[生物医药论文精品a]盐酸法舒地尔对大鼠慢性低灌性脑缺血所致学习记忆障碍的改善作用

1盐酸法舒地尔对大鼠慢性低灌性脑缺血所致学习记忆障碍的改善作用A1A01,2A3A2A41A6A5A72A91A10A8A11A12A13A14A15A16A18A10A8100044A192A20A17A21A22A23A24A25A26A27A24A28A29A30A27A24A28A31A32A24A33A34A35A36430030A37A38A39A40A41A42A43RHOA44A45A46A47A48A49A50A51A52A53A54A55A56A57A58A59A60A61A59A62A63A64A65A66A67A68A69A70A71A72A73A74A59A75A76A56A57A77A78A79A80A81A82A47A83A56A57A58A59A60A61A59A62A63A64A65A66A84A85A70A86A87MORRISA88A89A90A91A92A93A94A56A57A95A96A97A98A99A100A101A102A103A86A87A104A105A106A107A108A109A110A99A111A93A94A56A57A112A113CA3A114A115A116A106A117A118A119A120A121A122A123A44A124A125A126A127A128A129A130A131A132A133LONGTIMEPOTENTIATION,LTPA67A134A135A103A136A137A94A138A139WESTERNBLOTA109A110A140A141NNOSA67A142A143A70A144A145MORRISA146A147A148A149A150A151A152A153A154A155A156A157A158A159A160A161A162A163A164A165A166A167A168A169A170A155A171A172A173A174A175A176A177A178A179A180A181A182A183A184A185A186A187A188A189A190A191A192A193A194A195A196A197A198A199A200A201A202LTPA203A204A205A206A189A198A199A200A201A202A207A208A209A210A211A212A213NNOSA214A215A216A217A218A219A220A221A222A223A224A225A226A227A185A228A229A230A231A232A233A234A235A201A202A236A237A195A238A239A240A241A242A243LTPA203A244A245A209A246A247A241A248A249NNOSA235A214A215A219A250A251A222A223A224A225A226A227A252A253A228A229A254A255A44A0A255A230A231A232A233A234A235A236A237A195A238A185A186A1A2A123A169A3A4A5A6A185A239A240A209A7A8A9A1A57A241A177A252A185A235A10A11A12A39A13A248A249NNOSA235A214A215A219A14A15A16A222A223A224A225A226A227A189A180A17A18A36A19A189A254A255A230A231A232A189MORRISA77A20A21A189A113A22A23A248A24A25LTPA33A189NNOS小G蛋白RHO参与调节多种细胞功能，如平滑肌细胞的收缩、细胞骨架的重塑、细胞粘附和移动、胞质分裂、基因表达等1。RHO激酶为RHO特征性的效应器。目前，RHO/RHO激酶途径在细胞水平的功能和信号转导已被广泛研究，然而，有关该信号通路在体水平的报道则很匮乏。盐酸法舒地尔（HYDROXYFASUDIL,HF），一种RHO激酶特异性抑制剂，是研究RHO/RHO激酶信号通路非常有效的工具药2。该信号通路可以调节平滑肌收缩的最终阶段肌球蛋白轻链的磷酸化水平，与血管痉挛3、动脉粥样硬化4和高血压5等疾病的发生均密切相关。G6117G1216前G7411的G4466G20576G1075表G7138HF可G13543G16311G2462G20056G19462G10411G17843发性G14053血管痉挛，G6925G2904G10411G17843发性G14053血管痉挛G8181G3423的G3835G14053G11394质血G8981，G17885G6333性地G3698G2164G14053血G8981G183396。然而，有关该通路在G14053G13582血G12082G13475G1815G6451G1272G7053G19766的报道很G4581。RHO/RHO激酶信号通路与G12082G13475细胞的生G19283和功能G8975动是密切相关的。在G1016种G11713G7254性G14053G13582血动G10301G8181G3423小G21748G3835G14053G1025动脉G7655G3634G8181G34237和G3835G21748G14053G5506血G7655G8181G34238G1025，法舒地尔G6122盐酸法舒地尔可G7186G14891G6925G2904G12082G13475功能G5194G1955G4581G14053G7787G8527体G12227。LEHMANN等报道C3G8614G13044抑制RHOG1186而G1431G17839G12082G13475G17736G12373生G192839。P160ROCK抑制剂G60G16G21G26G25G22G21G1431G17839G11394质G14046G20647G7475G6451G1272G3835G21748的G12082G13475G17736G12373生G19283，G2164G5567G1866G17828动功能的G5686G380910。因G8504，RHO/RHO激酶信号通路在G12082G13475G6451G1272的病G10714生G10714G17819G12255G1025G1075G2356有重G16213地G131311。目前，有关RHO/RHO激酶在G5942性G14053G13582血G6164G14280G12082G13475G6451G1272的研究G4590很G4581G16277。有研究G6363G1998G726G2464G1403G20060G5647动脉G8716G1049性G13479G6178G14280G5942性G1314G9760性G14053G13582血动G10301G8181G3423G1025，G3835G21748前G14053G2318G4628G18108G14053血G8981G18339和G14901G14808G12970G2045G11004G10587均G991G19489，而RHO激酶抑制剂HA1077可G6925G2904G17837G1135G2476化12。然而，RHO/RHO激酶信号通路是G2554参与G5942性G14053G13582血G6164G14280G16760G11705功能G19568G11873和G12082G13475G1815G6451G1272G731G7424G4466G20576G1025，G6117G1216G18331G11004G8716G1049性G13479G6178G2464G1403G20060G5647动脉G7053法制G1328G5942性G1314G9760性G14053G13582血G8181G3423，G16278G4531G19283G7411G13485予盐酸法舒地尔对G8181G3423G3835G21748学习记忆能力和G12373触传递功能的影响。G8504外，G6117G1216还探讨了药G10301发挥G1328G11004的可能机制。A10A72A26A27A186A28A291982A241A187A241A30A31A32A241TEL01088325020A241EMAILLINHUANG621HOTMAILCOM21材料和方法11实验动物雄性SPRAGUEDAWLEYG3835G21748，体重180220G，华G1025科技G3835学同济医学院G4466G20576动G10301G1025心提供。G3835G21748随机分笼饲养，维持室温2022，自由摄食与饮水，自然光照节律，每天提供足G18339的食G10301和水。12主要药品和试剂盐酸法舒地尔HYDROXYFASUDIL，HF，白色粉剂，纯度98，TOCRISCOOKSONLTDBRITOL,UK公司生产，批号040311，临G11004前G11004生G10714盐水溶G16311G5194稀释至G6164需浓度，注意避光；尼莫地平（NIMODIPINE）针剂，德国拜耳制药公司生产；兔抗G21748NNOS抗体购自SANTACRUZBIOTECHNOLOGY；即G11004G3423SABC试剂盒G2462二氨基联苯胺DIAMINOBENZIDINE,DABG7186色试剂盒购自武汉博士德生G10301工G12255有限公司；PMSF、钒酸钠、APROTININ、PEPSTATIN和LEUPEPTIN均购自美国SIGMA公司，ECL购自美国PIERCEBIOTECHNOLOGY。13主要仪器水迷宫检测仪器G2462软件分析系统G726ETHOVISION,NOLDUSINFORMATIONTECHNOLOGYBV,WAGENINGEN,THENETHERLANDS；SN3G3423G14053立体定G1313仪G726日G7424TOKYONARISHIGE公司产品；SEN7203电子刺激器G726日G7424NIHONKOHDEN公司产品；SS104J隔离器G726日G7424NIHONKOHDEN公司产品；SMUPPC生G10301信号处G10714系统软件G726上海嘉龙教仪厂产品；G1314温高速TGL台式高速冷冻离心机G726湖G2347仪器仪表G5647厂离心机厂；DYY8CG3423电G8903仪G726G2283G1152G1857一G16786G3803厂生产。14动物模型制备参G13783NI等G7053法13，G8716G1049性G13479G6178G3835G21748G2464G1403G20060G5647动脉G5326立G3835G21748G5942性G1314G9760性G14053G13582血G6451G1272G8181G3423（2VO）。G3835G21748G1100410G705水G2524G8707G18287035ML/100GG14157G14120G1881注G4568G21647G18269，G1220G2363G1313G3278定，G20060G18108G2447G8623，G5390力G11884G9052G8614，G20060G18108G8503G1025切G2487，分离G2464G1403G20060G5647动脉，G5194G3883以“0”号G13459，分G2047G13479G6178G2464G1403G20060G5647动脉的G17840G17829G12483，G5194G1186G1025G19400G2110G7041，以G11842G1457G19471G7041G20060G5647动脉血G8981。G13553G2524G2530G14157G14120注G4568生G10714盐水45ML，G6930G3250笼G1025饲养；G1563G6175G7427G13464G19512G993G13479G6178、G993G2110G7041G2464G1403G20060G5647动脉外，G1866G1325G17819G12255与G6175G7427G13464相同。G7427G1025G1457持G3835G21748G13935温365375。G2520G13464G3835G21748同G7477件饲养，在相同G7114G19400G9869G1328G2520种检测。15实验分组与给药SPRAGUEDAWLEYG3835G21748随机分为G1128G13464G726G1563G6175G7427G13464；G14053G13582血G8181G3423G13464；HFG1314剂G18339G8847G11115G13464G7262VOHF1MG/KG；HF高剂G18339G8847G11115G13464G7262VOHF10MG/KG；尼莫地平G8847G11115G13464G7262VONIMO0028MG/KG。G7427G2530G12544一天G5332G3999G14157G14120注G4568G13485药，每天一G8437，持G1350530天。16大鼠空间学习和记忆能力检测G2045G11004MORRIS水迷宫对G2520G13464动G10301学习记忆能力G17839G15904检测。G2520G13464均G1122G17908G818130天G2530G5332G3999G17839G15904。测试G12255G5219G2265G6336G7261定G1313G14334G15904G4466G20576；2G12366G19400探G13046G4466G2057614。G6980G6466由水迷宫统G16757软件G14731G5483，以均G6980G7643G1946G5058XS表G12046，G2520G13464G6980G6466G11004SPSS120软件处G10714，G17879离G9520G1251G7411的G13464G19400G5058异G11004G2464因G13044G7053G5058分析TWOANOVAG17839G15904检G20576，探G13046性G4466G20576G18331G11004G2345因G13044G7053G5058分析ONEANOVAG13479G2524DUANCANS检G20576。P005）。G16277FIG1A。212空间探索实验结果探G13046G17819G12255G1025可G16278G4531到G1563G6175G7427G13464G3835G21748主G16213在原来平台G6164在象限G17839G15904来G3250G12371梭，G1866G8437较多地在原平台象限相邻的左右G1016G1403象限寻找，很G4581跨至对G1403象限；而G8181G3423G13464在原来平台G6164在象限G12371梭G7114G19400G7138G7186G4581G1122G1563G6175G7427G13464（P005），盐酸法舒地尔和尼莫地平均可G7186G14891G3698G2164G3835G21748在靶象限G1025的游G8903G7114G19400（P005）。G1563G6175G7427G13464、G8181G3423G13464、盐酸法舒地尔G1314剂G18339G13464、高剂G18339G13464和阳性药G10301对照G13464在原平台G6164在象限探G13046G7114G19400G2356探G13046G5647G7114G19400百分比分G2047为3989568、（2017787）、3200400、（3370477）、（3380480）。G16277FIG1B。22盐酸法舒地尔对2VO大鼠海马突触传递功能的影响G1563G6175G7427G13464、G8181G3423G13464、G1314剂G18339G13464、高剂G18339G13464和阳性药G10301对照G13464G3835G21748G5390直刺激PPG13432维G253060MING1881海马CA3G2318PS幅值G2476化（FIG2A）。G13479果发现，G5390直刺激PPG13432维可诱导CA3G2318LTP形成，G1866G253060MING1881PS相对幅值持G13505升高G5194稳定在基础幅值的（19639943）水平，G7186G14891高G1122高频刺激前（10000411）G705P001；G8181G3423G13464G3835G21748LTP诱导G7138G7186被抑制，G1866PS相对幅值在G2520G7114G19400G9869均G7186G14891G1314G1122LTPG13464P005，60MING1881PS相对幅值平均为（12449112）；与G8181G3423G13464相比，G1314剂G18339G13464、高剂G18339G13464和阳性药G10301对照G13464G3835G21748LTP诱导情况均G5483以G6925G2904，G1866PS相对幅值在G2520G7114G19400G9869均G7186G14891高G1122G8181G3423G13464P005。G16277FIG2B和FIG2C。23盐酸法舒地尔对NNOS表达的影响1免疫G13464化G13479果G7186G12046G726G13475DAB染色G2530光镜G991NNOS阳性反应产G10301呈深棕色，G3835G21748G14053G1881G2520G18108G1313都有NNOS表达,以G3835G14053G11394质、海马CA1G2318表达最丰富。G1563G6175G7427G13464G1025，可G16277胞浆G1881NNOS表达，细胞形G5589完整；与G1563G6175G7427G13464相比，G8181G3423G13464胞浆NNOS阳性染色G7138G7186G1955G4581；G8847G11115G13464胞浆NNOS阳性染色G3698G5390，阳性对照药G1328G11004G993如HF。G16277FIG3A。2免疫G2372G17869G13479果G7186G12046G726WESTERNBLOTG13479果与免疫G13464化G13479果一G14280。在G13582血G14053G6451G1272G13464G1025，G11394G4630和海马NNOS阳性反应产G10301G7186G14891G19489G1314P005。与之比较，HFG2462阳性药G8847G11115均可上调G1866表达P005。G16277FIG3B。3讨论G6117G1216的G4466G20576G13479果G7186G12046G8716G1049性G13479G6178G2464G1403G20060G5647动脉G14280G5942性G13582血30天G2530，G3835G21748G11394G4630和海马G13464G13467NNOS蛋白表达水平均G991G19489。G19283G7411G13485予RHO激酶抑制剂盐酸法舒地尔能G1955G5381G17837G1135G2476化，G5194G6925G2904G14053G13582血G6164G14280的G3835G21748学习记忆能力G6451G4487，提高LTP诱导G10587和幅值，G1955G4581G12082G13475G1815G1014G3845。G15904为学检测发现，G7427G253030天G8181G3423G13464G1998现G7138G7186的学习记忆功能G19568G11873，表现为G17879离G9520G1251G7411的延G19283和在目G7643象限G1025游G8903G7114G19400的缩G11713，表G7138G5942性G14053G13582血可以导G14280学习记忆G19568G11873和G12082G13475G1815G6451G1272，与G7003G10498报道一G1428010。有意G1053的是，G14157G14120注G4568RHO抑制剂盐酸法舒地尔，一天一G8437，连G1350530天G2530，G14053G13582血G6451G1272的SDG3835G21748在习G5483性试G20576G2462探G13046性试G20576G1025，学习能力和记忆G1457持能力均G7138G7186提高。提G12046盐酸法舒地尔对G3835G21748G5942性G1314G9760G6164引起的G16760G11705功能G19568G11873和G12082G13475G1815G8527G1141具有G1457G6264G1328G11004。G19283G7114G12255G3698G5390（LONGTERMPOTENTIATION,LTP）是高频刺激引起的G12082G13475特征的稳定G2476化，是反应学习记忆G17819G12255G1025G12082G13475G1815生G10714G8975动的一个重G16213的G4470G16278G6363G764317。以前研究18G2462G6117G1216的G17829G7411研究19G1146G16789G4466刺激G12371通G13432维可激G8975CA3G2318G19193体细胞G5194诱发特征性G3342电G1313。因G8504，刺激G12371通通路记录CA3G2318G3342电G1313是研究海马信G5699处G10714机制G2462探究药G10301G5190G20056G1328G11004的G14403G3921途径。体G1881外G4466G20576表G7138G13582氧G6122G13582氧G13582G12970均可G13635ATP产生G1955G4581，导G14280G12373触传递的抑制，G5194可影响G12082G13475递质的G2524成、动G2604和释G6930，特G2047是在高频电刺激G2530，可G7186G14891G1955G4581小G8885G1881ATP和递质的G1660G4396，G1186而影响LTP的诱导和维持20。G7424G4466G20576发现，G8181G3423G13464G3835G21748PERFORANTPATHCA3通路处LTP诱发G3268G19602，G1866诱导G10587和幅值均G1314G1122G1563G6175G7427G13464，而盐酸法舒地尔G8847G11115G13464LTP诱导情况G5483以G7186G14891G6925G2904，表G7138G5942性G14053G13582血抑制LTP，盐酸法舒地尔可以G1431G17839海马G12373触传递功能。LTP诱导G17819G12255G1025，海马G19193体G12082G13475细胞的树G12373G7852和分G6915发生动G5589G6925G2476，RHO/RHO激酶信号通路对G17837G1135G13479G7512的产生和维持密切相关21。G17837G1135电生G10714学G4466G20576G13479果与G6117G1216在G15904为学G4466G20576G1025的发现相一G14280，G1861同表G7138了RHO激酶抑制剂盐酸法舒地尔对G3835G21748G5942性G1314G9760性G14053G13582血G6451G1272具有G1457G6264G1328G11004。G15441然G14053G1881NO的G17819G18339释G6930对G1866G2620G3272G12082G13475G1815具有G8614性G1328G11004，但NOG1075是一种重G16213的血管、G12082G13475G8975性G10301质。在G8503常生G10714情况G991NNOSG1664化产生的NOG1328为G1025G7542G12082G13475系统细胞G19400信G1363分子，在学习记忆机制G1025具有重G16213G1328G11004。NO在G12373触G2530产生G5194G5369G6967G1998G12082G13475G1815，G17882G2533G17828G15904至G12373触前以G2462G2620G3272相关G12082G13475G1815，透G17819细胞膜G8975化G21491G14539酸G10627化酶，G1363CGMP水平升高，G1431G17839G12082G13475递质（如G16907氨酸）释G6930，G16907氨酸G1328G11004G1122G12373触G2530NMDAG2462非NMDAG2475体，CA2G1881G8981G17839入G12373触G2530与G19053调蛋白一起激G8975NOS，诱发产生NO，诱导和维持G19283G7114G12255G3698G5390（LTP）G17819G12255，因而NOG1328为G17882G15904信G1363G1183导LTP的形成22。G7424研究G1025，G5942性G1314G9760注G13582血性G14053G6451G127230天G2530G3835G21748G11394G4630和海马NNOS表达比G1563G6175G7427G13464G7186G14891G19489G1314，G8504G13479果与以G5460研究G13479果一G14280。G5942性G14053G13582血G2530G7411，G14053血G8981G1017重G1955G4581，G12082G13475G1815G2462血管G1881G11394G1017重G2475G6451，NNOS表达持G13505G1955G4581，NOG2559G18339G7186G14891G1314G1122G8503常水平，可以G2164重G14053G13582血的G11163状。与G8181G3423G13464比较，盐酸法舒地尔G8847G11115G13464G7138G7186提高NNOS的表达，G3698G2164NO的G2559G18339。G8504G7114，上调NNOS的表达G1431G17839NO的G2524成对G14053G13464G13467有G1457G6264G1328G11004。G13520上G6164G17860，RHO/RHO激酶信号通路与G5942性G14053G13582血G6451G1272的病G10714生G10714学G17819G12255密切相关。G19283G7411G13485予盐酸法舒地尔G8847G11115可以G6925G2904G8181G3423G3835G21748G12366G19400学习记忆能力G6451G4487，提高LTP诱导G10587和幅值，G1955G4581G12082G13475G1815G1014G3845，G1866G12082G13475G1457G6264G1328G11004可能通G17819G3698G2164G81G49G50G54的表达而G4466现。参考文献1HIROAKISHIMOKAWA,AKIRATAKESHITARHOKINASEISANIMPORTANTTHERAPEUTICTARGETINCARDIOVASCULARMEDICINEJARTERIOSCLERTHROMBVASCBIOL,2005,9176717752STEPHENPD,HELENR,MATILDEC,ETALSPECIFICITYANDMECHANISMOFACTIONOFSOMECOMMONLYUSEDPROTEINKINASEINHIBITORSJBIOCHEM2000351951053TACHIBANAE,HARADAT,SHIBUYAM,ETALINTRAARTERIALINFUSIONOFFASUDILHYDROCHLORIDEFORTREATINGVASOSPASMFOLLOWINGSUBARACHNOIDHAEMORRHAGEJACTANEUROCHIRWIEN19991411394SHIMOKAWAH,HIRAMORIK,IINUMAH,ETALANTIANGINALEFFECTOFFASUDIL,ARHOKINASEINHIBITOR,INPATIENTSWITHSTABLEEFFORTANGINAAMULTICENTERSTUDYJJCARDIOVASCPHARMACOL2002407517615MASUMOTOA,HIROOKAY,SHIMOKAWAH,ETALPOSSIBLEINVOLVEMENTOFRHOKINASEINTHEPATHOGENSISOFHYPERTENSIONINHUMANSJHYPERTENSION200138130713106HUANGL,LIQ,WANGWT,ETALEFFECTSOFHYDROXYLFASUDILONVASCULARRELAXATIONANDCONTRACTIONACTIVITYJCHINESEPHARMACOLOGICALBULLETIN2007A34232A35251A372567NIJ,OHTAH,MATSUNOTOK,ETALPROGRESSIVECOGNITIVEIMPAIRMENTFOLLOWINGCHRONICCEREBRALHYPOPERFUSIONINDUCEDBYPERMANENTOCCLUSIONOFBILATERALCAROTIDARTERIESINRATSJ6BRAINRES,199465323168PAPPASBA,DELATORREJC,DAVIDSONCM,ETALCHRONICREDUCTIONOFCEREBRALBLOODFLOWINTHEADULTRATLATEEMERGINGCA1CELLLOSSANDMEMORYDYSFUNCTIONJBRAINRES,19967085089NIJW,MATSUNOTOK,LIHB,ETALNEURONALDAMAGEANDDECREASEOFCENTRALACETYLCHOLINELEVELFOLLOWINGPERMANENTOCCULSIONOFBILATERALCOMMONCAROTIDARTERIESINRATJBRAINRES,199567329010WANGLM,HANYF,TANGXCHUPERZINEAIMPROVESCOGNITIVEDEFICITSCAUSEDBYCHRONICCEREBRALHYPOPERFUSIONINRATSJEURJPHARMACOL,2000398657211BLISSTV,COLLINGRIDGEGLASYNAPTICMODELOFMEMORYLONGTERMPOTENTIATIONINTHEHIPPOCAMPUSJNATURE,19933616407313912BERZHANSKAYAJ,URBANNN,BARRIONUEVOGELECTROPHYSIOLOGICALANDPHARMACOLOGICALCHARACTERIZATIONOFTHEDIRECTPERFORANTPATHINPUTTOHIPPOCAMPALAREACA3JJNEUROPHYSIOL1998792111211813NIJW,MATSUMOTOK,WATANABEHTETRAMETHYLPYRAZINEIMPROVESSPATIALCOGNITIVEIMPAIRMENTINDUCEDBYPERMANENTOCCLUSIONOFBILATERALCOMMONCAROTIDARTERIESORSCOPOLAMINEINRATSJJPNJPHARMACO,1995FEB6721374114BOMBILEE,YOUNGKOOKCHOI,HOCHEOLKIM,ETALPROTECTIVEEFFECTSOFMETHANOLEXTRACTOFACORIGRAMINEIRHIZOMEANDUNCARIAERAMULUSETUNCUSONISCHEMIAINDUCEDNEURONALDEATHANDCOGNITIVEIMPAIRMENTSINTHERATJLIFESCIENCES74200343545015BLISSTV,COLLINGRIDGEGLASYNAPTICMODELOFMEMORYLONGTERMPOTENTIATIONINTHEHIPPOCAMPUSJNATURE,1993,3616407313916KIYOSHIM,HIROKOT,KENICHI,ETALAMINOGUANIDINEPREVENTEDTHEIMPAIRMENTBEHAVIORANDHIPPOCAMPALLONGTERMPOTENTIATIONFOLLOWINGTRANSIENTCEREBRALISHEMIAJBEHAVIOURALBRAINRESEARCH200112015916917BLISSTV,COLLINGRIDGEGLASYNAPTICMODELOFMEMORYLONGTERMPOTENTIATIONINTHEHIPPOCAMPUSJNATURE,19933616407313918DOV,MARTINEZCO,MARTINEZJL,ETALLONGTERMPOTENTIATIONINDIRECTPERFORANTPATHPROJECTIONSTOTHEHIPPOCAMPALCA3REGIONINVIVOJJNEUROPHYSIOL20028766967819ZHENGM,GUOLJ,XUXL,ETALZD7288INHIBITSTHESYNAPTICTRANSMISSIONOFTHEPATHWAYFROMPERFORANTPATHWAYPPFIBERSTOCA3REGIONINRATHIPPOCAMPUSJACTAPHARMACEUTICASINICA,20064156557120LYUBKINM,DURANDDM,HAXHIUMAINTERACTIONBETWEENTETANUSLONGTERMPOTENTIATIONANDHYPOXIAINDUCEDPOTENTIATIONINTHERATHIPPOCAMPUSJNEUROPHYSIOL,19977852475248221NAKAYAMAAY,HARMSMB,LUOLSMALLGTPASESRACANDRHOINTHEMAINTENANCEOFDENDRITICSPINESANDBRANCHESINHIPPOCAMPALPYRAMIDALNEURONSJJNEUROSCI2000205329533822BONCL,GARTHWAITEJONTHEROLEOFNITRICOXIDEINHIPPOCAMPALLONGTERMPOTENTIATIONJJNEUROSCI,20032319417LONGTERMINHIBITIONOFRHOKINASEIMPROVESCHRONICCEREBRALISCHEMIAINDUCEDCOGNITIVEDEFICITANDNEURONALDAMAGEINRATSLINHUANG1,LIANJUNGUO2LIYUZHEN11DEPARTMENTOFPHARMACY,PEKINGUNIVERSITYPEOPLESHOSPITAL,BEIJING,100044,PRCHINA2DEPARTMENTOFPHARMACOLOGY,TONGJIMEDICALCOLLEGE,HUAZHONGUNIVERSITYOFSCIENCEANDTECHNOLOGY,WUHAN430030,PRCHINACORRESPONDENCETOLINHUANG,TEL01088325020,EMAILLINHUANG621HOTMAILCOMABSTRACTOBJECTIVETOSTUDYTHEEFFECTSOFHYDROXYLFASUDIL,ARHOKINASEINHIBITOR,ONCHRONICCEREBRALHYPOPERFUSIONINDUCEDDEFICITSINRATSMETHODSCHRONICCEREBRALHYPOPERFUSIONINRATSWASPERFORMEDBYPERMANENTBILATERALLIGATIONOFTHECOMMONCAROTIDARTERIESMORRISWATERMAZEWASUSEDTOMEASURESPATIALMEMORYPERFORMANCEELECTROPHYSIOLOGICALEQUIPMENTSWEREUSEDTORECORDLONGTERMPOTENTIATIONLTPTHEEXPRESSIONOFNNOSWASASSAYEDBYIMMUNOHISTOCHEMISTRYANDWESTERNBLOTRESULTSCHRONICCEREBRALHYPOPERFUSIONINRATSRESULTEDINSPATIALMEMORYIMPAIRMENTSSHOWNBYLONGERESCAPELATENCYANDSHORTERTIMESPENTINTHETARGETQUADRANTTHESEBEHAVIORALDYSFUNCTIONSWEREACCOMPANIEDWITHREDUCTIONOFLTP,DECREASESINNNOSPROTEINEXPRESSIONLONGTERMADMINISTRATIONOFHYDROXYLFASUDILMARKEDLYIMPROVEDTHESPATIALMEMORYIMPAIRMENT,PREVENTEDTHEREDUCTIONOFLTP,ATTENUATEDNEURONALDAMAGE,ENHANCEDTHEEXPRESSIONOFNNOSCONCLUSIONLONGTERMHYDROXYLFASUDILTREATMENTPROVIDESNEUROPROTECTIVEEFFECTSONMEMORYDEFICITANDNEURONALDAMAGEAFTERISCHEMIA,WHICHMAYASSOCIATEDWITHENHANCEMENTOFNNOSEXPRESSIONMOREOVER,RHOKINASEPLAYSACRITICALROLEINTHEPATHOGENESISOFCHRONICISCHEMICCEREBRALDAMAGEKEYWORDSHYDROXYLFASUDILRHOKINASECHRONICCEREBRALISCHEMIAMORRISWATERMAZELTPNNOS8ABFIG1EFFECTOFHYDROXYFASUDILONWATERMAZEPERFORMANCEDEFICITS30DAYSAFTER2VOINRATSAEACHPOINTREPRESENTSTHEMEANOFESCAPELATENCYRESULTSFROMTHESTARTPOINTONTOTHEHIDDENPLATFORMFOREACHDAYBTHEBARGRAPHSHOWSPERCENTAGEOFTHETIMESPENTINTHETARGETQUADRANTQ3IN180SPROBETRIALNOPLATFORMFOLLOWINGCEREBRALISCHEMIA,THERATSWEREGIVENINTRAPERITONEALINJECTIONOFSALINEORHYDROXYFASUDIL1MG/KGOR10MG/KG,ONCEDAILYFOR30DAYSTHESHAMOPERATEDGROUPWASGIVENONLYSALINEFORAANDB,EACHDATAPOINTREPRESENTSMEANSD,N710AP005ANDAAP001WHENCOMPAREDTOSHAMOPERATEDGROUPBP005ANDBBP001COMPAREDTOISCHEMIAGROUPA1891A41A38A40A42A43A45A462VOA95A4730A190A48A49A50A51A52A53A54A55A56A58A61A59AA60A135A62A63A64A65A66A67A68A69A70A195A71A189A73A59BA60A82A74A75A76A91A78A79A80A81A91A83A84A85A86A67A68A87A85A86A88A67A68A55A89A90A92A61A9BCFIG2INVIVOEFFECTOFHYDROXYFASUDILONLTPINTHEPERFORANTPATHCA3SYNAPSESOFRATSWITHCHRONICHYPOPERFUSIONAFTER2VOAPSAMPLITUDEWASMEASUREDBEFORELEFTANDAFTERRIGHTTETANUSSTIMULATIONLTPWASINHIBITEDINTHEISCHEMIAGROUPASCOMPAREDTOSHAMOPERATEDGROUPHYDROXYFASUDILAT10MG/KGABOLISHEDTHEINHIBITIONBTHELINEARGRAPHILLUSTRATESTHERELATIVEPSAMPLITUDEALTERATIONATDIFFERENTTIMEPOINTWITHINTHE60MINAFTERTETANUS