專題2 阿爾茨海默病及其他神經退行性疾?。褐委熍c機制

ZHU Xiong-wei

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

專題2 阿爾茨海默病及其他神經退行性疾?。褐委熍c機制

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，日本東京大學藥學博士，現任中國科學院上海藥物研究所黨委書記、副所長。國家杰出青年基金獲得者，中國科學院百人計劃入選者，國家“973”計劃“糖化學糖生物學研究”項目首席科學家。長期致力于抗老年癡呆（AD）和抗腫瘤藥物研發及標志物研究。申請國內外發明專利70余項，授權30余項。4個候選新藥已實現轉讓，合同額近10億。獲國家技術發明一等獎。在Cancer Cell，Cell Res，J Nat Cancer Inst，Hepatology，Cancer Res和Clin Cancer Res等雜志發表文章180余篇。兼任基金委醫學部“十三五戰略規劃”專家組副組長，基金委醫學部“炎癌轉變”重大研究計劃專家組成員。

目的阿爾茨海默?。ˋD），是一種由多因素引起的神經系統退行性疾病，嚴重危害人類健康。目前臨床治療藥物主要為膽堿酯酶抑制劑等疾病癥狀改善藥物，存在療效不確切、毒副作用大等缺點，無法有效防止AD的進展。因此開發能夠改變疾病進程的抗AD藥物是目前醫藥界共同關注的焦點。方法采用基于SPR的芯片篩選方法，針對糖庫進行篩選；采用一系列的生物化學和物理方法，觀察對amyloid β（Aβ）聚集以及神經毒性的影響；采用轉基因動物模型，觀察對轉基因動物行為學的影響。結果我們通過篩選獲得國際首個靶向Aβ的寡糖分子——971。核磁共振技術直接證明971能夠與Aβ多位點結合；通過其獨特的結合方式，971能夠抑制Aβ聚集，并且能夠促進已經聚集的Aβ解聚，同時抑制Aβ的神經毒性。體內研究表明971能夠明顯改善轉基因小鼠的學習記憶能力以及日常生活能力。Ⅱ期臨床研究表明，971安全性好、能明顯改善輕中度AD患者認知功能障礙。臨床Ⅲ期正在進行中。結論971有望成為近十幾年來首個靶向Aβ的抗AD新藥。

阿爾茨海默??；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，南方醫科大學藥學院神經藥理與新藥發現學科主任、南方醫科大學中心實驗室主任、二級崗教授、博士生導師。廣東省高等學?！扒О偈こ獭钡谄吲皣壹墶迸囵B對象。中國藥理學會神經精神藥理專業委員會，廣東省藥理學會常務理事，廣東省藥理學會神經藥理學專業委員會主任委員，廣東省藥理學會藥物毒理學專業委員會副主任委員，兼任國家食品藥品監督管理局新藥及保健食品評審專家。長期從事神經精神疾病如阿爾茨海默病、抑郁癥和腦卒中的發病機制及藥物篩選研究，著重于研究磷酸二酯酶4(PDE4)的結構及生理功能、PDE4抑制劑在神經退行性疾病及精神疾病中作用等。近5年來在Molecular Neurodegeneration，International Journal of Neuro?psychopharmacology，Neuropharmacology，ACS Chemical Neuroscience，Psychopharmacology，Journal of Alzheimers Disease等雜志發表SCI論文40余篇，先后主持國家自然科學基金5項，國家新藥創制重大專項2項，廣東省及其他科技項目多項。獲授權發明專利5項、國際PCT專利1項，廣東省科技技術三等獎1項。作為副主編、編委參與編寫《藥理學》教材10部。任J Alzheimers Dis，Frontiers in Pharmacology，Pharm Biol和J Pharmacol Sci等雜志審稿專家。

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)

袁增強，博士，杰青。2003-2007哈佛醫學院博士后。2007-2016，中科院生物物理所研究員，“百人計劃”。2016-至今，軍事醫學科學院基礎醫學研究所特聘教授。實驗室長期從事腦損傷和神經退行性疾病的分子生物學、細胞凋亡及其信號轉導研究，主要成績有：（1）發現了MST1-FOXO信號轉導通路并揭示其在氧化應激導致的細胞凋亡中的重要作用。（2）鑒定了Cdk1-FOXO1信號轉導通路并闡明其調控細胞凋亡和細胞周期的重要作用及其機制。（3）發現MST1和自噬通路在細胞凋亡和神經炎癥的調控新機制及其在腦卒中和神經退行性疾病中的作用。目前共發表SCI論文60余篇，分別刊登在Science,Cell,PNAS，EMBO Rep,JNS,Cell Death和Differentiation等雜志。中國神經科學學會理事，中國卒中學會理事，北京市生化學會理事，北京市神經科學學會的理事，《中國科學》編委。承擔國家科技部和基金委、北京市基金委、總后衛生局的重大重點項目若干。

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炎性小體通路研究葡萄籽原花青素對AD大鼠的保護作用

羅遠超，鄭 敏，劉劍橋，陳美華，陳 偉

（泰山醫學院藥學院，山東泰安 271016）

摘要：目的通過雙側海馬注射Aβ1～42制備大鼠AD模型，探討葡萄籽原花青素(GSP)抑制小膠質細胞NLRP3炎性小體通路保護AD大鼠學習記憶能力的可能機制。方法雙側海馬注射Aβ1～42建立AD大鼠模型，造模48 h后開始灌胃給予GSP 100,200和400 mg·kg-1，假手術組和模型組灌胃給予相同容量的生理鹽水。藥后通過新物體識別實驗和Morris水迷宮實驗觀察大鼠的學習記憶能力，WB法檢測各組大鼠腦組織NLRP3的含量，ELISA法檢測大鼠海馬和皮質IL-1β和IL-6的含量。結果GSP各劑量均可明顯增加AD大鼠的新物體識別指數。Morris水迷宮實驗中GSP對定位航行實驗的逃避潛伏期無顯著影響；GSP各劑量組可明顯縮短空間探索實驗的大鼠探索潛伏期，并且200和400 mg·kg-1可顯著性增加AD大鼠進入平臺區域的次數，100 mg·kg-1可增加AD大鼠進入平臺區域的次數，但無統計學差異。GSP可明顯減少大鼠腦組織的NLRP3表達，進而減少海馬和皮質中IL-1β和IL-6含量。結論GSP對Aβ1～42誘導的AD大鼠學習記憶障礙具有明顯的改善作用，其機制可能是通過抑制腦組織NLRP3炎性小體通路，減少炎性因子IL-1β和IL-6的產生，減輕Aβ1～42誘導的炎癥反應而實現。

關鍵詞：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生物堿類磷酸二酯酶抑制劑治療帕金森疾病可行性探討

萬 葉,郭春燕

(河北北方學院,河北張家口 075000)

摘要：帕金森疾病是一種常見的與年齡相關的神經退行性疾病，隨年齡增長，發病幾率增大，多發病于中老年人群中，其病理特征主要是紋狀體區的多巴胺含量減少，發病機制復雜，至今尚不明確。目前，帕金森的治療以維持多巴胺和乙酰膽堿平衡為主要治療手段。治療帕金森病的主要有多巴胺能藥和抗膽堿藥。但是副作用較大，且只能緩解癥狀而不能阻止神經退化。近年來的研究發現磷酸二酯酶家族生理作用廣泛，得到越來越多學者的關注。其中磷酸二酯酶1中的磷酸二酯酶1B參與神經系統的多項生理活動，有多種中藥提取物對其具有抑制作用，磷酸二酯酶1B抑制劑對認知功能障礙有一定的改善作用，并在臨床用于帕金森病的治療。中藥治療帕金森可彌補西藥治療的缺陷，具有毒副作用小，療效持久的特點，是帕金森藥物治療的研究熱點。中藥治療具有明顯的優勢和一定的發展前景，本文根據近年文獻綜述生物堿類中藥對帕金森疾病治療的可行性。

關鍵詞：帕金森??；磷酸二酯酶；中藥；治療

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 新型抗阿爾茨海默病藥物甘露寡糖二酸

耿美玉
（中國科學院上海藥物研究所，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)

山東省高等學?？萍加媱潱↗14LM03）;國家級大學生創新創業訓練項目（201610439136）

陳 偉，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.