background： The interaction between activated microglia and T lymphocytes can yield abundant pro-inflammatory cytokines. Our previous study proved that thymus immune tolerance could alleviate the inflammatory response. This study aimed to investigate whether intrathymic injection of myelin basic protein （MBP） in mice could suppress the inflammatory response after co-culture ofT lymphocytes and BV-2 microglia cells. Methods： Totally, 72 male C57BL/6 mice were randomly assigned to three groups （17 - 24 in each）： Group A： intrathymic injection of 100 μl M BP （1 mg/ml）; Group B： intrathymic injection of 100 μ1 phosphate-buffered saline （PBS）; and Group C： sham operation group. Every eight mice in each group were sacrificed to obtain the spleen at postoperative days 3, 7, and 14, respectively. T lymphocytes those were extracted and purified from the spleens were then co-cultured with activated BV-2 microglia cells at a proportion of 1：2 in the medium containing MBP for 3 days. After identified the T lymphocytes by CD3, surface antigens oft lymphocytes （CD4, CD8, CD152, and CD154） and BV-2 microglia cells （CD45 and CD54） were detected by flow cytometry. The expressions of pro-inflammatory factors of BV-2 microglia cells （interleukin [1L]- 1β, tumor necrosis factor-o~ [TNF-α], and inducible nitric oxide synthase [iNOS]） were detected by quantitative real-time polymerase chain reaction （PCR）. One-way analysis of variance （ANOVA） and the least significant difference test were used for data analysis. Results： The levels of CD152 in Group A showed an upward trend from the 3rd to 7th day, with a downward trend from the 7th to 14th day （20.12 ± 0.71%, 30.71 ± 1.14%, 13.50 ± 0.71% at postoperative days 3, 7, and 14, respectively, P 〈 0.05）. The levels of CD 154 in Group A showed a downward trend from the 3ra to 7th day, with an upward trend from the 7th to 14th day （1 0.00± 0.23%, 5.28 ±0.69%, 14.67 ± 2.71% at postoperative days 3, 7, and 14, respectively, P 〈 0.05）. The ratio ofCD4＋/CD8 ＋ T in Group A showed a downward trend

关键词： brain injuries Immune Inflammation lntrathymic Injection Myelin Basic Protein

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ONO-1078 reduces NMDA-induced brain injury and vascular cell adhesion molecule-1 expression in rats

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Acta Pharmacologica Sinica 2005年第4期26卷 435-440页

作者： Li-hui ZHANG~(2,3) Er-qing WEI~(2,4) 2 Department of Pharmacology,School of Medicine,Zhejiang University,Hangzhou 310031 3 Medical School,Hangzhou Normal University,Hangzhou 310018,China Department of Pharmacology School of Medicine Zhejiang University Hangzhou China Medical School Hangzhou Normal University Hangzhou China

Aim:To determine whether ONO-1078 （pranlukast）,a potent cysteinyl leukotrienereceptor 1 （CysLTI） antagonist,has an effect on N-methyl-D-aspartate （NMDA）-induced brain injury and vascular cell adhesion molecule-1 （VCAM-1） expres-sion in rats.Methods:brain injury was induced by direct microinjection of NMDA（0.3 μmol in 1 μL of sterile 0.1 mol/L PBS,pH 7.4） into the cerebral cortex.Thelesion volume （area）,brain edema and neuron density were assessed by an imageanalyzer and the expression of VCAM-1 in the cortex was detected by Westernblot 24 h after NMDA injection.ONO-1078 （0.03,0.1,or 0.3 mg/kg） andedaravone （MCI-186,10 mg/kg）,a neuroprotective agent,were ip injected 30rain before and after NMDA injection.Results:NMDA microinjection producedwell-defined focal lesions （Figure 1） dose- and time-dependently.ONO-1078（0.1,0.3 mg/kg） and edaravone （10 mg/kg） decreased the total lesion volume,lesion area and brain edema induced by NMDA.Furthermore,ONO-1078 （0.1,0.3mg/kg） significantly inhibited the enhanced expression of VCAM-1 in the injuredcortices,but edaravone did not have this effect.Conclusion:CysLT1receptorantagonist ONO-1078 at tenufftes NMDA-induced brain damage in rats,and thismight relate to the attenuation of NMDA receptor-dependent neurotoxicity andthe inhibition of the upregulation of VCAM-1 expression.

关键词： leukotriene antagonists pranlukast N-methylaspartate vascular cell adhesion molecule-1 neurotoxicity brain injuries

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An experimental study on thymus immune tolerance to treat surgical brain injury

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Chinese Medical Journal 2014年第4期127卷 685-690页

作者： Zheng Yongtao Kang Jianmin Liu Baolong Fan Weijia Wu Qiaoli Yan Hua Graduate School of Tianjin Medical University Tianjin 300070China Tianjin Cerebral Vascular and Neural Degenerative Disease Key Laboratory Department of Neurosurgery Tianjin Huanhu HospitalTianjin 300060 China

Background Many researches demonstrate that the secondary brain injury which is caused by autoimmune attack toward brain antigens plays an important role in surgical brain injury （SBI）.Although traditional immunosuppression can reduce autoimmune attack,it will lower the body immunity.Immune tolerance,by contrast,not only does not lower the body immunity,but also could lighten autoimmunity.This study used thymus tolerance to develop an immune system that is tolerant to autologous cerebrospinal fluid （CSF） and autologous brain tissue so that autoimmune injury can be suppressed following the disruption of the blood-brain barrier,thereby reducing brain damage.Methods Eighty experimental rabbits were divided into five groups by random number table method：16 in SBI group （group A）,16 in SBI＋CSF drainage group （group B）,16 in SBI＋CSF drainage＋PBS injection group （group C）,16 in SBI＋CSF drainage＋CSF intrathymic injection group （group D）,and 16 in SBl＋brain homogenate intrathymic injection group （group E）.Rabbits＆#39; CSF was drained in group B; was drained and injected PBS into thymus in group C; was drained and injected CSF into thymus in group D; and was injected brain homogenate in group E.Half of the rabbits in each group were phlebotomized on 1st,3rd,7th,and 14th days to observe the changes in IL-I,TGF-β by ELISA test,and CD4CD25 regulatory T cells ratio by flow cytometry,and in other animals brain tissues were taken on 7th day for exploring FasL expression by RT-PCR.The least significant difference （LSD） test was used to make paired comparisons; P ＜0.05 was considered statistically significant.Results The levels of FasL,TGF-β,and the ratios of CD4CD25 regulatory T cells in groups D and E were apparently higher than those in other three groups （P ＜0.05）.Likewise,the levels of IL-1 in these two groups were lower than the other three groups （P ＜0.05）.Moreover,the ratios of CD4CD25 regulatory T cells and the levels of TGF-β in groups B and C were higher than those in group A,but the level of IL-1 was lower than that in

关键词： brain injuries immune tolerance regulatory T cells

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Distribution of cysteinyl leukotriene receptor 2 in human traumatic brain injury and brain tumors

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Acta Pharmacologica Sinica 2005年第6期26卷 685-690页

作者： Hua HU~(2,3), Gao CHEN~2, Jian-min ZHANG~2, Wei-ping ZHANG~3, Lei ZHANG~3, Qiu-fu GE~3, Hong-tian YAO~4, WeiDING~4, Zhong CHEN~3, Er-qing WEI~(3,5) ~2 Department of Neurosurgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009 ~3 Department of Pharmacology School of Medicine, Zhejiang University, Hangzhou 310031 ~4 Department of Pathology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Department of Neurosurgery the Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou China Department of Pharmacology School of Medicine Zhejiang University Hangzhou China Department of Pathology the First Affiliated Hospital School of Medicine Zhejiang University Hangzhou China

Aim: To determine the distribution of cysteinyl leukotriene receptor 2 (CysLT2), one of the cysteinyl leukotriene receptors, in human brains with traumatic injury and tumors. Methods: brain specimens were obtained from patients who underwent brain surgery. CysLT2in brain tissues was examined using immunohis-tochemical analysis. Results: CysLT2was expressed in the smooth muscle cells (not in the endothelial cells) of arteries and veins. CysLT2was also expressed in the granulocytes in both vessels and in the brain parenchyma. In addition, CysLT2was detected in neuron- and glial-appearing cells in either the late stages of traumatic injury or in the area surrounding the tumors. Microvessels regenerated 8 d after trauma and CysLT2expression was recorded in their endothelial cells. Conclusion: CysLT2is distributed in vascular smooth muscle cells and granulocytes, and brain trauma and tumor can induce its expression in vascular endothelial cells and in a number of other cells.

关键词： cysteinyl leukotriene receptor 2 brain injuries brain neoplasms vascular smooth muscle cell

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Marrow stromal cells administrated intracisternally to rats after traumatic brain injury migrate into the brain and improve neurological function

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Chinese Medical Journal 2004年第10期117卷 1576-1578页

作者：胡德志周良辅朱剑虹 Department of Neurosurgery Huashan HospitalFudan University Shanghai 200040 China

Marrow stromal cells(MSCs) have been reported to transplant into injured brain via intravenous or intraarterial or direct intracerebral administration.1-3 In the present study, we observed that MSCs migrated into the brain, survived and diffeneriated into neural cells after they were injected into the cisterna magna of rats, and that the behavior of the rats after traumatic brain injury (TBI) was improved.

关键词： brain injuries transplantation stromal cells bone marrow Cisterna Magna

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The apparent diffusion coefficient does not reflect cytotoxic edema on the uninjured side after traumatic brain injury

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Neural Regeneration Research 2014年第9期9卷 973-977页

作者： Hong Lu Xiaoyan Lei Department of Radiology Affiliated Haikou Hospital Xiangya School of Medicine Central South University

After traumatic brain injury, vasogenic and cytotoxic edema appear sequentially on the involved side. Neuroimaging investigations of edema on the injured side have employed apparent diffusion coefficient measurements in diffusion tensor imaging. We investigated the changes occurring on the injured and uninjured sides using diffusion tensor imaging/apparent diffusion coefficient and histological samples in rats. We found that, on the injured side, that vasogenic edema appeared at 1 hour and intracellular edema appeared at 3 hours. Mixed edema was observed at 6 hours, worsening until 12–24 hours post-injury. Simultaneously, microglial cells proliferated at the trauma site. Apparent diffusion coefficient values increased at 1 hour, decreased at 6 hours, and increased at 12 hours. The uninjured side showed no significant pathological change at 1 hour after injury. Cytotoxic edema appeared at 3 hours, and vasogenic edema was visible at 6 hours. Cytotoxic edema persisted, but vasogenic edema tended to decrease after 12–24 hours. Despite this complex edema pattern on the uninjured side with associated pathologic changes, no significant change in apparent diffusion coefficient values was detected over the first 24 hours. Apparent diffusion coefficient values accurately detected the changes on the injured side, but did not detect the changes on the uninjured side, giving a false-negative result.

关键词： nerve regeneration brain injuries blood-brain barrier magnetic resonance imaging apparent diffusion coefficient intracranial edema cytotoxic edema vasogenic edema pathology NSFC grant neural regeneration

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Treatment of traumatic brain injury in rats with transplantation of human amniotic cells

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Chinese Medical Journal 2006年第21期119卷 1843-1845页

作者： LU Yi HUI Guo-zhen WU Zhi-yuan GUO Li-he JI Xun-he WU Xin Department of Neurosurgery First Affiliated Hospital of Soochow University Suzhou 215006 China Institute of Biochemistry and Cell Biology Shanghai Institutes of Biological Sciences Chinese Academy of Sciences Shanghai 200031 China

Traumatic brain injury （TBI）, which is an important reason of human mortality and morbidity in industrialized countries, still cannot be treated effectively. Since the self-repair capacity of brain is limited, cellular transplantation in TBI may be a therapeutic option.Human amniotic cells （HACs） from fertilized ovum are able to differentiate into all the tissues of the body. They can not only express the markers of neuronal and glial cells^1 but also synthesize and release the neurotrophic factors.^2 Moreover, transplanted HACs rarely induce immunologic rejection.^3,4 In this study, we investigated whether HAC cultures conditioned by traumatic brain tissue extracts can acquire the phenotype of neuron, and examined the effects of transplanted HACs on the affected hindlimb of rats with TBI.

关键词： brain injuries amnion transplantation rats

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