ZHU Xiong-wei

（Department of Pathology,Case Western Reserve University,Cleveland,Ohio 44106,USA）

专题2 阿尔茨海默病及其他神经退行性疾病：治疗与机制

S2-1 Mitochondrial dynamics as a therapeutic target for Alzheimer disease

ZHU Xiong-wei

（Department of Pathology,Case Western Reserve University,Cleveland,Ohio 44106,USA）

耿美玉，日本东京大学药学博士，现任中国科学院上海药物研究所党委书记、副所长。国家杰出青年基金获得者，中国科学院百人计划入选者，国家“973”计划“糖化学糖生物学研究”项目首席科学家。长期致力于抗老年痴呆（AD）和抗肿瘤药物研发及标志物研究。申请国内外发明专利70余项，授权30余项。4个候选新药已实现转让，合同额近10亿。获国家技术发明一等奖。在Cancer Cell，Cell Res，J Nat Cancer Inst，Hepatology，Cancer Res和Clin Cancer Res等杂志发表文章180余篇。兼任基金委医学部“十三五战略规划”专家组副组长，基金委医学部“炎癌转变”重大研究计划专家组成员。

目的阿尔茨海默病（AD），是一种由多因素引起的神经系统退行性疾病，严重危害人类健康。目前临床治疗药物主要为胆碱酯酶抑制剂等疾病症状改善药物，存在疗效不确切、毒副作用大等缺点，无法有效防止AD的进展。因此开发能够改变疾病进程的抗AD药物是目前医药界共同关注的焦点。方法采用基于SPR的芯片筛选方法，针对糖库进行筛选；采用一系列的生物化学和物理方法，观察对amyloid β（Aβ）聚集以及神经毒性的影响；采用转基因动物模型，观察对转基因动物行为学的影响。结果我们通过筛选获得国际首个靶向Aβ的寡糖分子——971。核磁共振技术直接证明971能够与Aβ多位点结合；通过其独特的结合方式，971能够抑制Aβ聚集，并且能够促进已经聚集的Aβ解聚，同时抑制Aβ的神经毒性。体内研究表明971能够明显改善转基因小鼠的学习记忆能力以及日常生活能力。Ⅱ期临床研究表明，971安全性好、能明显改善轻中度AD患者认知功能障碍。临床Ⅲ期正在进行中。结论971有望成为近十几年来首个靶向Aβ的抗AD新药。

阿尔茨海默病；甘露寡糖二酸

S2-3 LW-AFC,a new traditional Chinese medicine formula,shows promising therapeutic effects on Alzheimer disease

ZHOU Wen-xia,WANG Jian-hui,CHENG Bing,HUANG Yan,CHENG Xiao-rui,ZHANG Yong-xiang

（Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures,Beijing 100850,China）

ZZHOUU WWeenn--xxiiaa,PhD.,Professor of Pharmacology,Deputy secretary-general of Chinese Pharmacological Society(CNPHARS),Chair of the Committee of Network Pharmacology of CNPHARS,and Director of Department of Neuroimmunopharmacology and traditional Chinese medicine in Beijing Institute of Pharmacology and Toxicology.Her research interests include the study of function of neuroendocrine immunomodulation(NIM)network and the pharmaco⁃logical studies of immunomodulators,endocrinomoduators,antiaging(especially anti-Alzheimer′s disease)drugs and cognition-enhancing drugs.Dr.ZHOU has published over 150 peerreviewed publications,more that 60 of them were published in international journals,such asPharmacology&Therapeutics,Neurobiology of Aging,Journal of Proteome Research, Pharmacology&Therapeutics,British Journal of Pharmacology,Brain Research,Journal ofEthnopharmacology,et al.

Key words:Alzheimer disease;Liuwei Dihuang decoction;hypothalamic-pituitary-adrenal axis

S2-4 A novel mechanism underlying the protective effect of PDE4 inhibitor against cognitive impairment:inhibiting neuroinflammation through inducing autophagy in microglial cells

YOU Ting-ting,GUO Hai-biao,WANG Hai-tao,XU Jiang-ping

(Department of Neuropharmacology and Drug Discovery,School of Pharmaceutical Sciences, Southern Medical University,Guangzhou 510515,China)

徐江平，南方医科大学药学院神经药理与新药发现学科主任、南方医科大学中心实验室主任、二级岗教授、博士生导师。广东省高等学校“千百十工程”第七批“国家级”培养对象。中国药理学会神经精神药理专业委员会，广东省药理学会常务理事，广东省药理学会神经药理学专业委员会主任委员，广东省药理学会药物毒理学专业委员会副主任委员，兼任国家食品药品监督管理局新药及保健食品评审专家。长期从事神经精神疾病如阿尔茨海默病、抑郁症和脑卒中的发病机制及药物筛选研究，着重于研究磷酸二酯酶4(PDE4)的结构及生理功能、PDE4抑制剂在神经退行性疾病及精神疾病中作用等。近5年来在Molecular Neurodegeneration，International Journal of Neuro⁃psychopharmacology，Neuropharmacology，ACS Chemical Neuroscience，Psychopharmacology，Journal of Alzheimers Disease等杂志发表SCI论文40余篇，先后主持国家自然科学基金5项，国家新药创制重大专项2项，广东省及其他科技项目多项。获授权发明专利5项、国际PCT专利1项，广东省科技技术三等奖1项。作为副主编、编委参与编写《药理学》教材10部。任J Alzheimers Dis，Frontiers in Pharmacology，Pharm Biol和J Pharmacol Sci等杂志审稿专家。

Abstract:OBJECTIVEInhibition of phosphodiesterase 4(PDE4)improves the learning and memory abilities in Alzheimer disease animal models.The cognition-enhancing effects of PDE4 inhibition involve reduced inflammatory responses in the brain.However,the underlying mechanisms are illunderstood.cAMP induces autophagy,and deficiency of autophagy leads to elevated inflammatory factors. In the present study,we aimed to investigate the contribution of autophagy to the anti-inflammatory effect of PDE4 inhibitor ROF.METHODSAcidic vesicles were traced by Lysotracker(LYT)red and acridine orange(AO)staining.Autophagosomes in BV-2 cells was observed by immunofluorescence staining of microtubule-associated protein 1 light chain 3(LC3).Aβ25-35or lipopolysaccharide(LPS)with ATP were used to activate microglial cells and inflammasome.Cytokine levels were measured by ELISA method.The levels of pro-inflammatory factors and essential proteins involved in the formation of autophagosome were detected by Western blotting.RESULTSROF increased the level of LC3-Ⅱ, while the level of p62 was decreased.Enhanced fluorescent signals were observed in BV-2 cells treat⁃ed with ROF by AO and LYT red staining.In addition,immunofluorescence indicated a significant in⁃crease in punctate LC3.Both LPS plus ATP and Aβ25-35enhanced the conversion of pro-caspase-1 to cleaved-caspase-1 and increased the production of mature IL-1β.Interestingly,these effects were blocked by the treatment of ROF.Moreover,ROF decreased the apoptosis of neuronal N2a cells in conditioned media from BV-2 microglia.These effects were reversed by inhibition of microglial autophagy. Treatment with ROF also showedenhanced autophagy in mcie treated with LPS.CONCLUSIONPDE4 inhibitor ROF inhibits inflammasome activities and reduces the release of IL-1β by inducing autophagy.

Key words:phosphodiesterase 4;autophagy;inflammasome;microglia

Corresponding author:XU Jiang-ping,E-mail:jpx@smu.edu.cn

S2-5 Loss of microglial autophagy causes Parkinson disease-like symptom in mice

CHENG Jin-bo1,LIAO Ya-jin1,LI Xiao-heng2,DONG Yuan3,TANG Bai-sha4,YUAN Zeng-qiang1

(1.Institute of Basic Medical Sciences,AMMS;2.Capital Medical University;3.Qingdao University, College of Medicine;4.Xiangya Hospital,Zhongnan University)

袁增强，博士，杰青。2003-2007哈佛医学院博士后。2007-2016，中科院生物物理所研究员，“百人计划”。2016-至今，军事医学科学院基础医学研究所特聘教授。实验室长期从事脑损伤和神经退行性疾病的分子生物学、细胞凋亡及其信号转导研究，主要成绩有：（1）发现了MST1-FOXO信号转导通路并揭示其在氧化应激导致的细胞凋亡中的重要作用。（2）鉴定了Cdk1-FOXO1信号转导通路并阐明其调控细胞凋亡和细胞周期的重要作用及其机制。（3）发现MST1和自噬通路在细胞凋亡和神经炎症的调控新机制及其在脑卒中和神经退行性疾病中的作用。目前共发表SCI论文60余篇，分别刊登在Science,Cell,PNAS，EMBO Rep,JNS,Cell Death和Differentiation等杂志。中国神经科学学会理事，中国卒中学会理事，北京市生化学会理事，北京市神经科学学会的理事，《中国科学》编委。承担国家科技部和基金委、北京市基金委、总后卫生局的重大重点项目若干。

Abstract:Microglia activation induced neuroinflammation closely relates with the development of Parkinson disease.Autophagy regulates many biological processes,but the role in microglial activation and the development of Parkinson disease is not clear.In this study,we show that loss of microglialAtg5cause neuroinflammation and motor and cognitive learning impairment in mice,with accumulation of α-synuclein and decrease of dopamine levels in the striatum.Inhibition of autophagy aggravates the activation of NLRP3 inflammasomeviaPDE10a-cAMP signaling in microglia.Furthermore,the down⁃stream cytokine IL-1 increases Mif levels in a transcriptional dependent manner.Interestingly,Mif levels are significantly elevated in Parkinson disease patients.Taken together,our results reveal a protective role of autophagy in microglial activation-driven Parkinson disease,thus providing a potential targets for the clinical treatment.

Key words:microglia;Parkinson disease;autophagy

Corresponding author:YUAN Zeng-qiang,E-mail:zyuan620@yahoo.com

S2-6 Modulation of abnormal neuronal circuit in temporal lobe epilepsy

WANG Yi,XU Ceng-lin,CHEN Zhong

(Department of Pharmacology,Key Laboratory of Medical Neurobiology of the Ministry of Health of China,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,China)

Abstract:OBJECTIVETemporal lobe epilepsy(TLE)is one of the most common types of human epilepsy,and they are often resistant to current treatments.METHODSBy using optogenetic,electro⁃physiological,imaging and pharmacology strategies,we aimed toinvestigate the underlying circuit mechanism of TLE and tried to developthe novel and efficient approach to control epilepsy.RESULTS(1)Deep brain stimulation,especially low frequency stimulation,targeted the epileptic focus and the areas outside of the focus(critical regions for seizure spread),such as entorhinal cortex or subiculum, reduced seizure severity in TLE.Its anti-epileptic effect is time-window dependent and polarity dependent, which shows a promising strategy for treating epileptic seizures.(2)Using an optogenetic strategy,we demonstrated that excitatory projection from entorhinal cortex to hippocampus instructs the brain-stimu⁃lation treatments of epilepsy.(3)Our data from both the clinical and experimental studies further dem⁃onstrated that a disinhibitory GABAergic neuron-mediated microcircuit in the subiculum contributes to secondary generalized seizures in TLE.(4)Finally,based on abnormal synchronization of the electrical activity in epileptic circuit,we developed electro-responsive hydrogel nanoparticles modified with angiopep-2 to facilitate the delivery of the antiepileptic drug phenytoin sodium,which greatly improves the therapeutic index.CONCLUSIONOur findings may update the current view of epileptic neuronal networks and suggest possible promising ways for epilepsy treatment.

Key words:epilepsy;neural circuits;brain stimulation;optogenetics;electro-responsive

Foundation item:The project supported by National Natural Science Foundation of China(91332202, 81630098)

S2-7 The decrease of connexin43 mediated down-regulation of glutamate transporter1 in spinal astrocytes under inflammatory condition

ZHANG Fang-fang1,Norimitsu MORIOKA2,Shiori FUJII2，ZHOU Yan-meng1,ZHAO Xiao-min1，ZHANG Han-ting1

(1.Taishan Medical University,619 Changcheng Road,Tai′an,Shandong,271016,China; 2.Department of Pharmacology,Hiroshima University Graduate School of Biomedical Health Sciences,1-2-3Kasumi,Minami-ku,Hiroshima 734-8553,Japan)

Abstract:OBJECTIVEAstrocytic gap junctions formed by connexin 43(Cx43)are crucial for intercel⁃lular communication between spinal cord astrocytes.Various neurological disorders include chronic pain are associated with dysfunctional Cx43-gap junctions.A previous study showed that treatment of spinal astrocytes in culture with pro-inflammatory cytokines tumor necrosis factor-α(TNF-α)and inter⁃feron-γ(IFN-γ)decreased both Cx43 expression and gap junction intercellular communication(GJIC) via a c-jun terminal kinase-dependent pathway.However,the exact mechanism that Cx43 does this in the context of spinal astrocytic dysfunction is unclear.The current study investigated the downstream signaling of Cx43-gap junction in rat primary cultured spinal astrocytes stimulated with cytokines.METHODSWefocused on the glutamate transporters,examined the alteration of GLT-1 and gluta⁃mate-aspartate transporter(GLAST)expression and function in rat primary cultured spinal astrocytes stimulated with cytokines by real-time PCR and Western blotting.The function of GLT-1 was analyzed using the carbon 14.To elucidate the effect of Cx43 on glutamate transporters in spinal astrocytes, changes in glutamate transporters expression and function were quantif i ed after Cx43 siRNA treatment.RESULTSThe transcriptional and translational levels of Cx43 were reduced after 12 hr co-treatment with TNF-α(10 ng·mL-1)or IFN-γ(5 ng·mL-1).Furthermore,transcriptional and translational levels of GLT-1 and GLAST were also signif i cantly reduced 24 and 48 h co-treatment with TNF-α or IFN-γ. Moreover,functional GLT-1 and GLAST uptake were inhibited by the mixture of TNF-α and IFN-γ.In addition,Both the decrease of GLT-1 expression and the reduction in functional GLT-1 uptake induced by the Cx43 siRNA,but both the expression and functional GLAST were no changes.CONCLUSIONThese results indicate that a Cx43 downregulation is induced under inflammatory condition that disrupts spinal astrocytic GLT-1 expression and function,leading to astrocytic dysfunction and the maintenance of the neuroinflammatory state.

Key words:spinalastrocytes;connexin 43;GLT-1

S2-8 Gngerol in the improvement of Aβ -induced learning and memory impairment

YUAN Sheng-nan,LIU Qian-qian,LIU Yong-zhi,ZHANG Feng,HOU Xue-qin,WANG Lei

(Institute of Pharmacology,Taishan Medical University,Tai′an 271016,China)

Abstract:OBJECTIVETo investigate the influence of gingerol on the improvement of learning and memory impairment of rat model of Alzheimer disease induced by β-amyloid peptide fragment 25-35 (Aβ25-35)and to analysis the possible mechanism.METHODSSD rats were randomly divided into 5 groups:blank control group,model group,sham-operated group,low dose drug group(gingerol emulsion, 10 mg·kg-1·d-1),high dose drug group(gingerol emulsion,50 mg·kg-1·d-1).Model group and two drug groups were injected Aβ25-35(5 μL)in lateral cerebral ventricle.Sham-operated group were injected the same amount of sterile PBS solution.For blank control group without any treatment.When all the rats refresh themselves and had post-operated activities,two drug groups were gavaged with different concentration of gingerol emulsion,Meanwhile,sham-operated group were gavaged with sterile physio⁃logical saline,the remaining two groups without any treatment.After three weeks,we make use of Y labyrinth to test the ability of space learning and memory of rats.Finally,rats were sacrificed to collect blood by abdominal aortic method.The content of acetylcholine(ACh),SOD and MDA were detected in serum.RESULTS①Compared with blank control group,the ability of learning and memory of model group rats were weakened,the error times increased in Y labyrinth experiment.In addition,the content of ACh and the activity of SOD significantly decreased,the content of MDA increased(P＜0.05).②On the contrary,the rats gavaged with gingerol emusion have less error times in Y labyrinth experiment compared with model group.the content of Ach and the activity of SOD significantly increased,the content of MDA decreased(P＜0.05).However,two different gingerol emusion concentration groups have no significantly difference.CONCLUSIONThe ability of learning and memory of rats gavaged with gingerol emusion were significantly improved compared with Aβ25-35induced rats without any treatment. Its mechanism may be related to antioxidant and neurotransmitter.

Key words:gingerol;learning and memory

Foundation item:The project supported by National College Students′Innovative and Entrepreneurial Training Project(201510439078);and Science and Technology Development Plan of Tai′an City (201540707)

Corresponding author：WANG Lei，E-mail：wang.lei1118@163.com，Tel：13105380208

S2-9 Protective effects of Radix Cynanchum bungei on ischemia-induced neuronal and cognitive impairment in mice

CHEN Mei-hua,CHEN Wei,MA Jian,ZHANG Fang-fang，ZHOU Yan-meng

(Institute of Pharmacology,Taishan Medical College,Tai′an 271016,China)

Abstract:OBJECTIVETo investigate the effects of Radix Cynanchum bungei extract(RCBE)on cerebral ischemia-reperfusion(I/R)and acute cerebral ischemia induced impairment in mice.METHODSI/R model was induced by bilateral carotid artery occlusion(BCAO)-reperfusion method and Y-maze learning and memory performance was assessed after reperfusion.Na+-K+-ATPase,Ca2+-ATPase and SOD activity,as well as MDA content in mouse brain tissue were measured.Numbers of mouth-opening breaths of the isolated mouse head were observed in acute cerebral ischemia mice.RESULTSLearning and memory ability in mice with RCBE were improved significantly compared with model group.The activity of SOD,Na+-K+-ATPase and Ca2+-ATPase were increased,while MDA contents decreased after RCBE(0.5,1.0 and 2.0 g·kg-1)and piracetam(0.5 g·kg-1)treatment compared with the model group.RCBE at all concentrations significantly prolonged the number of mouth-opening breaths of the isolated mouse head.CONCLUSIONRCBE preconditioning exerts a marked neuropro⁃tective effect on the ischemia brain,which is related to improve the learning and memory via regulating energy metabolism and anti-oxidation.

Key words:Radix Cynanchum bungei;cerebral ischemia-reperfusion;acute cerebral ischemia;neuro⁃protection

Foundation item:The project supported by Medical Science and Technology Development Plan of Shandong Province(2016WS0611);and Science and Technology Development Plan of Tai′an City (2016NS1070)

S2-10基于NLRP3炎性小体通路研究葡萄籽原花青素对AD大鼠的保护作用

罗远超，郑 敏，刘剑桥，陈美华，陈 伟

（泰山医学院药学院，山东泰安 271016）

摘要：目的通过双侧海马注射Aβ1～42制备大鼠AD模型，探讨葡萄籽原花青素(GSP)抑制小胶质细胞NLRP3炎性小体通路保护AD大鼠学习记忆能力的可能机制。方法双侧海马注射Aβ1～42建立AD大鼠模型，造模48 h后开始灌胃给予GSP 100,200和400 mg·kg-1，假手术组和模型组灌胃给予相同容量的生理盐水。药后通过新物体识别实验和Morris水迷宫实验观察大鼠的学习记忆能力，WB法检测各组大鼠脑组织NLRP3的含量，ELISA法检测大鼠海马和皮质IL-1β和IL-6的含量。结果GSP各剂量均可明显增加AD大鼠的新物体识别指数。Morris水迷宫实验中GSP对定位航行实验的逃避潜伏期无显著影响；GSP各剂量组可明显缩短空间探索实验的大鼠探索潜伏期，并且200和400 mg·kg-1可显著性增加AD大鼠进入平台区域的次数，100 mg·kg-1可增加AD大鼠进入平台区域的次数，但无统计学差异。GSP可明显减少大鼠脑组织的NLRP3表达，进而减少海马和皮质中IL-1β和IL-6含量。结论GSP对Aβ1～42诱导的AD大鼠学习记忆障碍具有明显的改善作用，其机制可能是通过抑制脑组织NLRP3炎性小体通路，减少炎性因子IL-1β和IL-6的产生，减轻Aβ1～42诱导的炎症反应而实现。

关键词：葡萄籽原花青素；NLRP3；IL-1β；IL-6

Abstract:Betaine have protective effects on liver,cardiovascular system,and cancer,but there is no report about I/R injury in heart.So the purpose of this experiment is to study the effect of betaine on I/R injury by Langendorff model and to discuss the mechanisms.SD rat were randomly divided into 4groups:control group(perfused with KH buffer),10-4mol·L-1,5×10-4mol·L-1,and 10-3mol·L-1(perfused with betaine in different concentration respectively for 10 min before ischemia followed by KH buffer perfused).During the experiment we detected LVEDP,LVDP,dp/dt,and store the tissue to do western blot and TTC staining.The result showed that in control group the recovery rate is 19.6%,after pretreatment of betaine the recovery rate all increased significantly and in a dose-dependent manner.The LVEDP is markedly decreased in betaine treatment groups compare to control group.Coronary flow only in highest betaine treatment group(10-3mol·L-)is markedly increased compare to control group,other two groups have no change.Western blotting showed that SOD level is significantly increased in betaine treatment group compare to control group and in a dose dependent manner.TTC staining suggested that infarction size is reduced in betaine treatment group compare to control group.Above all,the results suggest that betaine have protect effect on I/R injury in heart and this effect may relate to ROS signaling pathway.

Key words:betaine;I/R injury;SOD

Foundation item:The project supported by National Natural Science Foundation of China(81400182); and National Training Programs of Innovation and Entrepreneurship for Undergraduates(201610439129)

S2-12 Role of endothelial receptor-tyrosine kinase ErbB4 in regulating brain function

LIU Xiu-xiu1,2,WU Gang1,2,LU Nan-nan2,LIU Qi-bing3,TIAN Yun2,YE Wei-feng2,JIANG Guo-jun4, TAO Rong-rong2,HAN Feng2,LU Ying-mei1

(1.School of Medicine,Zhejiang University City College,Hangzhou,China;2.College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,China;3.School of Pharmacy,Hainan Medical College, Haikou,China;4.Department of Pharmacy,Zhejiang Xiaoshan Hospital,Hangzhou,China)

Abstract:OBJECTIVEThe receptor-tyrosine kinase ErbB4 is present throughout the primate brain and has a distinct functional profile.In the present study,we investigate the potential role of endothelial ErbB4 receptor signaling in the brain.METHODSErbB4 conditional KO mice were generated by a loxP/Cre strategy.The experimenter conducting the experimentsand scoring the behavior was blinded to the genotype of the mice.Open field test,Y-maze and novel-object exploration test,novel object recognition task,step-through passive avoidance task,Morris water maze and memory reconsolidation task were carried out in WT andCdh5-Cre;ErbB4loxP/loxPmice.A high-resolution microPET/CT scanner was used for brain metabolism imaging.RESULTSHere,we show thatCdh5Cre;ErbB4f/fmice have lower levels ofexploration activity as measured by these particular behavior tests.However,our data indicate that conditional knockout of ErbB4 in endothelial cells did not impair working memory,memory acquisition,retrieval,and reconsolidation in mice.Furthermore,18F-FDG-uptake was reduced in theCdh5Cre;ErbB4f/fmice as revealed by the significantly decreased SUVs in compared with the WT mice.Consistently,the immunoblot data demonstrate the downregulation of brain Glut1,phospho-ULK1(Ser555)and TIGAR in the endothelial ErbB4 conditional knockout mice.Collectively,the endo⁃thelial ErbB4 deletion induced impairment in exploratory activity in adult mice,which may be due to the decreased brain energy metabolism.CONCLUSIONOur study provides insight into the potential patho⁃physiological mechanisms of endothelial ErbB4 and therapeutic strategies for neurological disorders.

Key words:ErbB4;endothelial;CaMKII;exploratory behavior;brain metabolism

S2-13 Neuroprotective effect of isoliquriitin on corticosterone-induced apoptosis in PC12 cells

LI Xiao1,2,GONG Wen-xia1,2,ZHOU Yu-zhi1,QIN Xue-mei1

(1.Modern Research Center for Traditional Chinese Medicine,Shanxi University,Taiyuan 030006, China；2.College of Chemistry and Chemical Engineering,Shanxi University,Taiyuan 030006,China）

Abstract:OBJECTIVEIsoliquiritin,a flavonoid glycosides compound,possess a broad spectrum of pharmacological activities including antioxidant,antiinflammatory.However,rare studies in the field of isoliquiritin antidepressant-like effects have been carried out,the molecular mechanism also remains unclear.In this study，the model of corticosterone-damaged rat adrenal pheochromocytoma(PC12) cells has been used to generate anin vitroexperimental model of depression.The aim was to investigate thecytoprotective efficiency and potential mechanisms of isoliquiritin in corticosterone-damaged PC12 cells.METHODSThe cells were treated with 400 μmol·L-1corticosterone in the absence or presence of isoliquiritin for 24 h;cells viability and lactate dehydrogenase(LDH)leakage were then determined, Hoechst 33342/PI and Annexin V/PI double staining were performed to evaluate the cytoprotective efficiency of isoliquiritin.Next,intracellular calcium([Ca2+]i),mitochondrial membrane potential(MMP), reactive oxygen species(ROS),malondialdehyde(MDA),the activity of superoxide dismutase(SOD) and catalase(CAT),and Western blotting analysed for the expression of Bcl,Bax,caspase-3 and cytochrome C(Cyt-C)were investigated to explore the potential mechanisms.RESULTSThe results of the present study showed that pretreatment of PC12 cells with isoliquiritinsignificantly prevented the corticosterone-induced cell apoptosis.In addition,isoliquiritin increased the activity of SOD and CAT, decreased the contents of ROS and MDA.These findings suggest that isoliquiritin provided a protective action against corticosterone-induced celldamage by reducing oxidative stress.Furthermore pretreat⁃mented with isoliquiritin reduced corticosterone-induced mitochondrial dysfunction by preventing mito⁃chondrial membrane potentials dissipation.Our findings indicated that isoliquiritin might exert its thera⁃peutic effects viaregulating mitochondrial dysfunction.Moreover isoliquiritin strongly attenuated[Ca2+]ioverload and down-regulation of Bax,caspase-3 and Cyt-C protein expression,up-regulation of Bcl protein expression.CONCLUSIONIsoliquiritin has acytoprotective effect on corticosterone-induced cytotoxicity in PC12 cells,which may be related to its antioxidant action,inhibition of[Ca2+]ioverload and inhibition of the mitochondrial apoptotic pathway.

Key words:isoliquiritin;neurotoxicity;oxidative stress;mitochondria apoptotic;calcium

Foundation item：The project supported by National Natural Science Foundation of China(81673572); the Applied Basic Research Project of Shanxi Province(201601D021164);and Innovation Project of Higher Education Institutions in Shanxi Province(2016120)

Corresponding author:QIN Xue-mei,E-mail：qinxm@sxu.edu.cn

S2-14 A review of studies on neuroprotective aspects of bioactive polysaccharides

SU Lei1,JING Yong-shuai2,ZHANG Dan-shen2

(1.College of Chemistry and Pharmaceutical Engineering,Hebei University of Science and Technology, Shijiazhuang 050200,China;2.Hebei University of Science and Technology, Shijiazhuang 050200,China)

Abstract:With the aging of the population intensified,neurodegenerative diseases have become amajor problem that plagues modern people.In the organism,the pathological process common to these diseases is the damage and death of neurons in the central nervous system.Therefore,neurons the protection is the key issuesof neurological disease prevention and treatment.Polysaccharide is one of the important active substances in life activities,and has many biological activities.Polysaccharides are one of the most important active substances in life activities.They have many biological activities, such as energy storage,structural support,defense and antigen characterization.In addition,it is characterized by small toxicity,high safety and versatility.Polysaccharides also have other biological activities,such as anti-tumor,hypoglycemic,immune regulation,anti-inflammatory,anti-oxidation, neuroprotection and so on.As the active polysaccharide safe,non-toxic,in medicine,agriculture,food and other industries have a broad development and application value and prospects,having become a hot topic in many disciplines at home and abroad.More and more research evidence shows that poly⁃saccharides in the neuroprotective aspects of the study more and more comprehensive and in-depth. In this paper,we reviewed the role of polysaccharides in neuroprotective mechanisms,including antioxi⁃dant,anti-inflammatory,promoting proliferation of neural cells,promoting neuronal differentiation,and inhibiting apoptosis of neurons.

Key words:polysaccharide;neuroprotection;anti-oxidation;anti-inflammatory;nerve cells

Corresponding author:ZHANG Dan-shen

S2-15 Application of nanoparticles modified with angiopep-2 in the diagnosis and treatment of glioma

SU Xiao-mei,ZHANG Dan-shen

（Hebei University of Science and Technology,Shijiazhuang 050000,China）

Abstract:OBJECTIVETo review the application of nanoparticles modified with angiopep-2,providing theoretical guidance for the diagnosis and treatment of glioma.METHODSAccording to domestic and foreign research reports of nanoparticles modified with angiopep-2 in recent years,the application in the diagnosis and treatment of glioma was summarized and analyzed.RESULTSAngiopep-2 can be modified to the surface of nanoparticles loaded with imaging agents or chemotherapeutic agents,which can significantly improve the imaging effect of glioma and achieve targeted drug delivery.CONCLUSIONAngiopep-2 exhibits a high brain penetration capability in blood brain barrier and in glioma cells.The nanoparticles modified with angiopep-2 can delivery various imaging agents and chemotherapeutic agents to glioma cells,the dual-targeting delivery systems can provide theoretical guidance for the diagnosis and treatment of glioma.

Key words:angiopep-2;nanoparticles delivery system;nanoparticles imaging system

S2-16 Protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration

WANG Hong-shen,XU Yan-hao，CHANG Sheng,LI Li,WANG Hao,HAO Ji-fu

(College of Pharmacy，Taishan Medical university，Tai′an 271016,China)

Abstract:OBJECTIVETo evaluate the protective effects of resveratrol nanosuspensions loadedinsituhydrogel on Alzheimer disease model mice after intranasal administration.METHODSResveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into 0.5%gellan gum to form resveratrol nanosuspenisons loaded ionic sensitivein situhydrogel.The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ25～35and the protection and treatment effects of resveratrol nanosuspensions loadedin situhydrogel on study and memory capability were performed after intranasal administration in water maze experiments.The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetyl⁃choline(ACh),choline acetyltransferase(ChAT)and acetylcholinesterase(AChE).RESULTSBehavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform.Compared with the control group,av⁃erage latency of model group significantly increased.While compared with the model group,treatment group′s average latency was significantly shorter.Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group.But the crossing times of treatment group with resveratrol increased compared with the model group.As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased;the ChAT activity decreased,while the activity of AChE with the ability to hydrolysis acetylcholine increased.The administration of resveratrol can decrease the activity of ACh enzymes but increase ChAT activity and the levels of acetylcholine.CONCLUSIONResveratrol nanosuspension loadedin situgel can amelio⁃rate the declining ability of learning and memory of AD model mice after intranasal administration.As a promising approach for the treatment of central nervous system(CNS)disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.

Key words:resveratrol;intranasal administration;Alzheimer disease;water maze experiments

Foundation item:The project supported by the National Training Program of Innovation and Entrepre⁃neurship for Undergraduates（201610439108）

Corresponding author:HAO Ji-fu,E-mail:haojifu@163.com

S2-17生物碱类磷酸二酯酶抑制剂治疗帕金森疾病可行性探讨

万 叶,郭春燕

(河北北方学院,河北张家口 075000)

摘要：帕金森疾病是一种常见的与年龄相关的神经退行性疾病，随年龄增长，发病几率增大，多发病于中老年人群中，其病理特征主要是纹状体区的多巴胺含量减少，发病机制复杂，至今尚不明确。目前，帕金森的治疗以维持多巴胺和乙酰胆碱平衡为主要治疗手段。治疗帕金森病的主要有多巴胺能药和抗胆碱药。但是副作用较大，且只能缓解症状而不能阻止神经退化。近年来的研究发现磷酸二酯酶家族生理作用广泛，得到越来越多学者的关注。其中磷酸二酯酶1中的磷酸二酯酶1B参与神经系统的多项生理活动，有多种中药提取物对其具有抑制作用，磷酸二酯酶1B抑制剂对认知功能障碍有一定的改善作用，并在临床用于帕金森病的治疗。中药治疗帕金森可弥补西药治疗的缺陷，具有毒副作用小，疗效持久的特点，是帕金森药物治疗的研究热点。中药治疗具有明显的优势和一定的发展前景，本文根据近年文献综述生物碱类中药对帕金森疾病治疗的可行性。

关键词：帕金森病；磷酸二酯酶；中药；治疗

ong iong-weiwei received his BS.in 1995 and MS.in 1998 from the Department of Biochemistry at Wuhan University in China.He received his PhD in 2002 from the Department of Pathology at Case Western Reserve University.He was a postdoctoral fellow and instructor in pathology until he became Assistant Professor in 2004.He was promoted to Associate Professor with tenure in 2009 and full professor in 2015.His research focuses on the neurode⁃generative mechanisms underlying Alzheimer disease and other neurodegenerative diseases with a focus on mitochondrial dysfunction and oxidative stress.His research is continuously funded by NIH,NASA and/or Alzheimer′s Association.Dr.ZHU′s research areas of interests include:mitochondrial dysfunction during neurodegeneration,oxidative stress signaling path⁃ ways during neurodegeneration,and epigenomics research of Alzheimer disease and Parkinson disease.

Alzheimer disease;mitochondrial

ZHU Xiong-wei,E-mail:xiongwei.zhu@case.edu

S2-2 新型抗阿尔茨海默病药物甘露寡糖二酸

耿美玉
（中国科学院上海药物研究所，上海）

Alzheimer disease(AD)is the leading cause of dementia that affects millions of elderly people worldwide.The currently available therapies have limited efficacy.Liuwei Dihuang decoction(LW),a classical traditional Chinese medicine(TCM)formula,has long been used to treat various diseases, including dementia.A large number of pharmacological studies have showed thatLW has beneficial effects on AD.LW-AFC is a new formula consisted of the main active components prepared from LW. In this study,we found that administration of LW-AFC significantly improved behavioral performances in spontaneous locomotor activity,object recognition memory,spatial learning and memory,passive and active avoidance impairment in some AD mouse models,such as SAMP8 and APP/PS1 transgenic mice.Meanwhile,the impairments of long-term potentiation(LTP)were significantly ameliorated by LW-AFC administration in SAMP8 mice,as well as in corticosterone-induced LTP inhibition mice model. These effects were companied by alleviating of the neuron loss in the hippocampus,suppressing of A-beta deposition in the brain,and reducing of the concentration of Abeta42 in the hippocampus and plasma of APP/PS1 mice.The restoring and correcting of imbalance of hypothalamic-pituitary-adrenal (HPA)and hypothalamic-pituitary-gonadal(HPG)axis,the disorder of lymphocyte subsets,the abnor⁃mality of production of cytokine were also observed in LW-AFC treated SAMP8 and APP/PS1 mice. These findings indicated that LW-AFC ameliorated the behavioral and pathological deterioration of AD mice via the restoration of the NIM network in a holistic way,suggesting that LW-AFC might bea promising therapy for AD.

The project supported by National Natural Science Foundation of China(81373384)

S2-11 Protective effects of betaine on ischemia-reperfusion injury through ROS pathway in rat

XUE Shuang,JIA Xiao-ying,ZHOU Lu,GAO Shan
(Institute of Pharmacology,Taishan Medical University,Tai′an 271000,China)

山东省高等学校科技计划（J14LM03）;国家级大学生创新创业训练项目（201610439136）

陈 伟，E-mail：chenweilxq@163.com，Tel：13395481577

Abstract:Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer′s disease which likely plays a critical role in the pathogenesis of disease.Mito⁃chondria are dynamic organelles and the balance of mitochondrial fission and fusion determines Our initial studies revealed an imbalance in mitochondrial fission and fusion in fibroblasts from sporadic AD patients compared with normal healthy fibroblasts from age-matched control patients.Later it was dem⁃onstrated that overexpression of familial Alzheimer disease(FAD)-causing AβPP mutant or exposure to soluble Aβ oligomers led to mitochondrial fragmentation and redistribution in neuronal cells along with altered expression of mitochondrial fission/fusion proteins.Marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of AD mouse model CRND8 as early as three months of age before the accumulation of amyloid pathology.Importantly,we demonstrate significant changes in the expression and distribution of mitochondrial fission and fusion proteinsin vivoin AD in consistent with a shifted mitochondrial dynamics towards excessive fission.Most recently,we demonstrated that genetic and pharmaceutical methods to rescue mitochondrial morphology and distribution could effectively restore Aβ-induced mito⁃chondrial function and alleviate synaptic dysfunction bothin vitroandin vivo,suggesting a causal involvement of mitochondrial dynamics in mediating Aβ-induced mitochondrial dysfunction.Taken together,we suggest that such a fundamental shift in mitochondrial dynamics negatively impacts all aspect of mitochondrial function such as impaired bioenergetics,increased structural damage and ROS production and loss of mtDNA integrity which causes synaptic dysfunction and neuronal dysfunc⁃tion that is critical to AD pathogenesis.Therefore,strategies to modify abnormal mitochondrial dynam⁃ics may be an attractive therapeutic intervention target for AD.