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Magnesium-L-threonate exhibited a neuroprotective effect against oxidative stress damage in HT22 cells and Alzheimer’s disease mouse model

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World Journal of Psychiatry 2022年第3期12卷 410-424页

作者： Ying Xiong Yu-Ting Ruan Jing Zhao Yu-Wen Yang Li-Ping Chen Ying-Ren Mai Qun Yu Zhi-Yu Cao Fei-Fei Liu Wang Liao Jun Liu Department of Neurology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120Guangdong ProvinceChina Department of Rehabilitation Medicine The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510000Guangdong ProvinceChina Department of Radiology The First Affiliated HospitalSun Yat-Sen UniversityGuangzhou 510080Guangdong ProvinceChina Department of Medical Ultrasound Guangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhou 510180Guangdong ProvinceChina Department of Medical Ultrasound Xiang’an Hospital of Xiamen UniversityXiamen 361000Fujian ProvinceChina Department of Neurology The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510000Guangdong ProvinceChina

BACKGROUND Oxidative stress results in the production of excess reactive oxygen species(ROS)and triggers hippocampal neuronal damage as well as occupies a key role in the pathological mechanisms of neurodegenerative disorders such as Alzheimer’s disease(AD).A recent study confirmed that magnesium had an inhibitory effect against oxidative stress-related malondialdehyde in vitro.However,whether Magnesium-L-threonate(MgT)is capable of suppressing oxidative stress damage in amyloidβ(Aβ)_(25-35)-treated HT22 cells and the AD mouse model still remains to be investigated.AIM To explore the neuroprotective effect of MgT against oxidative stress injury in vitro and in vivo,and investigate the mechanism.METHODS Aβ_(25-35)-induced HT22 cells were preconditioned with MgT for 12 h.APPswe/PS1dE9(APP/PS1)mice were orally administered with MgT daily for 3 mo.After MgT treatment,the viability of Aβ_(25-35)-treated HT22 cells was determined via conducting cell counting kit-8 test and the cognition of APP/PS1 mice was measured through the Morris Water Maze.Flow cytometry experiments were applied to assess the ROS levels of HT22 cells and measure the apoptosis rate of HT22 cells or hippocampal neurons.Expression of B-cell lymphoma 2(Bcl-2),Bcl-2-associated X(Bax),hypoxiainducible factor(HIF)-1α,NADPH oxidase(NOX)4,Aβ_(1-42) and phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)pathway proteins was quantified by Western blot.RESULTS In vitro data confirmed that Aβ_(25-35)-induced HT22 cells had a significantly lower cell viability,higher ROS level and higher apoptosis rates compared with those of control cells(all P<0.001).MgT prevented the Aβ_(25-35)-triggered oxidative stress damage by elevating viability and decreasing ROS formation and apoptosis of HT22 cells(all P<0.001).APP/PS1 mice exhibited worse cognitive performance and higher apoptosis rate of hippocampal neurons than wild-type(WT)mice(all P<0.01).Meanwhile,significant higher expression of Aβ_(1-42) and NOX4 proteins was detected in APP/PS1 mice than those of WT mi

关键词： Alzheimer’s disease Magnesium neuroprotective effect Oxidative stress Hippocampal Neuronal apoptosis

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neuroprotective effect of epigallocatechin-3-gallate on hemisection-induced spinal cord injury in rats

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Neural Regeneration Research 2011年第6期6卷 405-411页

作者： Fengjun Deng Rubing Li Yingbao Yang Dan Zhou Qian Wang Jiangping Xu Department of Pharmaceutical Sciences Hunan Yiyang Medical College Yiyang 413000 Hunan Province China Pharmaceutical Preparation Section General Hospital of Guangzhou Military Command of PLA Guangzhou 510010 Guangdong Province China Department of Pharmacology School of Pharmaceutical Sciences Southern Medical University Guangzhou 510515 Guangdong Province China Pingxiang Healthy School Pingxiang 337000 Jiangxi Province China

Epigallocatechin-3-gallate （EGCG）, a naturally occurring compound in green tea, has been widely used as an antioxidant agent. In the present study, model rats with acute spinal cord injury were intraperitoneally injected with 25, 50, and 100 mg/kg EGCG, and spinal cord ultrastructure, oxidative stress reaction, inflammatory factors, and apoptosis-associated gene expression were observed. Results showed that EGCG attenuated neuronal and axonal injury 24 hours post injury. It also decreased serum intedeukin-113, tumor necrosis factor-a, and intercellular adhesion molecule-1 release, and decreased apoptosis-associated gene expression. Furthermore, it increased the level of the superoxide anion （O2-）, superoxide dismutase, and B-cell lymphoma/leukemia-2, and reduced malondialdehyde levels. Furthermore, it reduced the expression of the pro-apoptotic protein Bax. Noticeably, EGCG at the 100 mg/kg dosage exhibited similar effects as methylprednisolone sodium succinate, which has been frequently used for clinical acute spinal cord injury. The results demonstrated that EGCG can significantly inhibit inflammation, suppress oxidation, and reduce apoptosis in acute spinal cord injury.

关键词： epigallocatechin-3-gallate spinal cord injury neuroprotective effect oxidative stress inflammation apoptosis

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neuroprotective effect of shenfu injection after intra-arterial thrombolysis

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Neural Regeneration Research 2006年第5期1卷 428-431页

作者： Huaijun Liu Xiuchuan Jia Jiping Yang Zengpin Liu Guoshi Wang Linfang Li Department of Medical Imaging Second Hospital Hebei Medical University Shijiazhuang 050000 Hebei Province China

BACKGROUND： Within 3 hours after ischemic stroke, thrombolysis can improve prognosis of patients; however, cerebral edema and cerebral hemorrhage induced by vascular recanalization at an early phase can influence on therapeutic effect of thrombolysis; therefore, thrombolysis is combined with neuroprotective agent for recently clinical treatment. OBJECTIVE： To evaluate the neuroprotective effect of shenfu injection on patients with ischemic stroke after arterial thrombolysis and compare with the controls. DESIGN ： Case-controlled study.SETTING ： Department of Medical Image, Second Hospital of Hebei Medical University.PARTICIPANTS ： A total of 45 patients with acute stroke were selected from Emergency Department or Neurological Department of the Second Hospital of Hebei Medical University from August 2005 to May 2006. All patients were met the diagnosis criteria published by the Fourth National Stroke Conference and had middle cerebral arterial embolism with angiography. Attacked course was less than 6 hours. Patients did not have a history of stroke. Scores of the National Institutes of Health Stroke Scale （NIHSS） were not less than 4 points and patients were aged from 18 to 80 years. All subjects consented of the whole therapeutic process. METHODS ： ① Intermittent perfusion was used to treat intra-arterial thrombolysis. Thirty patients with vascular recanalization or partially vascular recanalization （18 males and 12 females） were randomly divided into treatment group and control group with 15 in each group. There was no significant difference of baseline data between the two groups. After recanalization, patients in treatment group were given 20 mL shenfu injection, which consisted of ginseng saponin and aconitine （Ya＇an Sanjiu Pharmaceutical Company, batch number： 041013, 10 mL/ampoule） and slowly injected into vein for longer than 5 minutes. And then, patients were intravenously dripped with 50 mL shenfu injection and 50 g/L 250 mL glucose solution once a day for 2 courses. Fourteen days were regarde

关键词： shenfu injection ischemic stroke cerebral hemorrhage adverse events side effects neuroprotective effect head CT therapeutic effect diagnosis criteria clinical treatment arterial embolism Medical Image acute stroke

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Pseudotargeted metabolomics for exploring the changes of neurotransmitters profile in aging rat brain and the potential neuroprotective effect of alkaloids from Uncaria rhynchophylla

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Traditional Medicine Research 2022年第5期7卷 1-9页

作者： Shi-Wei Li Yi-Song Wu Shi-Fei Wu Wen-Long Wei Ming-Yang Qiu Yun Li De-An Guo College of Pharmacy Changchun University of Chinese MedicineChangchun 130117China Shanghai Research Center for Modernization of Traditional Chinese Medicine National Engineering Research Center of TCM Standardization TechnologyShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

Background:Aging is an essential risk factor for most neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.However,changes in the levels of neurotransmitters that are associated with aging are not well understood.Methods:Methods such as liquid-liquid extraction,protein precipitation,and solid-phase extraction,using 20 different extraction solvents,were evaluated to optimize the extraction of neurotransmitters.A pseudotargeted metabolomics approach was developed to detect neurotransmitters in brain tissues using ultra-high-performance liquid chromatography coupled with tandem triple quadrupole mass spectrometry.Alkaloids that crossed into the brain were used to evaluate the effect of glutamic acid-induced excitatory neurotoxicity in SH-SY5Y cells.Results:The overall extraction efficiency using protein precipitation was high.The changes in neurotransmitters’levels in the brain exhibited changes during the different growth cycles.The levels of seven neurotransmitters(aspartic acid,tyrosine,isoleucine,leucine,tryptophan,valine,andγ-aminobutyric acid)were significantly different.Meanwhile,alkaloids could reduce the excitatory neurotoxicity of glutamic acid-induced SH-SY5Y cells via suppression of oxidative stress.Conclusion:Significant differences were observed in neurotransmitter profiling between 1-and 8-month-old rats,and the discrepant neurotransmitters were associated with aging.Seven indole alkaloids from Uncaria rhynchophylla,which could cross the blood-brain barrier,were screened and used to explore their protective effects against aging.Uncaria rhynchophylla alkaloids exhibited a neuroprotective effect by inhibiting oxidative stress,indicating that the alkaloid could be a potential therapeutic candidate for neurological disorders caused by glutamic acid toxicity.

关键词： neurotransmitters aging Uncaria rhynchophylla indole alkaloids neuroprotective effect pseudotargeted metabolomics

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URB597 exerts neuroprotective effect against transient cerebral ischemic injury via restor⁃ing autophagy flux and inhibiting neuronal necroptosis in mice

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中国药理学与毒理学杂志 2021年第9期35卷 677-678页

作者： YUAN Xiao-qian YE Wen-xuan LUO Dou-dou ZHOU Yu Department of Basic Medical Science School of MedicineXiamen UniversityXiamen 361102China Key Laboratory of Chiral Drugs Xiamen 361102China State Key Laboratory of Cellular Stress Biology Xiamen UniversityXiamen 361102China

OBJECTIVE URB597(KDS-4103)is a potent and selective inhibitor of the enzyme fatty acid amide hydrolase(FAAH)and can ele⁃vate the level of oleoylethanolamide(OEA),a naturally occurring endocannabinoid in the brain.However,the effect of URB597 on cerebral isch⁃emic injury in mice remains unclear.METHODS Focal cerebral ischemia was induced by middle cerebral artery occlusion for 30 min followed by reperfusion for 24 h in mice.To observe the dose-dependent effect,URB597(0.04-5.00 mg·kg-1,ip)was administered at the same time of reperfu⁃sion.To determine the time-dependent effect,URB597(1.00 mg·kg-1,ip)was administered as a single dose at 0,1,3 or 5 h after reperfusion.Twenty-four hours after brain ischemia,Beder⁃son scoring test and grip strength test were used to evaluate the neurological function;brain in⁃farct volume was assayed by 2,3,5-triphenyltetra⁃zolium chloride(TTC)staining or diffusion-weighted magnetic resonance imaging(MRI).Laser speckle imaging(LSI)technique was used to assay the regional cerebral blood flow(rCBF);NeuN immunofluorescence staining was used to observe the neuron survival in the penumbra.To further investigate the underlying mechanism,au⁃tophagy flux related proteins(LC3-Ⅱ,P62 and LAMP2)and necroptosis related proteins(pRIPK3 and pMLKL)were detected by Western blotting and immunofluorescence staining.RESULTS Twenty-four hours after brain ischemia,URB597 dose-dependently improved neurological func⁃tion and reduced brain infarct volume.The most effective dose was 1.00 mg·kg-1;the therapeutic time window was within 1 h after ischemic stroke.The protective effect is further confirmed by the results that post-ischemic treatment with URB597(1.00 mg·kg-1)significantly increased neurons survival,promoted autophagy flux and reduced cell necroptosis in cortical penumbra after cerebral I/R.CONCLUSION URB597 dose-and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury.This neu⁃roprotective effect of URB597 may be associated with its restoration of autophagy flux and inhib

关键词： URB597 ischemic stroke ischemic penumbra neuronal necroptosis autophagy flux neuroprotective effect

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Interleukin-4 promotes microglial polarization toward a neuroprotective phenotype after retinal ischemia/reperfusion injury

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Neural Regeneration Research 2022年第12期17卷 2755-2760页

作者： Di Chen Cheng Peng Xu-Ming Ding Yue Wu Chang-Juan Zeng Li Xu Wen-Yi Guo Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology ShanghaiChina

Glaucoma results from irreversible loss of retinal ganglion cells(RGCs)through an unclear mechanism.Microglial polarization and neuroinflammation play an important role in retinal degeneration.Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation.Retinal ischemia/reperfusion injury was induced in C57BL/6 mice.In a separate cohort of animals,interleukin(IL)-4(50 ng/mL,2μL per injection)or vehicle was intravitreally injected after retinal ischemia/reperfusion injury.RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein,mRNA processing factor in retinal flat mounts.The expression of classically activated(M1)and alternatively activated(M2)microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction,immunofluorescence,and western blotting.The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury.IL-4 was undetectable in the retina at all time points,and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury.In summary,we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.

关键词： glaucoma hyper-intraocular pressure in vivo interleukin-4 intravitreal injection M2 microglia neurodegeneration neuroprotective effect retinal ganglion cell retinal ischemia-reperfusion

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Diverse sesquiterpenoids from Litsea lancilimba Merr.with potential neuroprotective effects against H_(2)O_(2)-induced SH-SY5Y cell injury

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Chinese Journal of Natural Medicines 2022年第9期20卷 701-711页

作者： ZHANG Yi-Jie BAI Ming LI Jia-Yi QIN Shu-Yan LIU Yu-Yang HUANG Xiao-Xiao ZHENG Jiang SONG Shao-Jiang Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research&Development Liaoning ProvinceEngineering Research Center of Natural Medicine Active Molecule Research&DevelopmentLiaoning ProvinceKey Laboratory of Natural Bioactive Compounds Discovery&ModificationShenyangSchool of Traditional Chinese Materia MedicaShenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Provincial Key Laboratory of PharmaceuticsGuizhou Medical UniversityGuiyang 550004China

Five undescribed sesquiterpenoids(1–5),and nine known sesquiterpenoids(6–14)were obtained from the fruits of Litsea lancilimba Merr.by LC-MS/MS molecular networking strategies.Litsemene A(1)possessed a unique 8-member ring through unexpected cyclization of the methyl group on C-10 of guaiane.Their structures were elucidated by spectroscopic techniques including IR,UV,NMR,HR-ESI-MS,and their absolute configurations were assigned by ECD calculations.All isolated sesquiterpenoids were analyzed by bioinformatics and evaluated for their neuroprotective effects against H_(2)O_(2)-induced injury in human neuroblastoma SH-SY5Y cells.

关键词： Litsea lancilimba Lauraceae Sesquiterpenoids neuroprotective effect

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Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus

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中国天然药物:英文版 2023年第8期21卷 619-630页

作者： LI Jia MENG Xiao YIN Chengyue ZHANG Lixia LIN Bin LIU Peng ZHU Lingjuan WANG Haifeng LIU Hongwei ZHANG Xue YAO Xinsheng School of Traditional Chinese Materia Medica Key Laboratory of Structure-Based Drug Design&Discovery of Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China School of Pharmaceutical Engineering Shenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China State Key Laboratory of Mycology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Institute of Traditional Chinese Medicine&Natural Products College of PharmacyJinan UniversityGuangzhou 510632China

Six new ent-abietane diterpenoids,abientaphlogatones A−F(1−6),along with two undescribed ent-abietane diterpenoid glucosides,abientaphlogasides A−B(7−8)and four known analogs were isolated from the aerial parts of Phlogacanthus curviflorus(P.curviflorus).The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry(HR-ESI-MS),one-dimensional and two-dimensional nuclear magnetic resonance(NMR)spectroscopy,electronic circular dichroism(ECD)spectra,and quantum chemical calculations.Notably,compounds 5 and 6 represented the first reported instances of entnorabietane diterpenoids from the genus Phlogacanthus.In theβ-hematin formation inhibition assay,compounds 2,4,7−10,and 12 displayed antimalarial activity,with IC_(50) values of 12.97−65.01μmol·L−1.Furthermore,compounds 4,5,8,and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H_(2)O_(2) and MPP+.

关键词： Phlogacanthus curviflorus Acathaceae ent-Abietane diterpenoids Antimalarial activity neuroprotective effect

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neuroprotective effect of Val8-GLP-1(7-36) against a 1-40-induced neurotoxicity and its possible mechanism

Neuroprotective effect of Val8-GLP-1(7-36) against a 1-40-in...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Xiao-Hui WANG,Zhao-Jun WANG,Dong YANG,Li YUAN,Shao-Feng LI,Jin-Shun QI~* Department of Physiology,Shanxi Medical University,Taiyuan 030001,China

Objective One of the neuropathological features of Alzheimer’s disease(AD) is high density of senile plaques,mainly composed of amyloid P protein(Aβ).It has been found that type 2 diabetes mellitus(T2DM) is a risk factor for developing AD.One promising treatment for AD is using glucagon-like peptide-1(GLP-1),a modulator used in T2DM therapy.To characterize the neuroprotective role and possible mechanism of GLP-1 in the brain, we investigated the effects of Val-GLP-1(7-36),a GLP-1 analogue with greater biological activity,on the Aβ1-40- induced neurotoxicity.Methods We investigated:(1) the effects of Intracerebraventricular(i.e.v.) injection of Val- GLP-1(7-36) on the Aβ1-40-induced impairment of spatial learning and memory of rats in Morris water maze test;(2) the effects of Lev.injection of Val-GLP-1(7-36) on the Aβ1-40-induced impairment of in vivo late phase of long-term potentiation(L-LTP) in rat hippocampal CA1 region;(3) the effects of Val-GLP-1(7-36) on the Aβ1-40-induced changes in miniature postsynaptic currents(mEPSCs and mlPSCs) in rat hippocampal CA1 pyramidal neurons;(4) the effects of pretreatment with Val-GLP-1(7-36) on Aβ1-40-induced elevation of[Ca] in cultured primary rat cortical neurons.Results(1) Pretreatment with Val-GLP-1(7-36)(0.05 pmol,0.5 pmol or 5 pmol) effectively reversed Aβ1-40(5 nmol)-induced impairment of cognitive function in a dose dependent manner.(2) Pretreatment with Val- GLP-l(7-36) effectively reversed Aβ1-40(5 nmol)-induced suppression of L-LTP in a dose-dependent manner.(3) Pretreatment with Val-GLP-1(7-36)(10 nM) prevented the Aβ1-40(100 nM)-induced decrease of frequency of mEPSCs and mlPSCs.(4) Pretreatment with Val-GLP-l(7-36)(10 nM,100 nM or 1000 nM) effectively protected against Aβ1-40(10μM)-induced elevation of[Ca] in a dose-dependent manner.Conclusion GLP-1 plays an important positive role in attenuating Aβ-induced deficits and stable GLP-1 analogues such as Val-GLP-1(7-36) could be an effective promising strategy for AD patients,particularly when associate with T2D

关键词： Val~8-GLP-1（7-36） neuroprotective effect Aβ1-40

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A new peptide,VD11,promotes structural and functional recovery after spinal cord injury

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Neural Regeneration Research 2023年第10期18卷 2260-2267页

作者： Shan-Shan Li Bai-Yu Zhang Sai-Ge Yin Zi-Qi Wei Nai-Xin Liu Yi-Lin Li Si-Yu Wang Yu-Heng Shi Jian Zhao Li-Juan Wang Yue Zhang Jun Sun Ying Wang Xin-Wang Yang Department of Anatomy and Histology&Embryology Faculty of Basic Medical ScienceKunming Medical UniversityKunmingYunnan ProvinceChina Key Laboratory of Chemistry in Ethnic Medicinal Resources&Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes State Ethnic Affairs Commission&Ministry of EducationSchool of Ethnic MedicineYunnan Minzu UniversityKunmingYunnan ProvinceChina Department of Urology First Affiliated Hospital of Kunming Medical UniversityKunmingYunnan ProvinceChina Yunnan Province Clinical Research Center for Chronic Kidney Disease First Affiliated Hospital of Kunming Medical UniversityKunmingYunnan ProvinceChina

The regenerative capacity of the central nervous system is very limited and few effective treatments are currently available for spinal cord injury.It is therefore a priority to develop new drugs that can promote structural and functional recovery after spinal cord injury.Previous studies have shown that peptides can promote substantial repair and regeneration of injured tissue.While amphibians have a pronounced ability to regenerate the spinal cord,few studies have investigated the effect of amphibian spinal cord-derived peptides on spinal cord injury.Here we report for the first time the successful identification and isolation of a new polypeptide,VD11(amino acid sequence:VDELWPPWLPC),from the spinal cord of an endemic Chinese amphibian(Odorrana schmackeri).In vitro experiments showed that VD11 promoted the secretion of nerve growth factor and brain-derived neurotrophic factor in BV2 cells stimulated with lipopolysaccharide,as well as the proliferation and synaptic elongation of PC12 cells subjected to hypoxia.In vivo experiments showed that intravertebral injection of VD11 markedly promoted recovery of motor function in rats with spinal cord injury,alleviated pathological damage,and promoted axonal regeneration.Furthermore,RNA sequencing and western blotting showed that VD11 may affect spinal cord injury through activation of the AMPK and AKT signaling pathways.In summary,we discovered a novel amphibian-derived peptide that promotes structural and functional recovery after spinal cord injury.

关键词： Akt signaling pathway amphibian-derived bioactive peptide AMPK signaling pathway axonal regeneration brain-derived neurotrophic factor ischemia/reperfusion injury motor function nerve growth factor neuroprotective effect spinal cord injury

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